Deloxi

Overdose

In postmarketing experience, fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine only, at doses as low as 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting.

There is no specific antidote to Deloxi, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug.

An adequate airway, oxygenation, and ventilation should be assured, and cardiac rhythm and vital signs should be monitored. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients.

Activated charcoal may be useful in limiting absorption of duloxetine from the gastrointestinal tract. Administration of activated charcoal has been shown to decrease AUC and Cmax by an average of one-third, although some subjects had a limited effect of activated charcoal. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial.

In managing overdose, the possibility of multiple drug involvement should be considered. A specific caution involves patients who are taking or have recently taken Deloxi and might ingest excessive quantities of a TCA. In such a case, decreased clearance of the parent tricyclic and/or its active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation. The physician should consider contacting a poison control center (1-800-222-1222 or www.poison.org) for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR).

Cases of overdoses, alone or in combination with other medicinal products, with duloxetine doses of 5,400 mg were reported. Some fatalities have occurred, primarily with mixed overdoses, but also with duloxetine alone at a dose of approximately 1,000 mg. Signs and symptoms of overdose (duloxetine alone or in combination with other medicinal products) included somnolence, coma, serotonin syndrome, seizures, vomiting and tachycardia.

No specific antidote is known for duloxetine but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. A free airway should be established. Monitoring of cardiac and vital signs is recommended, along with appropriate symptomatic and supportive measures. Gastric lavage may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal may be useful in limiting absorption. Duloxetine has a large volume of distribution and forced diuresis, haemoperfusion, and exchange perfusion are unlikely to be beneficial.

Cases of overdoses, alone or in combination with other medicinal products, with Deloxi doses of 5400 mg were reported. Some fatalities have occurred, primarily with mixed overdoses, but also with Deloxi alone at a dose of approximately 1000 mg. Signs and symptoms of overdose (Deloxi alone or in combination with other medicinal products) included somnolence, coma, serotonin syndrome, seizures, vomiting and tachycardia.

No specific antidote is known for Deloxi but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. A free airway should be established. Monitoring of cardiac and vital signs is recommended, along with appropriate symptomatic and supportive measures. Gastric lavage may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal may be useful in limiting absorption. Deloxi has a large volume of distribution and forced diuresis, haemoperfusion, and exchange perfusion are unlikely to be beneficial.

Deloxi price

Contraindications

Monoamine Oxidase Inhibitors (MAOIs) — The use of MAOIs intended to treat psychiatric disorders with Deloxi or within 5 days of stopping treatment with Deloxi is contraindicated because of an increased risk of serotonin syndrome. The use of Deloxi within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.

Starting Deloxi in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome.

Liver disease resulting in hepatic impairment.

Duloxetine should not be used in combination with nonselective, irreversible monoamine oxidase inhibitors - MAOIs.

Duloxetine should not be used in combination with CYP1A2 inhibitors, like fluvoxamine, ciprofloxacin or enoxacin since the combination results in elevated plasma concentrations of duloxetine.

Severe renal impairment (creatinine clearance < 30 ml/min).

The initiation of treatment with duloxetine is contraindicated in patients with uncontrolled hypertension that could expose patients to a potential risk of hypertensive crisis.

Liver disease resulting in hepatic impairment.

Deloxi should not be used in combination with nonselective, irreversible monoamine oxidase inhibitors - MAOIs.

Deloxi should not be used in combination with CYP1A2 inhibitors, like fluvoxamine, ciprofloxacin or enoxacin since the combination results in elevated plasma concentrations of Deloxi.

Severe renal impairment (creatinine clearance <30 ml/min).

The initiation of treatment with Deloxi is contraindicated in patients with uncontrolled hypertension that could expose patients to a potential risk of hypertensive crisis.

Incompatibilities

Not applicable.

Undesirable effects

The following serious adverse reactions are described below and elsewhere in the labeling:

• Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults
• Hepatotoxicity
• Orthostatic Hypotension, Falls and Syncope
• Serotonin Syndrome
• Abnormal Bleeding
• Severe Skin Reactions
• Discontinuation of Treatment with Deloxi
• Activation of Mania/Hypomania
• Angle-Closure Glaucoma
• Seizures
• Effect on Blood Pressure
• Clinically Important Drug Interactions
• Hyponatremia
• Urinary Hesitation and Retention

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 the rates observed in practice.

