Summary

Commonly reported side effects of fluoxetine/olanzapine include: asthenia, drowsiness, edema, eyelid edema, facial edema, facial swelling, hypersomnia, increased serum alanine aminotransferase, increased serum aspartate aminotransferase, joint swelling, lethargy, localized edema, periorbital edema, peripheral edema, sedated state, swelling of eye, weight gain, hyperprolactinemia, increased serum prolactin, increased serum triglycerides, anasarca, increased appetite, and xerostomia. Other side effects include: abnormal hepatic function tests, abnormality in thinking, diarrhea, increased gamma-glutamyl transferase, increased liver enzymes, increased serum transaminases, pharyngitis, tremor, and amblyopia. Continue reading for a comprehensive list of adverse effects.

Applies to fluoxetine / olanzapine: oral capsule.

Serious side effects

Along with its needed effects, fluoxetine / olanzapine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking fluoxetine / olanzapine:

More common

• Bloating or swelling of the face, arms, hands, lower legs, or feet
• body aches or pain
• confusion
• congestion
• cough
• delusions
• dementia
• dryness or soreness of the throat
• fever
• hoarseness
• rapid weight gain
• runny nose
• shakiness in the legs, arms, hands, or feet
• tender, swollen glands in the neck
• tingling of the hands or feet
• trembling or shaking of the hands or feet
• trouble with swallowing
• unusual weight gain or loss
• voice changes

Less common

• Blurred vision
• change in personality
• change in vision
• chest tightness
• decreased interest in sexual intercourse
• difficult or labored breathing
• difficulty with sleeping
• difficulty with speaking
• dizziness
• ear pain
• headache
• impaired vision
• inability to have or keep an erection
• increase in body movements
• loss in sexual ability, desire, drive, or performance
• loss of memory
• nervousness
• pounding in the ears
• problems with memory
• slow, fast, pounding, or irregular heartbeat or pulse

Rare

• Inability to move the eyes
• increased blinking or spasms of the eyelid
• sticking out of the tongue
• uncontrolled twisting movements of the neck, trunk, arms, or legs
• unusual facial expressions

Incidence not known

• Bloody or black, tarry stools
• constipation
• delayed or inability to have an orgasm
• painful or prolonged erection of the penis
• severe stomach pain
• vomiting of blood or material that looks like coffee grounds

Other side effects

Some side effects of fluoxetine / olanzapine may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.

Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Diarrhea
• dry mouth
• increased appetite
• lack or loss of strength
• weight gain

Less common

• Change or problem with discharge of semen
• decreased interest in sexual intercourse
• difficulty with moving
• inability to have or keep an erection
• loss in sexual ability, desire, drive, or performance
• muscle pain or stiffness
• not able to have an orgasm
• pain, swelling, or redness in the joints
• tooth disorder
• twitching

For Healthcare Professionals

Applies to fluoxetine / olanzapine: oral capsule.

General

Commonly reported side effects associated with fluoxetine-olanzapine treatment in short-term controlled studies at an incidence of at least 5% and double that of placebo were disturbance in attention, dry mouth, fatigue, hypersomnia, increased appetite, peripheral edema, sedation, somnolence, tremor, blurred vision, and increased weight.

Statistically significant differences in the incidence of weight gain, prolactin elevation, fatigue, and dizziness have been observed in a single 8-week randomized, double-blind, fixed dose study comparing 10 mg, 20 mg, and 40 mg olanzapine in patients with schizophrenia or schizoaffective disorder. Side effects associated with treatment discontinuation were increased weight and sedation.

In a single, 8-week, randomized, placebo-controlled clinical trial of fluoxetine-olanzapine for the treatment of bipolar I depression in patients aged 10 to 17 years, the side effects that lead to discontinuation that occurred at an incidence of at least 1% and greater than that of the placebo group were increased weight, suicidal ideation, bipolar disorder, and somnolence.^[Ref]

Psychiatric

Antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. An increased risk of suicidal thinking and behavior in children, adolescents, and young adults (aged 18 to 24 years) with major depressive disorder (MDD) and other psychiatric disorders has been reported with short-term use of antidepressant drugs.

Adult and pediatric patients receiving antidepressants for MDD, as well as for psychiatric and nonpsychiatric indications, have reported symptoms that may be precursors to emerging suicidality, including anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and mania. Causality has not been established.

Placebo-controlled clinical trials in elderly patients with dementia-related psychosis showed a significantly increased risk of death in olanzapine-treated patients (3.5%) compared to placebo-treated patients (1.5%).

