ZYPREXA RELPREVV SIDE EFFECTS

SIDE EFFECTS

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice.

The information below for ZYPREXA RELPREVV is derived primarily from a clinical trial database consisting of 2058 patients with approximately 1948 patient years of exposure to ZYPREXA RELPREVV. This database includes safety data from 6 open-label studies and 2 double-blind comparator studies, conducted in patients with schizophrenia or schizoaffective disorder. Additionally, data obtained from patients treated with oral olanzapine are also presented below. Adverse reactions were assessed by the collection of adverse reactions, vital signs, weights, laboratory analytes, ECGs, and the results of physical and ophthalmologic examinations. In the tables and tabulations that follow for ZYPREXA RELPREVV, the MedDRA terminology has been used to classify reported adverse reactions. Data obtained from oral olanzapine studies was reported using the COSTART and MedDRA dictionaries.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Reactions listed elsewhere in labeling may not be repeated below. The entire label should be read to gain a complete understanding of the safety profile of ZYPREXA RELPREVV.

The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing healthcare provider with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reaction incidence in the population studied.

Adverse Reactions Associated With Discontinuation Of Treatment In A Short-Term, Placebo-Controlled Trial

Overall, there was no difference in the incidence of discontinuation due to adverse reactions between ZYPREXA RELPREVV (4%; 13/306 patients) and placebo (5%; 5/98 patients) in an 8-week trial.

Commonly Observed Adverse Reactions In A Short-Term, Placebo-Controlled Trial

In an 8-week trial, treatment-emergent adverse reactions with an incidence of 5% or greater in at least one of the ZYPREXA RELPREVV treatment groups (210 mg/2 weeks, 405 mg/4 weeks, or 300 mg/2 weeks) and greater than placebo were: headache, sedation, weight gain, cough, diarrhea, back pain, nausea, somnolence, dry mouth, nasopharyngitis, increased appetite, and vomiting.

Adverse Reactions Occurring At An Incidence Of 2% Or More Among ZYPREXA RELPREVV-Treated Patients In A Short-Term, Placebo-Controlled Trial

Table 9 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred in 2% or more of patients treated with ZYPREXA RELPREVV and with incidence greater than placebo who participated in the 8-week, placebo-controlled trial.

Table 1: Treatment-Emergent Adverse Reactions: Incidence in a Short-Term, Placebo-Controlled Clinical Trial with ZYPREXA RELPREVV

Body System/Adverse Reaction	Percentage of Patients Reporting Adverse Event
	Placebo (N=98)	ZYPREXA RELPREVV 405 mg/4 wks (N=100)	ZYPREXA RELPREVV 210 mg/2 wks (N=106)	ZYPREXA RELPREVV 300 mg/2 wks (N=100)
Ear and Labyrinth Disorders
Ear pain	2	1	1	4
Gastrointestinal Disorders
Abdominal paina	2	3	3	3
Diarrhea	4	2	7	5
Dry mouth	1	2	6	4
Flatulence	0	2	2	1
Nausea	2	5	5	4
Toothache	0	3	4	3
Vomiting	2	6	1	2
General Disorders and Administration Site Conditions
Fatigue	2	4	2	3
Injection site pain	0	2	3	2
Pain	0	0	2	3
Pyrexia	0	2	0	0
Infections and Infestations
Nasopharyngitis	2	3	6	1
Tooth infectionb	0	4	0	0
Upper respiratory tract infection	2	3	1	4
Viral infection	0	0	0	2
Injury, Poisoning and Procedural Complications
Procedural pain	0	2	0	0
Investigations
Electrocardiogram QT-corrected interval prolonged	1	0	0	2
Hepatic enzyme increasedc	1	4	1	3
Weight increased	5	5	6	7
Metabolism and Nutrition Disorders
Increased appetite	0	1	4	6
Musculoskeletal and Connective Tissue Disorders
Arthralgia	0	3	3	3
Back pain	4	4	3	5
Muscle spasms	0	3	1	2
Musculoskeletal stiffness	1	1	4	4
Nervous System Disorders
Dizziness	2	4	4	1
Dysarthria	0	0	1	2
Headached	8	13	15	18
Sedatione	7	13	8	13
Tremor	1	3	0	1
Psychiatric Disorders
Abnormal dreams	0	0	0	2
Hallucination, auditory	2	3	1	0
Restlessness	2	2	3	1
Sleep disorder	1	0	0	2
Thinking abnormal	1	3	0	0
Reproductive System and Breast Disorders
Vaginal discharge	0	0	4	4
Respiratory, Thoracic and Mediastinal Disorders
Cough	5	3	5	9
Nasal congestionf	3	2	1	7
Pharyngolaryngeal pain	2	2	3	3
Sneezing	0	0	0	2
Skin and Subcutaneous Tissue Disorders
Acne	0	2	0	2
Vascular Disorders
Hypertension	0	3	2	0
a The term abdominal pain upper was combined under abdominal pain. b The term tooth abscess was combined under tooth infection. c The terms alanine aminotransferase increased, aspartate aminotransferase increased, and gamma-glutamyltransferase increased were combined under hepatic enzyme increased. d The term tension headache was combined under headache. e The term somnolence was combined under sedation. f The term sinus congestion was combined under nasal congestion.

