CAELYX SIDE EFFECTS
- Generic Name: pegylated liposomal doxorubicin hydrochloride injection
- Brand Name: Caelyx
- Drug Class: Antineoplastics, Anthracycline
SIDE EFFECTS
Clinical Trial Adverse Drug Reactions
Breast Cancer
Breast Cancer Patients: 254 patients with advanced breast cancer who had not received prior chemotherapy for metastatic disease were treated with CAELYX® at a dose of 50 mg/m2 body surface, every 4 weeks in a phase III clinical trial. The most frequently reported treatmentrelated adverse effects included palmar-plantar erythrodysesthesia (PPE) (48.0%) and nausea (37.0%) (Table 1). These effects were mostly mild and reversible, with severe (Grade III) cases reported in 17.0% and 3.0% respectively, and no reported incidences of life-threatening (Grade IV) cases for either PPE or nausea. Infrequently, these effects resulted in permanent treatment discontinuation (7.0% and 0% respectively). Pronounced alopecia (or total hair loss) was seen in only 7.0% of CAELYX®-treated patients as compared with 54.0% of patients treated with doxorubicin.
Hematologic adverse effects were infrequently reported, were mostly mild or moderate in severity, and manageable. Anemia, neutropenia, leukopenia and thrombocytopenia were infrequently reported at incidences of 5.0%, 4.0%, 2.0%, and 1.0%, respectively. Lifethreatening (Grade IV) hematologic effects were reported at incidences of <1.0 %. The need for either growth factor support or transfusion support was minimal (5.1% and 5.5% of patients, respectively). Febrile neutropenia was reported in 3/254 (1.2%) patients treated with CAELYX® and 8/255 (3.1%) patients treated with doxorubicin.
Laboratory Abnormalities
Clinically significant laboratory abnormalities (Grades III and IV) in this breast cancer group included increases in total bilirubin (2.4%) and AST (1.6%). Increases in ALT were less frequent (<1%). No clinically significant increases in serum creatinine were reported. Clinically significant hematologic measurements were infrequent and low as measured by leukopenia (4.3%), anemia (3.9%), neutropenia (1.6%) and thrombocytopenia (1.2%). Sepsis was reported at an incidence of 1%.
Table 1- Treatment-related Undesirable Effects Reported in ≥5% of CAELYX® -treated Patients by Severity and Body System in Breast Cancer Clinical Trial (I97-328).
| AE body system | I97-328 All severities % |
I97-328 Grades III/IV % |
| Body as a Whole | ||
| Asthenia | 10 | 1 |
| Erythema | 7 | <1 |
| Fatigue | 12 | <1 |
| Fever | 8 | 0 |
| Weakness | 6 | <1 |
| Gastro-intestinal System | ||
| Abdominal | 8 | 1 |
| Anorexia | 11 | 1 |
| Constipation | 8 | <1 |
| Diarrhea | 7 | 1 |
| Mouth Ulceration | 5 | <1 |
| Mucositis Nose | 23 | 4 |
| Nausea | 37 | 3 |
| Stomatitis | 22 | 5 |
| Vomiting | 19 | <1 |
| Red Blood Cell Disorders | ||
| Anemia | 5 | 1 |
| Skin and Appendages | ||
| Alopecia | 20 | 0 |
| PPE* | 48 | 17 |
| Pigmentation abnormal | 8 | <1 |
| Rash | 10 | 2 |
| * Palmar-plantar erythrodysesthesia (hand- foot syndrome). No cases of Grade IV (life-threatening) PPE were reported. | ||
Undesirable effects reported between ≥1% and <5% in 254 CAELYX®-treated breast cancer patients, not previously reported in CAELYX® clinical trials were breast pain, leg cramps, edema, leg edema, peripheral neuropathy, oral pain, ventricular arrhythmia, folliculitis, bone pain, musculo-skeletal pain, thrombocythemia, cold sores (non-herpetic), fungal infection, epistaxis, upper respiratory tract infection, bullous eruption, dermatitis, erythematous rash, dry skin, pruritus, skin discoloration, scaly skin, nail disorder, lacrimation, blurred vision, flushing, weight decrease, dyspepsia and dyspnea.
Ovarian Cancer
Ovarian Cancer Trials (Phase II And III)
Information on the adverse reactions is based on the experience in 512 patients with ovarian cancer treated at a dose of 50 mg/m2 body surface. The median cumulative dose in the ovarian cancer trials was 150.6 mg/m2, median cycle length was 30.0 days, and median days on drug was 65.5 days.
