Cymbalta (duloxetine): Undesirable effects

a. Summary of the safety profile

The most commonly reported adverse reactions in patients treated with Cymbalta were nausea, headache, dry mouth, somnolence and dizziness. However, the majority of common adverse reactions were mild to moderate; they usually started early in therapy, and most tended to subside even as therapy was continued.

b. Tabulated summary of adverse reactions

Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical trials.

Table 1: Adverse reactions

Frequency estimate: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Very common	Common	Uncommon	Rare	Very Rare
Infections and infestations
		Laryngitis
Immune system disorders
			Anaphylactic reaction Hyper-sensitivity disorder
Endocrine disorders
			Hypo-thyroidism
Metabolism and nutrition disorders
	Decreased appetite	Hyperglycaemia (reported especially in diabetic patients)	Dehydration Hyponatraemia SIADH6
Psychiatric disorders
	Insomnia Agitation Libido decreased Anxiety Orgasm abnormal Abnormal dreams	Suicidal ideation5,7 Sleep disorder Bruxism Disorientation Apathy	Suicidal behaviour5,7 Mania Hallucinations Aggression and anger4
Nervous system disorders
Headache Somnolence	Dizziness Lethargy Tremor Paraesthesia	Myoclonus Akathisia7 Nervousness Disturbance in attention Dysgeusia Dyskinesia Restless legs syndrome Poor quality sleep	Serotonin syndrome6 Convulsion1 Psychomotor restlessness6 Extra-pyramidal Symptoms6
Eye disorders
	Blurred vision	Mydriasis Visual impairment	Glaucoma
Ear and labyrinth disorders
	Tinnitus1	Vertigo Ear pain
Cardiac disorders
	Palpitations	Tachycardia Supra-ventricular arrhythmia, mainly atrial fibrillation
Vascular disorders
	Blood pressure increase3 Flushing	Syncope2 Hypertension3,7 Orthostatic hypotension2 Peripheral coldness	Hypertensive crisis3,6
Respiratory, thoracic and mediastinal disorders
	Yawning	Throat tightness Epistaxis	Interstitial lung disease10 Eosinophilic pneumonia6
Gastrointestinal disorders
Nausea Dry mouth	Constipation Diarrhoea Abdominal pain Vomiting Dyspepsia Flatulence	Gastrointestinal haemorrhage7 Gastroenteritis Eructation Gastritis Dysphagia	Stomatitis Haematochezia Breath odour Microscopic colitis9
Hepato-biliary disorders
		Hepatitis3 Elevated liver enzymes (ALT, AST, alkaline phosphatase) Acute liver injury	Hepatic failure6 Jaundice6
Skin and subcutaneous tissue disorders
	Sweating increased Rash	Night sweats Urticaria Dermatitis contact Cold sweat Photo-sensitivity reactions Increased tendency to bruise	Stevens-Johnson Syndrome6 Angio-neurotic oedema6	Cutaneous vasculitis
Musculoskeletal and connective tissue disorders
	Musculo-skeletal pain Muscle spasm	Muscle tightness Muscle twitching	Trismus
Renal and urinary disorders
	Dysuria Pollakiuria	Urinary retention Urinary hesitation Nocturia Polyuria Urine flow decreased	Urine odour abnormal
Reproductive system and breast disorders
	Erectile dysfunction Ejaculation disorder Ejaculation delayed	Gynaecological haemorrhage Menstrual disorder Sexual dysfunction Testicular pain	Menopausal symptoms Galactorrhoea Hyper- prolactinaemia Postpartum haemorrhage6
General disorders and administration site conditions
	Falls8 Fatigue	Chest pain7 Feeling abnormal Feeling cold Thirst Chills Malaise Feeling hot Gait disturbance
Investigations
	Weight decrease	Weight increase Blood creatine phosphokinase increased Blood potassium increased	Blood cholesterol increased

¹ Cases of convulsion and cases of tinnitus have also been reported after treatment discontinuation.

² Cases of orthostatic hypotension and syncope have been reported especially at the initiation of treatment.

³ See section 4.4.

⁴ Cases of aggression and anger have been reported particularly early in treatment or after treatment discontinuation.

⁵ Cases of suicidal ideation and suicidal behaviours have been reported during duloxetine therapy or early after treatment discontinuation.

⁶ Estimated frequency of post-marketing surveillance reported adverse reactions; not observed in placebo-controlled clinical trials.

⁷ Not statistically significantly different from placebo.

⁸ Falls were more common in the elderly (≥65 years old).

⁹ Estimated frequency based on all clinical trial data.

¹⁰ Estimated frequency based on placebo-controlled clinical trials.

c. Description of selected adverse reactions

Discontinuation of duloxetine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia or electric shock-like sensations, particularly in the head), sleep disturbances (including insomnia and intense dreams), fatigue, somnolence, agitation or anxiety, nausea and/or vomiting, tremor, headache, myalgia, irritability, diarrhoea, hyperhydrosis and vertigo are the most commonly reported reactions.

Generally, for SSRIs and SNRIs, these events are mild to moderate and self-limiting; however, in some patients they may be severe and/or prolonged. It is therefore advised that when duloxetine treatment is no longer required, gradual discontinuation by dose tapering should be carried out.

In the 12-week acute phase of three clinical trials of duloxetine in patients with diabetic neuropathic pain, small but statistically significant increases in fasting blood glucose were observed in duloxetine- treated patients. HbA1c was stable in both duloxetine-treated and placebo-treated patients. In the extension phase of these studies, which lasted up to 52 weeks, there was an increase in HbA1c in both the duloxetine and routine care groups, but the mean increase was 0.3% greater in the duloxetine- treated group. There was also a small increase in fasting blood glucose and in total cholesterol in duloxetine-treated patients, while those laboratory tests showed a slight decrease in the routine care group.

The heart rate-corrected QT interval in duloxetine-treated patients did not differ from that seen in placebo-treated patients. No clinically significant differences were observed for QT, PR, QRS, or QTcB measurements between duloxetine-treated and placebo-treated patients.

d. Paediatric population

A total of 509 paediatric patients aged 7 to 17 years with major depressive disorder and 241 paediatric patients aged 7 to 17 years with generalised anxiety disorder were treated with duloxetine in clinical trials. In general, the adverse reaction profile of duloxetine in children and adolescents was similar to that seen for adults.

A total of 467 paediatric patients initially randomized to duloxetine in clinical trials experienced a 0.1 kg mean decrease in weight at 10-weeks compared with a 0.9 kg mean increase in 353 placebo-treated patients. Subsequently, over the four- to six-month extension period, patients on average trended toward recovery to their expected baseline weight percentile based on population data from age- and gender-matched peers.

In studies of up to 9 months an overall mean decrease of 1% in height percentile (decrease of 2% in children (7-11 years) and increase of 0.3% in adolescents (12-17 years)) was observed in duloxetine-treated paediatric patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Reference

Cymbalta [Summary of Product Characteristics]. Utrecht, The Netherlands: Eli Lilly Nederland B.V.