 

Dose Dependency Of Adverse Reactions

Dose group differences have been observed for weight, fasting triglycerides and prolactin elevation for ZYPREXA RELPREVV.

A dose group difference for oral olanzapine has been observed for fatigue, dizziness, weight gain and prolactin elevation. In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200) and 40 (N=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, incidence of fatigue (10 mg/day: 1.5%; 20 mg/day: 2.1%; 40 mg/day: 6.6%) was observed with significant differences between 10 vs 40 and 20 vs 40 mg/day. The incidence of dizziness (10 mg/day: 2.6%; 20 mg/day: 1.6%; 40 mg/day: 6.6%) was observed with significant differences between 20 vs 40 mg. Dose group differences were also noted for weight gain and prolactin elevation.

Extrapyramidal Symptoms

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by categorical analyses of formal rating scales during acute therapy in a controlled clinical trial comparing oral olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week trial.

Table 2: Treatment-Emergent Extrapyramidal Symptoms Assessed by Rating Scales Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia – Acute Phase

	Percentage of Patients Reporting Event
	Placebo	Olanzapine 5 ± 2.5 mg/day	Olanzapine 10 ± 2.5 mg/day	Olanzapine 15 ± 2.5 mg/day
Parkinsonisma	15	14	12	14
Akathisiab	23	16	19	27
a Percentage of patients with a Simpson-Angus Scale total score >3. b Percentage of patients with a Barnes Akathisia Scale global score ≥2.

 

The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse reactions during acute therapy in the same controlled clinical trial comparing olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia in a 6-week trial.

Table 3: Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Reactions Incidence in a Fixed Dosage Range, Placebo-Controlled Clinical Trial of Oral Olanzapine in Schizophrenia – Acute Phase

	Percentage of Patients Reporting Event
	Placebo (N=68)	Olanzapine 5 ± 2.5 mg/day (N=65)	Olanzapine 10 ± 2.5 mg/day (N=64)	Olanzapine 15 ± 2.5 mg/day (N=69)
Dystonic eventsa	1	3	2	3
Parkinsonism eventsb	10	8	14	20
Akathisia eventsc	1	5	11	10
Dyskinetic eventsd	4	0	2	1
Residual eventse	1	2	5	1
Any extrapyramidal event	16	15	25	32
a Patients with the following COSTART terms were counted in this category: dystonia, generalized spasm, neck rigidity, oculogyric crisis, opisthotonos, torticollis. b Patients with the following COSTART terms were counted in this category: akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, masked facies, tremor. c Patients with the following COSTART terms were counted in this category: akathisia, hyperkinesia. d Patients with the following COSTART terms were counted in this category: buccoglossal syndrome, choreoathetosis, dyskinesia, tardive dyskinesia. e Patients with the following COSTART terms were counted in this category: movement disorder, myoclonus, twitching.

