Mania and seizures: Cymbalta should be used with caution in patients with a history of mania or a diagnosis of bipolar disorder, and/or seizures.
Mydriasis: Mydriasis has been reported in association with Cymbalta, therefore, caution should be used when prescribing Cymbalta to patients with increased intraocular pressure, or those at risk of acute narrow-angle glaucoma.
Blood pressure and heart rate: Cymbalta has been associated with an increase in blood pressure and clinically significant hypertension in some patients. This may be due to the noradrenergic effect of Cymbalta. Cases of hypertensive crisis have been reported with Cymbalta, especially in patients with pre-existing hypertension. Therefore, in patients with known hypertension and/or other cardiac disease, blood pressure monitoring is recommended, especially during the first month of treatment. Cymbalta should be used with caution in patients whose conditions could be compromised by an increased heart rate or blood pressure. Caution should also be exercised when Cymbalta is used with medicinal products that may impair its metabolism (see Interactions). For patients who experience a sustained increase in blood pressure while receiving Cymbalta, either dose reduction or gradual discontinuation should be considered (see Adverse Reactions). In patients with uncontrolled hypertension Cymbalta should not be initiated (see Contraindications).
Renal impairment: Increased plasma concentrations of Cymbalta occur in patients with severe renal impairment on haemodialysis (creatinine clearance <30 ml/min). For patients with severe renal impairment, see Contraindications. See Dosage & Administration for information on patients with mild or moderate renal dysfunction.
Serotonin syndrome: As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with Cymbalta treatment, particularly with concomitant use of other serotonergic agents [including selective serotonin reuptake inhibitors (SSRIs), serotonin/noradrenaline reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs) or triptans], with agents that impair metabolism of serotonin such as MAOIs, or with antipsychotics or other dopamine antagonists that may affect the serotonergic neurotransmitter systems (see Contraindications and Interactions).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea).
If concomitant treatment with Cymbalta and other serotonergic agents that may affect the serotonergic and/or dopaminergic neurotransmitter systems is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
St John's wort: Adverse reactions may be more common during concomitant use of Cymbalta and herbal preparations containing St John's wort (Hypericum perforatum).
Suicide: Major Depressive Disorder and Generalised Anxiety Disorder: Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.
Other psychiatric conditions for which Cymbalta is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.
Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal thoughts prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicidal behaviour, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant medicinal products in psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.
Cases of suicidal thoughts and suicidal behaviours have been reported during Cymbalta therapy or early after treatment discontinuation (see Adverse Reactions).
Close supervision of patients and in particular those at high risk should accompany medicinal product therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.
Diabetic Peripheral Neuropathic Pain: As with other medicinal products with similar pharmacological action (antidepressants), isolated cases of suicidal ideation and suicidal behaviours have been reported during Cymbalta therapy or early after treatment discontinuation. Concerning risk factors for suicidality in depression, see previously mentioned. Physicians should encourage patients to report any distressing thoughts or feelings at any time.
Haemorrhage: There have been reports of bleeding abnormalities, such as ecchymoses, purpura and gastrointestinal haemorrhage with SSRIs and SRNIs, including Cymbalta. Caution is advised in patients taking anticoagulants and/or medicinal products known to affect platelet function (e.g. NSAIDs or aspirin), and in patients with known bleeding tendencies.
Hyponatraemia: Hyponatraemia has been reported when administering Cymbalta, including cases with serum sodium lower than 110 mmol/l. Hyponatraemia may be due to a syndrome of inappropriate anti-diuretic hormone secretion (SIADH). The majority of cases of hyponatraemia were reported in the elderly, especially when coupled with a recent history of, or condition pre-disposing to, altered fluid balance. Caution is required in patients at increased risk for hyponatraemia, such as elderly, cirrhotic, or dehydrated patients or patients treated with diuretics. Discontinuation of Cymbalta should be considered in patients with symptomatic hyponatraemia and appropriate medical intervention should be instituted.
Discontinuation of treatment: Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see Adverse Reactions). In clinical trials adverse events seen on abrupt treatment discontinuation occurred in approximately 45% of patients treated with Cymbalta and 23% of patients taking placebo. The risk of withdrawal symptoms seen with SSRIs and SNRIs may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction. The most commonly reported reactions are listed in Adverse Reactions. Generally these symptoms are mild to moderate, however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that Cymbalta should be gradually tapered when discontinuing treatment over a period of no less than 2 weeks, according to the patient's needs (see Dosage & Administration).
Fibromyalgia: Of the 1,761 patients in fibromyalgia premarketing studies, 7.9% (140) were 65 years of age or over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. However, as with all drugs, greater sensitivity of some older individuals cannot be ruled out.
Akathisia/psychomotor restlessness: The use of Cymbalta has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.
Medicinal products containing duloxetine: Duloxetine is used under different trademarks in several indications (treatment of diabetic peripheral neuropathic pain, major depressive disorder, generalised anxiety disorder and stress urinary incontinence). The use of more than one of these products concomitantly should be avoided.
Hepatitis/increased liver enzymes: Cases of liver injury, including severe elevations of liver enzymes (>10 times upper limit of normal), hepatitis and jaundice have been reported with Cymbalta (see Adverse Reactions). Most of them occurred during the first months of treatment. The pattern of liver damage was predominantly hepatocellular. Cymbalta should be used with caution in patients treated with other medicinal products associated with hepatic injury.
Because it is possible that Cymbalta and alcohol may interact to cause liver injury or that Cymbalta may aggravate pre-existing liver disease, Cymbalta should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.
Patients prescribed Cymbalta should be warned to report any symptoms of liver dysfunction e.g., pruritus, dark urine, jaundice, right upper quadrant tenderness or unexplained flu-like symptoms. Cymbalta should be discontinued in patients with jaundice or laboratory evidence of liver injury. Excessive alcohol consumption should be avoided during treatment with Cymbalta.
Urinary Hesitation and Retention: Cymbalta is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with Cymbalta, consideration should be given to the possibility that they might be drug-related. In post marketing experience, cases of urinary retention have been observed. In some instances of urinary retention associated with Cymbalta use, hospitalization and/or catheterization has been needed.
Sucrose: Cymbalta hard gastro-resistant capsules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed. Cymbalta may be associated with sedation and dizziness. Patients should be instructed that if they experience sedation or dizziness they should avoid potentially hazardous tasks such as driving or operating machinery.
Use in children and adolescents under 18 years of age: Cymbalta should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempts and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger), were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking (see Adverse Reactions).
Use in the Elderly: Data on the use of Cymbalta 120 mg in elderly patients with major depressive disorder and generalised anxiety disorder are limited. Therefore, caution should be exercised when treating the elderly with the maximum dosage (see Dosage & Administration, Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions).