Vesanoid (Tretinoin Oral) - Side Effects and Adverse Reactions

ADVERSE REACTIONS

Virtually all patients experience some drug-related toxicity, especially headache, fever, weakness, and fatigue. These adverse effects are seldom permanent or irreversible nor do they usually require interruption of therapy. Some of the adverse events are common in patients with APL, including hemorrhage, infections, gastrointestinal hemorrhage, disseminated intravascular coagulation, pneumonia, septicemia, and cerebral hemorrhage. The following describes the adverse events, regardless of drug relationship, that were observed in patients treated with VESANOID.

Typical Retinoid Toxicity

The most frequently reported adverse events were similar to those described in patients taking high doses of vitamin A and included headache (86%), fever (83%), skin/mucous membrane dryness (77%), bone pain (77%), nausea/vomiting (57%), rash (54%), mucositis (26%), pruritus (20%), increased sweating (20%), visual disturbances (17%), ocular disorders (17%), alopecia (14%), skin changes (14%), changed visual acuity (6%), bone inflammation (3%), visual field defects (3%).

RA-APL Syndrome

APL patients treated with VESANOID have experienced a potentially fatal syndrome characterized by fever, dyspnea, acute respiratory distress, weight gain, radiographic pulmonary infiltrates, pleural and pericardial effusions, edema, and hepatic, renal, and multi-organ failure. This syndrome has occasionally been accompanied by impaired myocardial contractility and episodic hypotension and has been observed with or without concomitant leukocytosis. Some patients have expired due to progressive hypoxemia and multi-organ failure. The syndrome generally occurs during the first month of treatment, with some cases reported following the first dose of VESANOID. The management of the syndrome has not been defined rigorously, but high-dose steroids given at the first signs of the syndrome appear to reduce morbidity and mortality. Treatment with dexamethasone, 10 mg intravenously administered every 12 hours for 3 days or until resolution of symptoms, should be initiated without delay at the first suspicion of symptoms (one or more of the following: fever, dyspnea, weight gain, abnormal chest auscultatory findings or radiographic abnormalities). Sixty percent or more of patients treated with VESANOID may require high-dose steroids because of these symptoms. The majority of patients do not require termination of VESANOID therapy during treatment of the syndrome.

Body as a Whole

General disorders related to VESANOID administration and/or associated with APL included malaise (66%), shivering (63%), hemorrhage (60%), infections (58%), peripheral edema (52%), pain (37%), chest discomfort (32%), edema (29%), disseminated intravascular coagulation (26%), weight increase (23%), injection site reactions (17%), anorexia (17%), weight decrease (17%), myalgia (14%), flank pain (9%), cellulitis (8%), face edema (6%), fluid imbalance (6%), pallor (6%), lymph disorders (6%), acidosis (3%), hypothermia (3%), ascites (3%).

Respiratory System Disorders

Respiratory system disorders were commonly reported in APL patients administered VESANOID. The majority of these events are symptoms of the RA-APL syndrome (see boxed WARNINGS). Respiratory system adverse events included upper respiratory tract disorders (63%), dyspnea (60%), respiratory insufficiency (26%), pleural effusion (20%), pneumonia (14%), rales (14%), expiratory wheezing (14%), lower respiratory tract disorders (9%), pulmonary infiltration (6%), bronchial asthma (3%), pulmonary edema (3%), larynx edema (3%), unspecified pulmonary disease (3%).

Ear Disorders

Ear disorders were consistently reported, with earache or feeling of fullness in the ears reported by 23% of the patients. Hearing loss and other unspecified auricular disorders were observed in 6% of patients, with infrequent (<1%) reports of irreversible hearing loss.

Gastrointestinal Disorders

GI disorders included GI hemorrhage (34%), abdominal pain (31%), other gastrointestinal disorders (26%), diarrhea (23%), constipation (17%), dyspepsia (14%), abdominal distention (11%), hepatosplenomegaly (9%), hepatitis (3%), ulcer (3%), unspecified liver disorder (3%).

Cardiovascular and Heart Rate and Rhythm Disorders

Arrhythmias (23%), flushing (23%), hypotension (14%), hypertension (11%), phlebitis (11%), cardiac failure (6%) and for 3% of patients: cardiac arrest, myocardial infarction, enlarged heart, heart murmur, ischemia, stroke, myocarditis, pericarditis, pulmonary hypertension, secondary cardiomyopathy.

Central and Peripheral Nervous System Disorders and Psychiatric

Dizziness (20%), paresthesias (17%), anxiety (17%), insomnia (14%), depression (14%), confusion (11%), cerebral hemorrhage (9%), intracranial hypertension (9%), agitation (9%), hallucination (6%) and for 3% of patients: abnormal gait, agnosia, aphasia, asterixis, cerebellar edema, cerebellar disorders, convulsions, coma, CNS depression, dysarthria, encephalopathy, facial paralysis, hemiplegia, hyporeflexia, hypotaxia, no light reflex, neurologic reaction, spinal cord disorder, tremor, leg weakness, unconsciousness, dementia, forgetfulness, somnolence, slow speech.