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 reported during the studies were not necessarily caused by the therapy, and the frequencies do not reflect investigator impression (assessment) of causality.

The data described below reflect exposure to Deloxi in placebo-controlled trials for MDD (N=3779), GAD (N=1018), OA (N=503), CLBP (N=600), DPNP (N=906), and FM (N=1294). The population studied was 17 to 89 years of age; 65.7%, 60.8%, 60.6%, 42.9%, and 94.4% female; and 81.8%, 72.6%, 85.3%, 74.0%, and 85.7% Caucasian for MDD, GAD, OA and CLBP, DPNP, and FM, respectively. Most patients received doses of a total of 60 to 120 mg per day.The data below do not include results of the trial examining the efficacy of Deloxi in patients ≥ 65 years old for the treatment of generalized anxiety disorder; however, the adverse reactions observed in this geriatric sample were generally similar to adverse reactions in the overall adult population.

The data described below reflect exposure to Deloxi in pediatric, 10-week, placebo-controlled trials for MDD (N=341) and GAD (N=135). The population studied (N=476) was 7 to 17 years of age with 42.4% children age 7 to 11 years of age, 50.6% female, and 68.6% white. Patients received 30-120 mg per day during placebo-controlled acute treatment studies. Additional data come from the overall total of 822 pediatric patients (age 7 to 17 years of age) with 41.7% children age 7 to 11 years of age and 51.8% female exposed to Deloxi in MDD and GAD clinical trials up to 36-weeks in length, in which most patients received 30-120 mg per day.

Approximately 8.4% (319/3779) of the patients who received Deloxi in placebo-controlled trials for MDD discontinued treatment due to an adverse reaction, compared with 4.6% (117/2536) of the patients receiving placebo. Nausea (Deloxi 1.1%, placebo 0.4%) was the only common adverse reaction reported as a reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the Deloxi-treated patients and at a rate of at least twice that of placebo).

Approximately 13.7% (139/1018) of the patients who received Deloxi in placebo-controlled trials for GAD discontinued treatment due to an adverse reaction, compared with 5.0% (38/767) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (Deloxi 3.3%, placebo 0.4%), and dizziness (Deloxi 1.3%, placebo 0.4%).

Approximately 12.9% (117/906) of the patients who received Deloxi in placebo-controlled trials for DPNP discontinued treatment due to an adverse reaction, compared with 5.1% (23/448) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (Deloxi 3.5%, placebo 0.7%), dizziness (Deloxi 1.2%, placebo 0.4%), and somnolence (Deloxi 1.1%, placebo 0.0%).

Approximately 17.5% (227/1294) of the patients who received Deloxi in 3 to 6 month placebo-controlled trials for FM discontinued treatment due to an adverse reaction, compared with 10.1% (96/955) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (Deloxi 2.0%, placebo 0.5%), headache (Deloxi 1.2%, placebo 0.3%), somnolence (Deloxi 1.1%, placebo 0.0%), and fatigue (Deloxi 1.1%, placebo 0.1%).

Approximately 15.7% (79/503) of the patients who received Deloxi in 13-week, placebo-controlled trials for chronic pain due to OA discontinued treatment due to an adverse reaction, compared with 7.3% (37/508) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (Deloxi 2.2%, placebo 1.0%).

Approximately 16.5% (99/600) of the patients who received Deloxi in 13-week, placebo-controlled trials for CLBP discontinued treatment due to an adverse reaction, compared with 6.3% (28/441) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (Deloxi 3.0%, placebo 0.7%), and somnolence (Deloxi 1.0%, placebo 0.0%).

The most commonly observed adverse reactions in Deloxi-treated patients (incidence of at least 5% and at least twice the incidence in placebo patients) were nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis.

The most commonly observed adverse reactions in Deloxi-treated patients (as defined above) were nausea, somnolence, decreased appetite, constipation, hyperhidrosis, and dry mouth.