Anxiety, restlessness, and suicidal ideation were reported as a treatment-emergent side effect in an 8-week randomized, double-blind, placebo-controlled clinical trial in pediatric bipolar I depression in patients aged 10 to 17 years.^[Ref]

Common (1% to 10%): Sinusitis

Uncommon (0.1% to 1%): Epistaxis, yawn

Rare (less than 0.1%): Laryngismus

Frequency not reported: Difficulty breathing, eosinophilic pneumonia, throat tightness

Postmarketing reports: Pulmonary embolism^[Ref]

Nervous system

Dystonias may occur in the first few days of treatment; males and younger age groups appear to be at a greater risk for acute dystonia. The frequency and severity of symptoms appear greater with high potency and at higher doses of first generation antipsychotic drugs, but may occur at low doses.

One retrospective study of 23 outpatients with Parkinson's disease treated with 40 mg of fluoxetine a day reported that three patients experienced worsening of parkinsonism, two patients experienced improvement of parkinsonism, and 18 patients experienced no change. Another small study reported a series of four patients who experienced worsening of parkinsonism during treatment with fluoxetine.

Potentially life-threatening serotonin syndrome has been reported with SSRIs and SNRIs as monotherapy, but particularly with concomitant use of other serotonergic drugs and drugs that impair the metabolism of serotonin.

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in connection to treatment with antipsychotic drugs, including olanzapine.

A number of case reports have implicated fluoxetine in causing seizures. Twelve of 6000 patients experienced convulsions during pre-marketing testing.

A case of dose-dependent exacerbation of preexisting, mild restless legs syndrome (which ultimately required discontinuation of fluoxetine) has been reported.

Somnolence and tremor were reported as a treatment-emergent side effect in an 8-week randomized, double-blind, placebo-controlled clinical trial in pediatric bipolar I depression in patients aged 10 to 17 years.^[Ref]

Very common (10% or more): Somnolence (up to 27%)

Common (1% to 10%): Amnesia, disturbance in attention, dizziness, neck rigidity, taste perversion, tremor

Uncommon (0.1% to 1%): Ataxia, coma, dysarthria, hypokinesia, movement disorder, myoclonus

Rare (less than 0.1%): Hyperkinesia

Frequency not reported: Dystonia, headache, lethargy, hypersomnia, neck muscle spasm, restless legs syndrome, sedation^[Ref]

Metabolic

Numerous cases of hyponatremia have been reported following treatment with an SSRI. Risk factors for the development of SSRI- associated hyponatremia including advanced age, female gender, concomitant use of diuretics, low body weight, and lower baseline serum sodium levels have been identified. Hyponatremia tends to develop within the first few weeks of treatment (range 3 to 120 days) and typically resolves within 2 weeks (range 48 hours to 6 weeks) after therapy has been discontinued with some patients requiring treatment. The proposed mechanism for the development of hyponatremia involves SIADH via release of antidiuretic hormone.

Hyperglycemia has been reported with olanzapine alone as well as in combination with fluoxetine. In an analysis of 7 controlled clinical studies, 2 of which were placebo controlled, with treatment duration up to 12 weeks, fluoxetine-olanzapine was associated with a greater mean change in random glucose compared to placebo (+8.65 mg/dL versus -3.86 mg/dL). The difference in mean changes was greater in patients with evidence of glucose dysregulation at baseline. Epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia in patients treated with atypical antipsychotics. The association between atypical antipsychotic therapy and increases in glucose levels appears greater with olanzapine than some other atypical antipsychotic agents.

Elevated uric acid, low albumin, low bicarbonate, and low inorganic phosphorus were observed at a statistically significant greater frequency in the fluoxetine-olanzapine group compared to the placebo group in adult clinical studies. Clinically meaningful increases in total cholesterol and triglyceride levels, sometimes greater than 500 mg/dL have also been observed in adults.

Clinically significant weight gain across all baseline BMI categories has been reported in clinical trials with fluoxetine-olanzapine. An analysis of 7 controlled clinical studies (2 of which were placebo-controlled) reported that, after a median exposure of eight weeks, 22% of patients treated with fluoxetine-olanzapine had gained at least 7% of their baseline weight. Long-term studies with fluoxetine-olanzapine (n=431), where patients were treated with this combination for at least 48 weeks, showed a mean weight gain of 6.7 kg.

Increased weight, appetite, blood triglycerides, and cholesterol were reported as treatment-emergent side effects in an 8 week randomized, double-blind, placebo-controlled clinical trial in pediatric bipolar I depression in patients aged 10 to 17 years. High fasting total cholesterol, high fasting LDL cholesterol, and high fasting triglycerides were observed at statistically significant greater frequencies in the fluoxetine-olanzapine group compared to the placebo group.^[Ref]

Very common (10% or more): Increased weight (up to 52.4%), high fasting triglycerides (up to 52.3%), high fasting total cholesterol (up to 28.9%), increased appetite (up to 20%), high fasting LDL cholesterol (up to 19.7%), low bicarbonate (up to 14%)

Common (1% to 10%): Elevated uric acid, low albumin, low inorganic phosphorus, weight loss

Rare (less than 0.1%): Gout

Frequency not reported: Hyperglycemia, increased creatine phosphokinase, random triglyceride levels of 1000 mg/dL or more^[Ref]

Cardiovascular

Very common (10% or more): Edema (up to 15%)

Common (1% to 10%): Generalized edema, vasodilatation

Frequency not reported: Bradycardia, hypotension, orthostatic hypotension, peripheral edema, periorbital edema, pitting edema, QT prolongation, tachycardia

Postmarketing reports: Deep vein thrombosis, venous thromboembolic events^[Ref]

The mean standing pulse rate in patients treated with fluoxetine-olanzapine was reduced by 0.7 beats/minute.

QTcF interval prolongation of 450 milliseconds or more for males and 470 milliseconds for females was reported at an incidence of at least 1% in clinical trials. The mean increase in QTc interval was reported as significantly greater in fluoxetine-olanzapine treated patients than placebo-treated patients, olanzapine-treated, and fluoxetine-treated patients.

Mean increases in QTcF interval of 8.2 milliseconds was observed at a statistically significant greater frequency in the fluoxetine-olanzapine group compared to the placebo group in a single 8-week randomized, placebo-controlled clinical trial for bipolar I depression in children and adolescents aged 10 to 17 years.

One placebo-controlled study has suggested that fluoxetine has no effects on intraventricular conduction. Other case reports have suggested that fluoxetine may rarely provoke dysrhythmias. Other conflicting case reports have suggested that fluoxetine may have a propensity to provoke and alleviate vasoconstriction. Several cases of unexpected death occurring shortly after initiation of fluoxetine therapy have been reported in elderly patients with multiple medical problems.

In one case report, QTc prolongation and torsades de pointes developed in an elderly woman 6 months after starting therapy with fluoxetine 20 mg daily. The QTc interval returned to normal following discontinuation of fluoxetine. Four additional cases suggesting fluoxetine-associated QTc prolongation or torsades de pointes have been reported.^[Ref]

Other

Very common (10% or more): Fatigue (up to 12%)

Common (1% to 10%): Accidental overdose, asthenia, chills, pain, pyrexia

Rare (less than 0.1%): Death

Frequency not reported: Body temperature dysregulation, face edema, gravitational edema, localized edema, sudden unexpected death, swelling^[Ref]

Accidental overdose was reported as a treatment-emergent side effect in an 8-week randomized, double-blind, placebo-controlled clinical trial in pediatric bipolar I depression in patients aged 10 to 17 years.^[Ref]

Genitourinary

Urinary retention and galactorrhea have been reported with other SSRIs.

The estimates of the incidence of untoward sexual experience and performance may underestimate their actual incidence, partly because patients and physicians may be reluctant to discuss this issue. In placebo-controlled clinical trials ejaculation disorder (primarily ejaculation delay) was reported as a treatment-emergent side effect at an incidence of 6% and at least twice the incidence in placebo-treated male patients.

Dysmenorrhea was reported as a treatment-emergent side effect in an 8-week randomized, double-blind, placebo-controlled clinical trial in pediatric bipolar I depression in patients aged 10 to 17 years.^[Ref]

Common (1% to 10%): Breast pain, dysmenorrhea, erectile dysfunction, menorrhagia, urinary frequency, urinary incontinence

Uncommon (0.1% to 1%): Amenorrhea, female lactation, hypomenorrhea, metrorrhagia, urinary retention, urinary urgency, impaired urination

Rare (less than 0.1%): Breast engorgement

Frequency not reported: Abnormal ejaculation, dysuria, galactorrhea, gynecological bleeding, ovulation disorder, priapism, sexual dysfunction^[Ref]

Dermatologic

Approximately 3% of fluoxetine-treated patients have been reported to develop a skin reaction.^[Ref]

Common (1% to 10%): Ecchymosis, photosensitivity reaction

Uncommon (0.1% to 1%): Alopecia, dry skin, pruritus

Rare (less than 0.1%): Exfoliative dermatitis, purpura

Frequency not reported: Erythema multiforme, face swelling, sweating^[Ref]

Endocrine

Very common (10% or more): Elevated prolactin (up to 85%)

Frequency not reported: Diabetic coma^[Ref]

Elevated prolactin levels were observed at a statistically significant greater frequency in the fluoxetine-olanzapine group compared to the placebo group in adult clinical studies and also in a single 8-week randomized, placebo-controlled clinical trial for bipolar I depression in children and adolescents aged 10 to 17 years.^[Ref]

Gastrointestinal

Very common (10% or more): Dry mouth (up to 15%)

Common (1% to 10%): Abdominal distension, diarrhea, dyspepsia, flatulence

Uncommon (0.1% to 1%): Buccoglossal syndrome, gastritis, gastroenteritis, nausea and vomiting, peptic ulcer

Rare (less than 0.1%): Gastrointestinal hemorrhage, intestinal obstruction, pancreatitis

Frequency not reported: Esophageal ulcer, swallowing difficulty, tongue protrusion^[Ref]

A study of 26,005 antidepressant users has reported 3.6 times more upper GI bleeding episodes with the use of SSRIs relative to the population who did not receive antidepressant medications. Upper gastrointestinal tract bleeding was observed in 3.9 times more frequently in patients receiving fluoxetine.

Dyspepsia was reported as a treatment-emergent side effect in an 8-week randomized, double-blind, placebo-controlled clinical trial in pediatric bipolar I depression in patients aged 10 to 17 years.^[Ref]

Hematologic

Low lymphocytes and low hemoglobin were observed at a statistically significant greater frequency in the fluoxetine-olanzapine group compared to the placebo group in adult clinical studies^[Ref]

Common (1% to 10%): Low hemoglobin, low lymphocytes

Uncommon (0.1% to 1%): Anemia, thrombocytopenia

Rare (less than 0.1%): Leukopenia

Frequency not reported: Aplastic anemia, neutropenia^[Ref]

Hepatic

ALT levels reported to return to normal, or were decreasing, at last follow-up in the majority of patients who either continued or discontinued treatment with fluoxetine-olanzapine.

Low total bilirubin levels were observed at a statistically significant greater frequency in the fluoxetine-olanzapine group compared to the placebo group in adult clinical studies. Elevated ALT and AST levels were observed at statistically significant greater frequencies in the fluoxetine-olanzapine group compared to the placebo group in a single 8-week randomized, placebo-controlled clinical trial for bipolar I depression in children and adolescents aged 10 to 17 years.^[Ref]

Very common (10% or more): Elevated ALT (up to 45.9%), elevated AST (up to 33.7%), low total bilirubin (up to 15%)

Common (1% to 10%): Clinically significant ALT elevation less than 3 times the upper limit of normal (ULN), ALT elevations 5 times the ULN or more

Rare (less than 0.1%): Bilirubinemia, liver fatty deposit

Frequency not reported: Abnormal liver function tests, cholestatic jaundice, increased alkaline phosphatase, increased gamma-glutamyltransferase, increased hepatic enzymes, jaundice

Postmarketing reports: Cholestatic or mixed liver injury, hepatitis^[Ref]

Musculoskeletal

Epidemiological studies, primarily in patients aged 50 years or older, have shown an increased risk of bone fractures in patients receiving SSRIs or TCAs.

Back pain was reported as a treatment-emergent side effect in an 8-week randomized, double-blind, placebo-controlled clinical trial in pediatric bipolar I depression in patients aged 10 to 17 years.^[Ref]

Common (1% to 10%): Arthralgia, back pain, musculoskeletal stiffness, pain in extremity

Rare (less than 0.1%): Osteoporosis

Frequency not reported: Joint swelling

Postmarketing reports: Rhabdomyolysis^[Ref]

Ocular

Common (1% to 10%): Blurred vision

Uncommon (0.1% to 1%): Abnormality of accommodation, dry eyes

Frequency not reported: Eye swelling, eyelid edema^[Ref]

Renal

Elevated urea nitrogen levels were observed at a statistically significant greater frequency in the fluoxetine-olanzapine group compared to the placebo group in adult clinical studies.

Glycosuria was reported at an incidence of 4.4% of patients treated with fluoxetine-olanzapine in an analysis of 6 controlled clinical studies, compared to 1.4% in the placebo group.^[Ref]

Common (1% to 10%): Elevated urea nitrogen, glycosuria

Rare (less than 0.1%): Increased creatinine^[Ref]

Respiratory

Common (1% to 10%): Sinusitis

Uncommon (0.1% to 1%): Epistaxis, yawn

Rare (less than 0.1%): Laryngismus

Frequency not reported: Eosinophilic pneumonia

Postmarketing reports: Pulmonary embolism^[Ref]