Seroquel - Side Effects & Drug Interactions

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It is important to emphasize that, although the events reported occurred during treatment with SEROQUEL, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/ 100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/ 100 to 1/ 1000 patients; rare events are those occurring in fewer than 1/ 1000 patients.

Nervous System

Frequent: hypertonia, dysarthria;

Infrequent: abnormal dreams, dyskinesia, thinking abnormal, tardive dyskinesia, vertigo, involuntary movements, confusion, amnesia, psychosis, hallucinations, hyperkinesia, libido increased*, urinary retention, incoordination, paranoid reaction, abnormal gait, myoclonus, delusions, manic reaction, apathy, ataxia, depersonalization, stupor, bruxism, catatonic reaction, hemiplegia;

Rare: aphasia, buccoglossal syndrome, choreoathetosis, delirium, emotional lability, euphoria, libido decreased*, neuralgia, stuttering, subdural hematoma.

Body as a Whole

Frequent: flu syndrome;

Infrequent: neck pain, pelvic pain*, suicide attempt, malaise, photosensitivity reaction, chills, face edema, moniliasis;

Rare: abdomen enlarged.

Digestive System:

Frequent: anorexia;

Infrequent: increased salivation, increased appetite, gamma glutamyl transpeptidase increased, gingivitis, dysphagia, flatulence, gastroenteritis, gastritis, hemorrhoids, stomatitis, thirst, tooth caries, fecal incontinence, gastroesophageal reflux, gum hemorrhage, mouth ulceration, rectal hemorrhage, tongue edema;

Rare: glossitis, hematemesis, intestinal obstruction, melena, pancreatitis.

Cardiovascular System

Frequent: palpitation;

Infrequent: vasodilatation, QT interval prolonged, migraine, bradycardia, cerebral ischemia, irregular pulse, T wave abnormality, bundle branch block, cerebrovascular accident, deep thrombophlebitis, T wave inversion;

Rare: angina pectoris, atrial fibrillation, AV block first degree, congestive heart failure, ST elevated, thrombophlebitis, T wave flattening, ST abnormality, increased QRS duration.

Respiratory System

Frequent: pharyngitis, rhinitis, cough increased, dyspnea;

Infrequent: pneumonia, epistaxis, asthma;Rare: hiccup, hyperventilation.

Metabolic and Nutritional System:

Frequent: peripheral edema;

Infrequent: weight loss, alkaline phosphatase increased, hyperlipemia, alcohol intolerance, dehydration, hyperglycemia, creatinine increased, hypoglycemia;

Rare: glycosuria, gout, hand edema, hypokalemia, water intoxication.

Skin and Appendages System:

Frequent: sweating;

Infrequent: pruritus, acne, eczema, contact dermatitis, maculopapular rash, seborrhea, skin ulcer;

Rare: exfoliative dermatitis, psoriasis, skin discoloration.

Urogenital System:

Infrequent: dysmenorrhea*, vaginitis*, urinary incontinence, metrorrhagia*, impotence*, dysuria, vaginal

moniliasis*, abnormal ejaculation*, cystitis, urinary frequency, amenorrhea*, female lactation*, leukorrhea*, vaginal hemorrhage*, vulvovaginitis* orchitis*;

Rare: gynecomastia*, nocturia, polyuria, acute kidney failure.

Special Senses

Infrequent:

conjunctivitis, abnormal vision, dry eyes, tinnitus, taste perversion, blepharitis, eye pain;

Rare: abnormality of accommodation, deafness, glaucoma.

Musculoskeletal System

Infrequent:

pathological fracture, myasthenia, twitching, arthralgia, arthritis, leg cramps, bone pain.

Hemic and Lymphatic System:

Frequent: leukopenia;

Infrequent: leukocytosis, anemia, ecchymosis, eosinophilia, hypochromic anemia; lymphadenopathy, cyanosis;

Rare: hemolysis, thrombocytopenia.

Endocrine System:

Infrequent: hypothyroidism, diabetes mellitus;

Rare: hyperthyroidism.

*adjusted for gender

Post Marketing Experience

Adverse events reported since market introduction which were temporally related to SEROQUEL therapy include the following: rarely leukopenia/ neutropenia. If a patient develops a low white cell count consider discontinuation of therapy. Possible risk factors for leukopenia/ neutropenia include pre-existing low white cell count and history of drug induced leukopenia/ neutropenia.

Drug-Drug Interactions

In vitro enzyme inhibition data suggest that quetiapine and 9 of its metabolites would have little inhibitory effect on in vivo metabolism mediated by cytochromes P450 1A2, 2C9, 2C19, 2D6 and 3A4. Quetiapine oral clearance is increased by the prototype cytochrome P450 3A4 inducer, phenytoin, and decreased by the prototype cytochrome P450 3A4 inhibitor, ketoconazole. Dose adjustment of quetiapine will be necessary if it is coadministered with phenytoin or ketoconazole (See Drug Interactions under PRECAUTIONS and DOSAGE AND ADMINISTRATION). Quetiapine oral clearance is not inhibited by the non-specific enzyme inhibitor, cimetidine.

Quetiapine at doses of 750 mg/ day did not affect the single dose pharmacokinetics of antipyrine, lithium or lorazepam (See Drug Interactions under PRECAUTIONS).

Clinical Efficacy Data

The efficacy of SEROQUEL in the treatment of schizophrenia was established in 3 short-term (6-week) controlled trials of patients with schizophrenia who met DSM III-R criteria for schizophrenia. Although a single fixed dose haloperidol arm was included as a comparative treatment in one of the three trials, this single haloperidol dose group was inadequate to provide a reliable and valid comparison of SEROQUEL and haloperidol.

Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients.

A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the Scale for Assessing Negative Symptoms (SANS), a more recently developed but less well evaluated scale, was employed for assessing negative symptoms. The results of the trials follow:

(1) In a 6-week, placebo-controlled trial (n= 361) involving 5 fixed doses of SEROQUEL (75, 150, 300, 600 and 750 mg/ day on a tid schedule), the 4 highest doses of SEROQUEL were generally superior to placebo on the BPRS total score, the BPRS psychosis cluster and the CGI severity score, with the maximal effect seen at 300 mg/ day, and the effects of doses of 150 to 750 were generally indistinguishable. SEROQUEL, at a dose of 300 mg/ day, was superior to placebo on the SANS.

(2) In a 6-week, placebo-controlled trial (n= 286) involving titration of SEROQUEL in high (up to 750 mg/ day on a tid schedule) and low (up to 250 mg/ day on a tid schedule) doses, only the high dose SEROQUEL group (mean dose, 500 mg/ day) was generally superior to placebo on the BPRS total score, the BPRS psychosis cluster, the CGI severity score, and the SANS.

(3) In a 6-week dose and dose regimen comparison trial (n= 618) involving two fixed doses of SEROQUEL (450 mg/ day on both bid and tid schedules and 50 mg/ day on a bid schedule), only the 450 mg/ day (225 mg bid schedule) dose group was generally superior to the 50 mg/ day (25 mg bid) SEROQUEL dose group on the BPRS total score, the BPRS psychosis cluster, the CGI severity score, and on the SANS.

Examination of population subsets (race, gender, and age) did not reveal any differential responsiveness on the basis of race or gender, with an apparently greater effect in patients under the age of 40 compared to those older than 40. The clinical significance of this finding is unknown.