The most commonly observed adverse reactions in Deloxi-treated patients (as defined above) were nausea, dry mouth, constipation, somnolence, decreased appetite, hyperhidrosis, and agitation.

The most commonly observed adverse reactions in Deloxi-treated patients (as defined above) were nausea, fatigue, constipation, dry mouth, insomnia, somnolence, and dizziness.

The most commonly observed adverse reactions in Deloxi-treated patients (as defined above) were nausea, dry mouth, insomnia, somnolence, constipation, dizziness, and fatigue.

Table 2 gives the incidence of treatment-emergent adverse reactions in placebo-controlled trials for approved indications that occurred in 5% or more of patients treated with Deloxi and with an incidence greater than placebo.

Table 2: Treatment-Emergent Adverse Reactions: Incidence of 5% or More and Greater than Placebo in Placebo-Controlled Trials of Approved Indicationsa

Table 3 gives the incidence of treatment-emergent adverse reactions in MDD and GAD placebo-controlled trials for approved indications that occurred in 2% or more of patients treated with Deloxi and with an incidence greater than placebo.

Table 3: Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than Placebo in MDD and GAD Placebo-Controlled Trialsa,b

Table 4 gives the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with Deloxi (determined prior to rounding) in the premarketing acute phase of DPNP, FM, OA, and CLBP placebo-controlled trials and with an incidence greater than placebo.

Table 4: Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than Placebo in DPNP, FM, OA, and CLBP Placebo-Controlled Trialsa

Changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders or diabetes, but they may also be a consequence of pharmacologic treatment. Because adverse sexual reactions are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in 4 MDD placebo-controlled trials. In these trials, as shown in Table 5 below, patients treated with Deloxi experienced significantly more sexual dysfunction, as measured by the total score on the ASEX, than did patients treated with placebo. Gender analysis showed that this difference occurred only in males. Males treated with Deloxi experienced more difficulty with ability to reach orgasm (ASEX Item 4) than males treated with placebo. Females did not experience more sexual dysfunction on Deloxi than on placebo as measured by ASEX total score. Negative numbers signify an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients. Physicians should routinely inquire about possible sexual side effects.

Table 5: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Trials

In placebo-controlled clinical trials across approved indications for change from baseline to endpoint, Deloxi treatment was associated with mean increases of 0.23 mm Hg in systolic blood pressure and 0.73 mm Hg in diastolic blood pressure compared to mean decreases of 1.09 mm Hg systolic and 0.55 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure.

Deloxi treatment, for up to 26 weeks in placebo-controlled trials across approved indications, typically caused a small increase in heart rate for change from baseline to endpoint compared to placebo of up to 1.37 beats per minute (increase of 1.20 beats per minute in Deloxi -treated patients, decrease of 0.17 beats per minute in placebo-treated patients).

Deloxi treatment in placebo-controlled clinical trials across approved indications, was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, and alkaline phosphatase; infrequent, modest, transient, abnormal values were observed for these analytes in Deloxi-treated patients when compared with placebo-treated patients. High bicarbonate, cholesterol, and abnormal (high or low) potassium, were observed more frequently in Deloxi treated patients compared to placebo.

The effect of Deloxi 160 mg and 200 mg administered twice daily to steady state was evaluated in a randomized, double-blinded, two-way crossover study in 117 healthy female subjects. No QT interval prolongation was detected. Deloxi appears to be associated with concentration-dependent but not clinically meaningful QT shortening.

Following is a list of treatment-emergent adverse reactions reported by patients treated with Deloxi in clinical trials. In clinical trials of all indications, 34,756 patients were treated with Deloxi. Of these, 26.9% (9337) took Deloxi for at least 6 months, and 12.4% (4317) for at least one year. The following 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 categorized by body system according to 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 reactions are those occurring in fewer than 1/1000 patients.

Cardiac Disorders — Frequent: palpitations; Infrequent: myocardial infarction and tachycardia.

Ear and Labyrinth Disorders — Frequent: vertigo; Infrequent: ear pain and tinnitus.

Endocrine Disorders — Infrequent: hypothyroidism.

Eye Disorders — Frequent: vision blurred; Infrequent: diplopia, dry eye, and visual impairment.

Gastrointestinal Disorders — Frequent: flatulence; Infrequent: dysphagia, eructation, gastritis, gastrointestinal hemorrhage, halitosis, and stomatitis; Rare: gastric ulcer.

General Disorders and Administration Site Conditions — Frequent: chills/rigors; Infrequent: falls, feeling abnormal, feeling hot and/or cold, malaise, and thirst; Rare: gait disturbance.

Infections and Infestations — Infrequent: gastroenteritis and laryngitis.

Investigations — Frequent: weight increased, weight decreased; Infrequent: blood cholesterol increased.

Metabolism and Nutrition Disorders — Infrequent: dehydration and hyperlipidemia; Rare: dyslipidemia.

Musculoskeletal and Connective Tissue Disorders — Frequent: musculoskeletal pain; Infrequent: muscle tightness and muscle twitching.

Nervous System Disorders — Frequent: dysgeusia, lethargy, and paraesthesia/hypoesthesia; Infrequent: disturbance in attention, dyskinesia, myoclonus, and poor quality sleep; Rare: dysarthria.

Psychiatric Disorders — Frequent: abnormal dreams and sleep disorder; Infrequent: apathy, bruxism, disorientation/confusional state, irritability, mood swings, and suicide attempt; Rare: completed suicide.

Renal and Urinary Disorders — Frequent: urinary frequency; Infrequent: dysuria, micturition urgency, nocturia, polyuria, and urine odor abnormal.

Reproductive System and Breast Disorders — Frequent: anorgasmia/orgasm abnormal; Infrequent: menopausal symptoms, sexual dysfunction, and testicular pain; Rare: menstrual disorder.

Respiratory, Thoracic and Mediastinal Disorders — Frequent: yawning, oropharyngeal pain; Infrequent: throat tightness.

Skin and Subcutaneous Tissue Disorders — Frequent: pruritus; Infrequent: cold sweat, dermatitis contact, erythema, increased tendency to bruise, night sweats, and photosensitivity reaction; Rare: ecchymosis.

Vascular Disorders — Frequent: hot flush; Infrequent: flushing, orthostatic hypotension, and peripheral coldness.

The adverse drug reaction profile observed in pediatric clinical trials (children and adolescents) was consistent with the adverse drug reaction profile observed in adult clinical trials. The specific adverse drug reactions observed in adult patients can be expected to be observed in pediatric patients (children and adolescents). The most common (≥5% and twice placebo) adverse reactions observed in pediatric clinical trials include: nausea, diarrhea, decreased weight, and dizziness.

Table 6 provides the incidence of treatment-emergent adverse reactions in MDD and GAD pediatric placebo-controlled trials that occurred in greater than 2% of patients treated with Deloxi and with an incidence greater than placebo.

Table 6: Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than Placebo in three 10week Pediatric Placebo-Controlled Trialsa

Other adverse reactions that occurred at an incidence of less than 2% but were reported by more Deloxi treated patients than placebo treated patients and are associated Deloxi treatment: abnormal dreams (including ni

Summary of the safety profile

The most commonly reported adverse events in patients treated with duloxetine in clinical trials in SUI and other lower urinary tract disorders were nausea, dry mouth fatigue and constipation. The data analysis of four 12-week, placebo-controlled clinical trials in patients with SUI, including 958 duloxetine-treated and 955 placebo-treated patients, showed that the onset of the reported adverse events typically occurred in the first week of therapy. However, the majority of the most frequent adverse events were mild to moderate and resolved within 30 days of occurrence (e.g. nausea).

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.

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

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).

9Estimated frequency based on all clinical trial data.

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.

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.

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.

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 the Yellowcard Scheme: www.mhra.gov.uk/yellowcard.

a. Summary of the safety profile

The most commonly reported adverse events in patients treated with Deloxi in clinical trials in SUI and other lower urinary tract disorders were nausea, dry mouth fatigue and constipation. The data analysis of four 12-week, placebo-controlled clinical trials in patients with SUI, including 958 Deloxi-treated and 955 placebo-treated patients, showed that the onset of the reported adverse events typically occurred in the first week of therapy. However, the majority of the most frequent adverse events were mild to moderate and resolved within 30 days of occurrence (e.g. nausea).