Of these 512 patients, a total of 509 patients (99.4%) in the ovarian cancer trials, reported a total of 5026 adverse events, and 484 (94.5%) patients reported treatment-related adverse events. Treatment-related fatal adverse events were reported in 4 (0.8%) patients, while Grade IV (lifethreatening) treatment-related adverse events were reported by 38 (7.4%) patients.
Myelosuppression was mostly mild or moderate and manageable. Leukopenia (33.2%) was the most frequently reported hematological adverse event, followed by anemia (32.2%), neutropenia (31.6%) and thrombocytopenia (10.7%). Life-threatening (Grade IV) haematological effects were extremely rare (1.6%, 0.4%, 2.9% and 0.2%, respectively). Growth factor support was required infrequently (<5%) and transfusion support was required in approximately 15% of patients.
Frequently reported treatment-related adverse effects included palmar-plantar erythrodysesthesia (PPE) (46.1%) and stomatitis (38.9%). These effects were mainly mild, with severe (Grade III) cases reported in 19.5% and 8.0% respectively, and life-threatening (Grade IV) cases reported in 0.6% and 0.8% respectively. These resulted infrequently in permanent treatment discontinuation (<5% and <1% respectively).
Other frequently reported drug-related effects (≥5%) included nausea (38.1%), asthenia (34.0%), rash (25.0%), vomiting (24.4%), alopecia (17.4%), constipation (12.9%), anorexia (12.1%), mucous membrane disorder (14.5%), diarrhea (11.7%), abdominal pain (8.2%), fever (9.4%), paresthesia (7.6%), pain (7.4%), skin discoloration (6.1%), pharyngitis (6.4%), dry skin (5.9%), dyspepsia (5.5%) and somnolence (5.1%).
Less frequently (1 to <5%) reported undesirable effects included peripheral edema, oral moniliasis, vasodilatation, mouth ulceration, pruritus, allergic reaction, dehydration, dyspnea, vesiculobullous rash, chills, infection, weight loss, esophagitis, skin disorder, exfoliative dermatitis, cardiovascular disorder, chest pain, dizziness, maculopapular rash, gastritis, myalgia, back pain, depression, insomnia, dysphagia, increased cough, sweating, nausea and vomiting, malaise, taste perversion, urinary tract infection, conjunctivitis, acne, gingivitis, herpes zoster, hypochromic anemia, anxiety, vaginitis, headache, flatulence, dry mouth, cachexia, neuropathy, hypertonia, skin ulcer and dysuria.
Table 2 – Summary of Frequently Reported (≥1%) Treatment-related Adverse Events by Severity (Grade III/IV), Body System and COSTART Preferred Term Reported in Ovarian Cancer Patients
| Adverse Event | Ovarian Cancer Patients treated with CAELYX® n=512 |
||
| No. (%) of Patients Reporting Treatment-related Adverse Events | n=484 (94.5%) | ||
| Grade III | Grade IV | All Severities | |
| Body as a Whole | |||
| Asthenia | 34 (6.6) | 0 | 174 (34.0) |
| Mucous Membrane Disorder | 16 (3.1) | 0 | 74 (14.5) |
| Digestive System | |||
| Stomatitis | 41 (8.0) | 5 (0.8) | 199 (38.9) |
| Nausea | 21 (4.1) | 1 (0.2) | 195 (38.1) |
| Vomiting | 22 (4.3) | 3 (0.6) | 125 (24.4) |
| Hemic and Lymphatic System | |||
| Leukopenia | 36 (7.0) | 8 (1.6) | 170 (33.2) |
| Anemia | 28 (5.5) | 2 (0.4) | 165 (32.2) |
| Neutropenia | 46 (9.0) | 15 (2.9) | 162 (31.6) |
| Thrombocytopenia | 6 (1.2) | 1 (0.2) | 55 (10.7) |
| Skin and Appendages | |||
| Hand-Foot Syndrome* | 100 (19.5) | 3 (0.6) | 236 (46.1) |
| Rash | 17 (3.3) | 1 (0.2) | 128 (25.0) |
| Alopecia | 6 (1.2) | 0 | 89 (17.4) |
| *Palmar-plantar erythrodysesthesia (PPE) | |||
Laboratory Abnormalities
In the subset of patients with ovarian cancer, clinically significant laboratory abnormalities occurring in clinical trials with CAELYX® included increases in total bilirubin (usually in patients with liver metastases) (5%) and serum creatinine levels (5%). Clinically significant measurements, measured by Grades III and IV neutropenia (11.4%), anemia (5.7%), and thrombocytopenia (1.2%) were low. Increases in AST were less frequently (<1%) reported. Sepsis related to leukopenia was observed infrequently (<1%).