 

Dystonia, Class Effect

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, the frequency and severity are greater with high potency and at higher doses of first generation antipsychotic drugs. In general, an elevated risk of acute dystonia may be observed in males and younger age groups receiving antipsychotics; however, events of dystonia have been reported infrequently (<1%) with olanzapine use.

Other Adverse Reactions

Local Injection Site Reactions

Eleven ZYPREXA RELPREVV-treated patients (3.6%) and 0 placebo-treated patients experienced treatment-emergent injection-related adverse reactions (injection site pain, buttock pain, injection site mass, induration, injection site induration) in the placebo-controlled database. The most frequently occurring treatment-emergent adverse reaction was injection site pain (2.3% ZYPREXA RELPREVV-treated; 0% placebo-treated).

Other Adverse Reactions Observed During the Clinical Trial Evaluation of Olanzapine for Extended-Release Injectable Suspension

Injection site abscess has been reported in clinical trials with ZYPREXA RELPREVV therapy. Isolated cases required surgical intervention.

Commonly Observed Adverse Reactions During the Clinical Trial Evaluation of Oral Olanzapine

In clinical trials of oral olanzapine monotherapy for the treatment of schizophrenia in adult patients, treatment-emergent adverse reactions with an incidence of 5% or greater in the olanzapine treatment arm and at least twice that of placebo were: postural hypotension, constipation, weight gain, dizziness, personality disorder, and akathisia.

Other Adverse Reactions Observed During the Clinical Trial Evaluation of Oral Olanzapine

Following is a list of treatment-emergent adverse reactions reported by patients treated with oral olanzapine (at multiple doses ≥1 mg/day) in clinical trials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo. Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare adverse reactions are those occurring in fewer than 1/1000 patients.

Body as a Whole – Infrequent: chills, face edema, photosensitivity reaction, suicide attempt ; Rare: chills and fever, hangover effect, sudden death .

Cardiovascular System – Infrequent: cerebrovascular accident, vasodilatation.

Digestive System – Infrequent: abdominal distension, nausea and vomiting, tongue edema; Rare: ileus, intestinal obstruction, liver fatty deposit.

Hemic and Lymphatic System – Infrequent: thrombocytopenia.

Metabolic and Nutritional Disorders – Frequent: alkaline phosphatase increased; Infrequent: bilirubinemia, hypoproteinemia.

Musculoskeletal System – Rare: osteoporosis.

Nervous System – Infrequent: ataxia, dysarthria, libido decreased, stupor; Rare: coma.

Respiratory System – Infrequent: epistaxis; Rare: lung edema.

Skin and Appendages – Infrequent: alopecia.

Special Senses – Infrequent: abnormality of accommodation, dry eyes; Rare: mydriasis.

Urogenital System – Infrequent: amenorrhea², breast pain, decreased menstruation, impotence², increased menstruation², menorrhagia², metrorrhagia², polyuria², urinary frequency, urinary retention, urinary urgency, urination impaired.

1. 1. These terms represent serious adverse events but do not meet the definition for adverse drug reactions. They are included here because of their seriousness.

1. Adjusted for gender.

Vital Signs And Laboratory Studies

Laboratory Changes

ZYPREXA RELPREVV in Adults

Statistically significant within group mean changes for ZYPREXA RELPREVV, which were also significantly different from placebo, were observed for the following: eosinophils, monocytes, cholesterol, lowdensity lipoprotein (LDL), triglycerides, and direct bilirubin. There were no statistically significant differences between ZYPREXA RELPREVV and placebo in the incidence of potentially clinically significant changes in any of the laboratory values studied.

Statistically significant within group mean changes for ZYPREXA RELPREVV, which were also significantly different from oral olanzapine (in a 24-week double-blind study), were observed for the following: gammaglutamyltransferase (GGT) and sodium.

From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, high GGT levels were recorded in ≥1% (88/5245) of patients.

Statistically significant differences were observed between ZYPREXA RELPREVV and oral olanzapine for the incidence of treatment-emergent low platelet count (0% ZYPREXA RELPREVV vs 1% oral olanzapine); and low total bilirubin (2.8% ZYPREXA RELPREVV vs 0.7% for oral olanzapine). There was a statistically significant difference between ZYPREXA RELPREVV and oral olanzapine in potentially clinically significant changes for high leukocyte count (0% ZYPREXA RELPREVV vs 1% oral olanzapine).