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.

Preclinical safety data

Duloxetine was not genotoxic in a standard battery of tests and was not carcinogenic in rats.

Multinucleated cells were seen in the liver in the absence of other histopathological changes in the rat carcinogenicity study. The underlying mechanism and the clinical relevance are unknown. Female mice receiving duloxetine for 2 years had an increased incidence of hepatocellular adenomas and carcinomas at the high dose only (144 mg/kg/day), but these were considered to be secondary to hepatic microsomal enzyme induction. The relevance of this mouse data to humans is unknown. Female rats receiving duloxetine before and during mating and early pregnancy had a decrease in maternal food consumption and body weight, oestrous cycle disruption, decreased live birth indices and progeny survival, and progeny growth retardation at systemic exposure levels estimated to be at the most at maximum clinical exposure (AUC). In an embryotoxicity study in the rabbit, a higher incidence of cardiovascular and skeletal malformations was observed at systemic exposure levels below the maximum clinical exposure (AUC). No malformations were observed in another study testing a higher dose of a different salt of duloxetine. In pre/postnatal toxicity study in the rat, duloxetine induced adverse behavioural effects in the offspring at systemic exposure levels below maximum clinical exposure (AUC).

Studies in juvenile rats reveal transient effects on neurobehaviour, as well as significantly decreased body weight and food consumption; hepatic enzyme induction; and hepatocellular vacuolation at 45 mg/kg/day. The general toxicity profile of duloxetine in juvenile rats was similar to that in adult rats. The no-adverse effect level was determined to be 20 mg/kg/day.

Deloxi was not genotoxic in a standard battery of tests and was not carcinogenic in rats.

Multinucleated cells were seen in the liver in the absence of other histopathological changes in the rat carcinogenicity study. The underlying mechanism and the clinical relevance are unknown. Female mice receiving Deloxi for 2 years had an increased incidence of hepatocellular adenomas and carcinomas at the high dose only (144 mg/kg/day), but these were considered to be secondary to hepatic microsomal enzyme induction. The relevance of this mouse data to humans is unknown. Female rats receiving Deloxi before and during mating and early pregnancy had a decrease in maternal food consumption and body weight, oestrous cycle disruption, decreased live birth indices and progeny survival, and progeny growth retardation at systemic exposure levels estimated to be at the most at maximum clinical exposure (AUC). In an embryotoxicity study in the rabbit, a higher incidence of cardiovascular and skeletal malformations was observed at systemic exposure levels below the maximum clinical exposure (AUC). No malformations were observed in another study testing a higher dose of a different salt of Deloxi. In pre/postnatal toxicity study in the rat, Deloxi induced adverse behavioural effects in the offspring at systemic exposure levels below maximum clinical exposure (AUC).

Studies in juvenile rats reveal transient effects on neurobehaviour, as well as significantly decreased body weight and food consumption; hepatic enzyme induction; and hepatocellular vacuolation at 45 mg/kg/day. The general toxicity profile of Deloxi in juvenile rats was similar to that in adult rats. The no-adverse effect level was determined to be 20 mg/kg/day.

Therapeutic indications

Deloxi® is indicated for the treatment of:

• Major Depressive Disorder
• Generalized Anxiety Disorder
• Diabetic Peripheral Neuropathy
• Fibromyalgia
• Chronic Musculoskeletal Pain

Deloxi is indicated for women for the treatment of moderate to severe Stress Urinary Incontinence (SUI).

Deloxi is indicated in adults.

Pharmacotherapeutic group

Pharmacodynamic properties

Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro. Duloxetine does not inhibit monoamine oxidase (MAO).

Deloxi is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with Deloxi, consideration should be given to the possibility that they might be drug-related.

Pharmacotherapeutic group: Other antidepressants.

ATC code: N06AX21.

Mechanism of action

Duloxetine is a combined serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor. It weakly inhibits dopamine reuptake with no significant affinity for histaminergic, dopaminergic, cholinergic and adrenergic receptors.