Urinary System Disorders

Renal insufficiency (11%), dysuria (9%), acute renal failure (3%), micturition frequency (3%), renal tubular necrosis (3%), enlarged prostate (3%).

Miscellaneous Adverse Events

Isolated cases of erythema nodosum, basophilia and hyperhistaminemia, Sweet's syndrome, organomegaly, hypercalcemia, pancreatitis and myositis have been reported.

Additional Adverse Reactions Reported With VESANOID

Cardiovascular

Cases of thrombosis (both venous and arterial) involving various sites (eg, cerebrovascular accident, myocardial infarction, renal infarct) have been reported rarely (see PRECAUTIONS: General).

Hematologic

Rare cases of thrombocytosis have been reported.

Skin

Genital ulceration

Miscellaneous Adverse Events

Rare cases of vasculitis, predominantly involving the skin, have been reported.

REPORTS OF SIDE EFFECTS / ADVERSE REACTIONS RELATED TO VESANOID

Possible Vesanoid side effects / adverse reactions in 60 year old female

Reported by a consumer/non-health professional from France on 2007-01-25

Patient: 60 year old female weighing 68.0 kg (149.6 pounds)

Reactions: Pneumonia, Haemoptysis, Hepatic Enzyme Increased, Liver Disorder, Weight Increased, Pneumocystis Jiroveci Pneumonia, Gamma-Glutamyltransferase Increased, Hypoxia, Pleural Effusion, Pancreatic Enzymes Increased, Renal Failure Acute

Adverse event resulted in: hospitalization

Suspect drug(s):
Aracytine
    Start date: 2006-08-22
    End date: 2006-08-28

Cardioxane
    Start date: 2006-08-22
    End date: 2006-08-24

Cerubidine
    Start date: 2006-08-22
    End date: 2006-08-24

Primperan
    Indication: Vomiting
    End date: 2006-08-29

Vesanoid
    Administration route: Oral
    Indication: Acute Myeloid Leukaemia
    Start date: 2006-08-18
    End date: 2006-09-05

Zofran
    Dosage: 2 doses taken every day.
    Indication: Vomiting
    Start date: 2006-08-22
    End date: 2006-09-05

Possible Vesanoid side effects / adverse reactions in 60 year old female

Reported by a consumer/non-health professional from France on 2007-01-25

Patient: 60 year old female weighing 68.0 kg (149.6 pounds)

Reactions: Dyspnoea, Pneumonia, Haemoptysis, Transaminases Increased, Weight Increased, Retinoic Acid Syndrome, Interstitial Lung Disease, Gamma-Glutamyltransferase Increased, Pleural Effusion, Tachypnoea, Pancreatic Enzymes Increased, Cough, Oxygen Saturation Decreased, Renal Failure Acute

Adverse event resulted in: hospitalization

Suspect drug(s):
Aracytine
    Dosage: 350mg per day
    Indication: Acute Myeloid Leukaemia
    Start date: 2006-08-22
    End date: 2006-08-28

Cardioxane
    Dosage: 2g per day
    Indication: Acute Myeloid Leukaemia
    Start date: 2006-08-22
    End date: 2006-08-24

Cerubidine
    Dosage: 110mg per day
    Indication: Acute Myeloid Leukaemia
    Start date: 2006-08-22
    End date: 2006-08-24

Primperan
    Indication: Vomiting
    Start date: 2006-08-18
    End date: 2006-08-29

Vesanoid
    Dosage: 80mg per day
    Administration route: Oral
    Indication: Acute Myeloid Leukaemia
    Start date: 2006-08-18
    End date: 2006-09-05

Zofran
    Dosage: 2inj per day
    Indication: Vomiting
    Start date: 2006-08-22
    End date: 2006-09-05

Other drugs received by patient: Zantac; Lexomil; Perfalgan; Fungizone; Heparin; Spasfon

Possible Vesanoid side effects / adverse reactions in 45 year old male

Reported by a physician from Canada on 2007-02-20

Patient: 45 year old male weighing 114.0 kg (250.8 pounds)

Reactions: Leukoencephalopathy, Progressive Multifocal Leukoencephalopathy

Adverse event resulted in: life threatening event, hospitalization

Suspect drug(s):
Vesanoid
    Administration route: Oral
    Start date: 2006-11-27
    End date: 2007-01-12

Vesanoid
    Administration route: Oral
    Start date: 2007-01-29

Other drugs received by patient: Idamycin; Acyclovir; Acyclovir; Voriconazole; Voriconazole