Pivotal Phase III Trial – Ovarian Cancer
In the pivotal phase III ovarian cancer trial, the toxicity profiles of the two agents, CAELYX® and topotecan were very different.
Hematologic toxicity was more frequent and usually Grade III, IV in the topotecan-treated patients in comparison with CAELYX® (neutropenia 77% vs 12%, thrombocytopenia 34% vs 1%, and anemia 28% vs 5% respectively). Grade III, IV hematologic adverse events were observed in 90% of topotecan-treated patients compared with 55% of CAELYX®-treated patients.
Most drug-related adverse events associated with CAELYX® were mild to moderate in severity with the exceptions of palmar-plantar erythrodysesthesia (PPE) and stomatitis. However, PPE and stomatitis were managed successfully with dose modifications and rarely resulted in study discontinuation (4% for PPE and 1% for stomatitis).
There was no evidence of a relationship between cumulative CAELYX® dose and change from baseline for LVEF (left ventricular ejection fraction).
Topotecan-associated toxicities more often resulted in morbidity and life-threatening sequelae than the primary CAELYX®-related adverse events.
In the pivotal phase III ovarian cancer study, comparing CAELYX® vs. topotecan, three deaths in the topotecan group due to neutropenic sepsis were considered treatment-related. There were no treatment-related deaths in the CAELYX® group. There were no cases of treatment-related sepsis or neutropenic fever in the CAELYX® group.
Table 3 –Treatment-Related Adverse Events Reported by >10% of Patients in Either Ovarian Cancer Treatment Group (Pivotal Phase III Study)
| Any Adverse Event | CAELYX® (n=239) |
Topotecan (n=235) |
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| All Grades | Grade III | Grade IV | All Grades | Grade III | Grade IV | |
| 222 (93%) | 132 (55%) | 20 (8%) | 232 (99%) | 176 (75%) | 158 (67%) | |
| Body as a whole | ||||||
| Asthenia | 75 (31%) | 13 (5%) | 0 | 104 (44%) | 17 (7%) | 0 |
| Mucous membrane disorder | 33 (14%) | 8 (3%) | 0 | 7 (3%) | 0 | 0 |
| Fever | 28 (12%) | 0 | 0 | 49 (21%) | 6 (3%) | 5 (2%) |
| Abdominal pain | 20 (8%) | 3 (1%) | 0 | 29 (12%) | 3 (1%) | 1 (<1%) |
| Digestive System | ||||||
| Stomatitis | 95 (40%) | 19 (8%) | 1 (<1%) | 35 (15%) | 1 (<1%) | 0 |
| Nausea | 85 (36%) | 6 (3%) | 1 (<1%) | 127 (54%) | 12 (5%) | 2 (1%) |
| Vomiting | 58 (24%) | 11 (5%) | 2 (1%) | 81 (35%) | 14 (6%) | 2 (1%) |
| Constipation | 33 (14%) | 0 | 0 | 58 (25%) | 3 (1%) | 1 (<1%) |
| Diarrhea | 28 (12%) | 4 (2%) | 0 | 49 (21%) | 5 (2%) | 1 (<1%) |
| Anorexia | 26 (11%) | 1 (<1%) | 0 | 32 (14%) | 1 (<1%) | 0 |
| Hematopoietic and Lymphatic System | ||||||
| Leukopenia | 87 (36%) | 21 (9%) | 3 (1%) | 149 (63%) | 82 (35%) | 35 (15%) |
| Anemia | 85 (36%) | 12 (5%) | 1 (<1%) | 169 (72%) | 58 (25%) | 8 (3%) |
| Neutropenia | 84 (35%) | 19 (8%) | 10 (4%) | 191 (81%) | 33 (14%) | 145 (62%) |
| Thrombo-cytopenia | 31 (13%) | 3 (1%) | 0 | 152 (65%) | 40 (17%) | 40 (17%) |
| Skin and Appendages | ||||||
| PPE* | 117 (49%) | 53 (22%) | 2 (1%) | 2 (1%) | 0 | 0 |
| Rash | 58 (24%) | 10 (4%) | 0 | 18 (8%) | 1 (<1%) | 0 |
| Alopecia | 38 (16%) | 3 (1%) | 0 | 115 (49%) | 14 (6%) | 0 |
| * Palmar-plantar erythrodysesthesia | ||||||
AIDS-KS
Information on adverse events is based on the experience reported in 711 patients with AIDS-KS enrolled in four open-label studies, as well as 254 patients enrolled in two controlled trials. The majority of patients were treated with 20 mg/m2 (body surface) of CAELYX® every two to three weeks.