Changes in aminotransferases observed with ZYPREXA RELPREVV treatment were similar to those reported with ZYPREXA treatment. In placebo-controlled ZYPREXA RELPREVV studies, clinically significant ALT elevations (≥3 times the upper limit of the normal range) were observed in 2.7% (8/291) of patients exposed to olanzapine compared to 3.2% (3/94) of the placebo patients. None of these patients experienced jaundice. In 3 of these patients, liver enzymes reverted to the normal range despite continued treatment, and in 5 cases enzymes values decreased, but were still above the normal range at the end of therapy.

Within the larger premarketing ZYPREXA RELPREVV database of 1886 patients with baseline ALT ≤90 IU/L, the incidence of ALT elevation to >200 IU/L was 0.8%. None of these patients experienced jaundice or other symptoms attributable to liver impairment and most had transient changes that tended to normalize while ZYPREXA RELPREVV treatment was continued.

From an analysis of the laboratory data in an integrated database of 41 completed clinical studies in adult patients treated with oral olanzapine, elevated uric acid was recorded in ≥3% (171/4641) of patients.

Olanzapine Monotherapy in Adults

An assessment of the premarketing experience for oral olanzapine revealed an association with asymptomatic increases in ALT, AST, and GGT. Within the original premarketing database of about 2400 adult patients with baseline ALT ≤90 IU/L, the incidence of ALT elevations to >200 IU/L was 2% (50/2381). None of these patients experienced jaundice or other symptoms attributable to liver impairment and most had transient changes that tended to normalize while olanzapine treatment was continued.

In placebo-controlled oral olanzapine monotherapy studies in adults, clinically significant ALT elevations (change from <3 times the upper limit of normal [ULN] at baseline to ≥3 times ULN) were observed in 5% (77/1426) of patients exposed to olanzapine compared to 1% (10/1187) of patients exposed to placebo. ALT elevations ≥5 times ULN were observed in 2% (29/1438) of olanzapine-treated patients, compared to 0.3% (4/1196) of placebo-treated patients. ALT values returned to normal, or were decreasing, at last follow-up in the majority of patients who either continued treatment with olanzapine or discontinued olanzapine. No patient with elevated ALT values experienced jaundice, liver failure, or met the criteria for Hy’s Rule.

Caution should be exercised in patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic drugs.

Oral olanzapine administration was also associated with increases in serum prolactin, with an asymptomatic elevation of the eosinophil count in 0.3% of patients, and with an increase in CPK.

ECG Changes

Comparison of ZYPREXA RELPREVV and oral olanzapine, in a 24 week study, revealed no significant differences on ECG changes. Between-group comparisons for pooled placebo-controlled trials revealed no significant oral olanzapine/placebo differences in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc, and PR intervals. Oral olanzapine use was associated with a mean increase in heart rate of 2.4 beats per minute compared to no change among placebo patients. This slight tendency to tachycardia may be related to olanzapine’s potential for inducing orthostatic changes.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ZYPREXA and ZYPREXA RELPREVV. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure.

Adverse reactions reported since market introduction that were temporally (but not necessarily causally) related to ZYPREXA therapy include the following: allergic reaction (e.g., anaphylactoid reaction, angioedema, pruritus or urticaria), cholestatic or mixed liver injury, diabetic coma, diabetic ketoacidosis, discontinuation reaction (diaphoresis, nausea, or vomiting), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), hepatitis, jaundice, neutropenia, pancreatitis, priapism, rash, restless legs syndrome, rhabdomyolysis, salivary hypersecretion, stuttering¹, and venous thromboembolic events (including pulmonary embolism and deep venous thrombosis). Random cholesterol levels of ≥240 mg/dL and random triglyceride levels of ≥1000 mg/dL have been reported. Additionally, injection site abscess has been reported in postmarketing reports with ZYPREXA RELPREVV therapy. Isolated cases required surgical intervention.

 

SRC: NLM .