Open-Label Trials
In the open-label trials, the median cumulative dose of CAELYX® (Pegylated Liposomal Doxorubicin Hydrochloride for Injection) was 120 mg/m2 body surface. Overall, the immune status was poor in 90.1% of the patients enrolled in these studies, with a median CD4 count of 20 cells/mm3.
As expected, patients were receiving many concomitant medications. Over half (58.1%) of the patients were taking one of the four available antiretroviral medications; zidovudine (AZT) was the most frequently employed in 34.3% of patients, with didanosine (ddI), zalcitabine (ddC) and stavudine (d4T) also used in decreasing order of frequency. Use and frequency of other antivirals was frequent: 55.7% received acyclovir at sometime during the trial, 28.9% received ganciclovir and 16.4% received foscarnet. Systemic antifungals were frequently employed with fluconazole being used by 75.7% of patients. Prophylactic therapy of opportunistic infections was used; sulfamethoxazole/trimethoprim being used the most, in 54.9% of patients.
In many instances, it was difficult to determine whether adverse events resulted from CAELYX®, from concomitant therapy, or from the patients’ underlying disease(s). Of the 711 patients for whom adverse events data are recorded, 84.6% reported one or more adverse events that were considered by the investigators to be possibly related, probably related or related to treatment with CAELYX®. For patients who discontinued therapy, death was the most common reason (32.3% of patients). Adverse reactions only infrequently (5.3%) led to discontinuation of treatment.
Controlled Trials
In the two controlled studies, the median dose of CAELYX® administered per cycle was 20mg/m2 body surface, and the mean duration of therapy with CAELYX® was 81.1 days. The majority of patients were classified as poor risk. In all three groups, subcutaneous KS lesions were present in more than 98.4% of patients; 21.7% of patients had evidence of pulmonary KS; and 15.7% of patients had evidence gastrointestinal involvement. In all of the three groups, the majority of patients had CD4 cell counts of less than 50 cells/mm3.
Fewer CAELYX®-treated patients died during the course of the controlled trials (16.9%). Early termination due to adverse events was observed in 10.6% of CAELYX®-treated patients. In general, the safety profile of the patients treated in the controlled studies was consistent with the safety profile of the patients that were treated with CAELYX® in the open-label trials. Opportunistic infections, such as candidiasis (47.8%), cytomegalovirus (37.5%), Pneumocystis carinii pneumonia (20.6%), and Mycobacterium avium complex (10.1%), regardless of causality, have been frequently observed in patients with AIDS-KS receiving CAELYX®. The table below shows all events occurring at ≥5% in the open-label and controlled trials, that were considered by investigators, at least possibly related to the study drug.
Table 4 – Possibly or Probably Drug-Related Adverse Events by Body System and Costart Preferred Term – Including Open Label Studies – Reported in ≥5% of AIDS-KS Patients.
| CAELYX® (Open Label)1 | CAELYX® (Comparator)2 | ABV3 | BV4 | |
| Number of Patients | 711 | 254 | 125 | 120 |
| Number of Patients Reporting Adverse Events | 566 (79.6%) | 192 (75.6%) | 114 (91.2%) | 92 (76.7%) |
| Number of Patients by Body System and Preferred COSTART Term Incidence | ||||
| Body as a whole | 165 (23.2%) | 55 (21.7%) | 72 (57.6%) | 43 (35.8%) |
| asthenia | 67 (9.4%) | 29 (11.4%) | 37 (29.6%) | 10 (8.3%) |
| fever | 62 (8.7%) | 13 (5.1%) | 38 (30.4%) | 22 (18.3%) |
| headache | 30 (4.2%) | 7 (2.8%) | 9 (7.2%) | 4 (3.3%) |
| abdominal pain | 16 (2.3%) | 3 (1.2%) | 7 (5.6%) | 1 (0.8%) |
| chills | 8 (1.1%) | 2 (0.8%) | 8 (6.4%) | 6 (5.0%) |
| pain | 10 (1.4%) | 3 (1.2%) | 7 (5.6%) | 2 (1.7%) |
| lab test abnormal | 3 (0.4%) | 8 (3.1%) | 0 | 7 (5.8%) |
| chills and fever | 2 (0.3%) | 2 (0.8%) | 6 (4.8%) | 6 (5.0%) |
| malaise | 3 (0.4%) | 2 (0.8%) | 6 (4.8%) | 1 (0.8%) |
| Cardiovascular system | 2 (0.3%) | 1 (0.4%) | 6 (4.8%) | 1 (0.8%) |
| phlebitis | 2 (0.3%) | 1 (0.4%) | 6 (4.8%) | 1 (0.8%) |
| Digestive system | 207 (29.1%) | 57 (22.4%) | 77 (61.6%) | 37 (30.8%) |
| nausea | 91 (12.8%) | 36 (14.2%) | 54 (43.2%) | 14 (11.7%) |
| diarrhea | 53 (7.5%) | 10 (3.9%) | 11 (8.8%) | 3 (2.5%) |
| stomatitis | 45 (6.3%) | 12 (4.7%) | 4 (3.2%) | 2 (1.7%) |
| nausea and vomiting | 29 (4.1%) | 2 (0.8%) | 15 (12.0%) | 10 (8.3%) |
| vomiting | 25 (3.5%) | 8 (3.1%) | 17 (13.6%) | 3 (2.5%) |
| oral moniliasis | 40 (5.6%) | 2 (0.8%) | 2 (1.6%) | 4 (3.3%) |
| anorexia | 8 (1.1%) | 6 (2.4%) | 17 (13.6%) | 3 (2.5%) |
| constipation | 12 (1.7%) | 2 (0.8%) | 8 (6.4%) | 9 (7.5%) |
| Hemic and lymphatic system | 471 (66.2%) | 144 (56.7%) | 63 (50.4%) | 49 (40.8%) |
| leukopenia | 435 (61.2%) | 138 (54.3%) | 56 (44.8%) | 46 (38,3%) |
| anemia | 145 (20.4%) | 19 (7.5%) | 14 (11.2%) | 9 (7.5%) |
| thrombocytopenia | 66 (9.3%) | 15 (5.9%) | 6 (4.8%) | 12 (10.0%) |
| hypochromic anemia | 68 (9.6%) | 9 (3.5%) | 6 (4.8%) | 6 (5.0%) |
| Nervous system | 15 (2.1%) | 10 (3.9%) | 30 (24.0%) | 28 (23.3%) |
| paresthesia | 6 (0.8%) | 6 (2.4%) | 14 (11.2%) | 14 (11.7%) |
| neuropathy | 4 (0.6%) | 3 (1.2%) | 9 (7.2%) | 11 (9.2%) |
| peripheral neuritis | 6 (0.8%) | 2 (0.8%) | 10 (8.0%) | 5 (4.2%) |
| Skin and appendages | 81 (11.4%) | 30 (11.8%) | 55 (44.0%) | 12 (10.0%) |
| alopecia | 63 (8.9%) | 18 (7.1%) | 53 (42.4%) | 10 (8.3%) |
| rash | 19 (2.7%) | 12 (4.7%) | 5 (4.0%) | 2 (1.7%) |
| 1. Patients treated with CAELYX® in the open-label studies. 2. Patients treated with CAELYX® in the controlled studies (vs. ABV or BV). 3. ABV (adriamycin, bleomycin, vincristine) 4. BV (bleomycin, vincristine) |
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Incidence 1% to 5% (Possibly or Probably Related) in CAELYX®-treated AIDS-KS Patients
Body as a Whole: allergic reaction, anaphylactoid reaction, back pain, chest pain, flu syndrome, infection, mucous membrane disorder, pain.
Cardiovascular: hypotension, tachycardia, vasodilatation.
Digestive System: aphthous stomatitis, dyspepsia, dysphagia, glossitis, liver function tests abnormal, mouth ulceration.
Hemic and Lymphatic System: hemolysis, pancytopenia, prothrombin increased.
Metabolic/Nutritional: bilirubinemia, SGOT increased, SGPT increased, weight loss.
Nervous System: dizziness, emotional lability, somnolence.
Respiratory System: dyspnea, pneumonia.
Skin and Appendages: dry skin, herpes simplex, pruritus.
Others: retinitis, albuminuria.
Incidence Less Than 1% (Possibly or Probably Related) in CAELYX®-Treated AIDS-KS Patients
Body As A Whole: abscess, cellulitis, substernal chest pain, cryptococcosis, facial edema, hypothermia, immune system disorder, injection site hemorrhage, injection site pain, injection site reaction, moniliasis, neoplasm, radiation injury, sepsis.
Cardiovascular System: arrhythmia, bradycardia, bundle branch block, cardiomegaly, cardiovascular disorder, congestive heart failure, deep thrombophlebitis, heart failure, hemorrhage, migraine, palpitation, pericardial effusion, peripheral vascular disorder, supraventricular extrasystoles, syncope, thrombophlebitis, thrombosis, ventricular arrhythmia, ventricular extrasystoles.
Digestive System: bloody diarrhea, cholestatic jaundice, colitis, dry mouth, eructation, esophageal ulcer, esophagitis, fecal impaction, gastritis, GI hemorrhage, gingivitis, hematemesis, hepatic failure, hepatitis, hepatosplenomegaly, increased appetite, jaundice, leukoplakia of mouth, liver damage, melena, pancreatitis, rectal disorder, sclerosing cholangitis, tenesmus, ulcerative proctitis, ulcerative stomatitis.
Endocrine System: diabetes mellitus.
Hemic and Lymphatic System: eosinophilia, erythrocytes abnormal, lymphadenopathy, lymphangitis, lymphedema, lymphoma-like reaction, marrow depression, petechia, purpura, thromboplastin decreased.
Metabolic/Nutritional: BUN increased, cachexia, creatinine increased, dehydration, edema, hypercalcemia, hyperkalemia, hyperlipemia, hypernatremia, hyperphosphatemia, hyperuricemia, hypoglycemia, hypokalemia, hypomagnesemia, hypophosphatemia, hypoproteinemia, ketosis, LDH increased, peripheral edema, weight gain.
Musculoskeletal System: arthralgia, bone disorder, bone pain, joint disorder, myalgia, myasthenia, myositis.
Nervous System: abnormal dreams, abnormal gait, acute brain syndrome, anxiety, cerebrovascular accident, confusion, convulsion, depression, dysarthria, dyskinesia, hypertonia, hypokinesia, hypotonia, insomnia, nervousness, nystagmus, paralysis, reflexes decreased, thinking abnormal, vertigo.
Respiratory System: asthma, bronchitis, cough increased, hiccup, hyperventilation, lung disorder, pharyngitis, pleural effusion, pneumothorax, rhinitis, sinusitis.
Skin and Appendages: acne, cutaneous moniliasis, eczema, erythema nodosum, exfoliative dermatitis, furunculosis, herpes zoster, leukoderma, maculopapular rash, psoriasis, pustular rash, seborrhea, skin discoloration, skin necrosis, skin ulcer.
Special Senses: abnormal vision, blindness, conjunctivitis, diplopia, eye disorder, eye pain, optic neuritis, otitis media, taste perversion, tinnitus.
Urogenital System: balanitis, cystitis, dysuria, genital edema, glycosuria, hematuria, kidney failure, kidney function abnormal, prostatic disorder, testis disorder, urine abnormality.
Post-Market Adverse Drug Reactions
The following serious adverse reactions have been derived from spontaneous case reports, literature cases, expanded access programs, and clinical studies other than the global registration trials. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and Lymphatic System: myelosuppression associated with anemia, thrombocytopenia, leukopenia, febrile neutropenia.
Neoplasms benign, malignant and unspecified (incl cysts and polyps): secondary oral cancer including fatal cases.
Nervous System: convulsions ).
Skin and Subcutaneous Tissue: serious skin conditions including erythema multiforme, Stevens Johnson syndrome, toxic epidermal necrolysis.
Vascular: thrombophlebitis, venous thrombosis, pulmonary embolism. Patients with cancer are at increased risk for thromboembolic disease.
SRC: NLM .