Pharmacodynamic effects

In animal studies, increased levels of 5-HT and NE in the sacral spinal cord, lead to increased urethral tone via enhanced pudendal nerve stimulation to the urethral striated sphincter muscle only during the storage phase of the micturition cycle. A similar mechanism in women is believed to result in stronger urethral closure during urine storage with physical stress that could explain the efficacy of duloxetine in the treatment of women with SUI.

Clinical efficacy and safety

The efficacy of duloxetine 40 mg given twice daily in the treatment of SUI was established in four double-blind, placebo-controlled studies that randomised 1,913 women (22 to 83 years) with SUI; of these, 958 patients were randomised to duloxetine and 955 to placebo. The primary efficacy measures were Incontinence Episode Frequency (IEF) from diaries and an incontinence specific quality of life questionnaire score (I-QOL).

Incontinence Episode Frequency

In all four studies the duloxetine-treated group had a 50% or greater median decrease in IEF compared with 33% in the placebo-treated group. Differences were observed at each visit after 4 weeks (duloxetine 54% and placebo 22%), 8 weeks (52% and 29%), and 12 weeks (52% and 33%) of medication.

In an additional study limited to patients with severe SUI, all responses with duloxetine were achieved within 2 weeks.

The efficacy of duloxetine has not been evaluated for longer than 3 months in placebo-controlled studies. The clinical benefit of duloxetine compared with placebo has not been demonstrated in women with mild SUI, defined in randomised trials as those with IEF < 14 per week. In these women, duloxetine may provide no benefit beyond that afforded by more conservative behavioural interventions.

Quality of Life

Incontinence Quality of Life (I-QOL) questionnaire scores were significantly improved in the duloxetine-treated patient group compared with the placebo-treated group (9.2 versus 5.9 score improvement, p < 0.001). Using a global improvement scale (PGI), significantly more women using duloxetine considered their symptoms of stress incontinence to be improved with treatment compared with women using placebo (64.6% versus 50.1%, p < 0.001).

Duloxetine and Prior Continence Surgery

There are limited data that suggest that the benefits of duloxetine are not diminished in women with stress urinary incontinence who have previously undergone continence surgery.

Duloxetine and Pelvic Floor Muscle Training (PFMT)

During a 12-week blinded, randomised, controlled study, duloxetine demonstrated greater reductions in IEF compared with either placebo treatment or with PFMT alone. Combined therapy (duloxetine + PFMT) showed greater improvement in both pad use and condition-specific quality of life measures than duloxetine alone or PFMT alone.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with duloxetine in all subsets of the paediatric population in the treatment of stress urinary incontinence.

Pharmacotherapeutic group: psychoanaleptics, other antidepressants, ATC code: N06AX21.

Mechanism of action

Deloxi is a combined serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor. It weakly inhibits dopamine reuptake with no significant affinity for histaminergic, dopaminergic, cholinergic and adrenergic receptors.

Pharmacodynamic effects

In animal studies, increased levels of 5-HT and NE in the sacral spinal cord, lead to increased urethral tone via enhanced pudendal nerve stimulation to the urethral striated sphincter muscle only during the storage phase of the micturition cycle. A similar mechanism in women is believed to result in stronger urethral closure during urine storage with physical stress that could explain the efficacy of Deloxi in the treatment of women with SUI.

Clinical efficacy and safety

The efficacy of Deloxi 40 mg given twice daily in the treatment of SUI was established in four double-blind, placebo-controlled studies that randomised 1913 women (22 to 83 years) with SUI; of these, 958 patients were randomised to Deloxi and 955 to placebo. The primary efficacy measures were Incontinence Episode Frequency (IEF) from diaries and an incontinence specific quality of life questionnaire score (I-QOL).

Incontinence Episode Frequency: In all four studies the Deloxi-treated group had a 50% or greater median decrease in IEF compared with 33% in the placebo-treated group. Differences were observed at each visit after 4 weeks (Deloxi 54% and placebo 22%), 8 weeks (52% and 29%), and 12 weeks (52% and 33%) of medication.

In an additional study limited to patients with severe SUI, all responses with Deloxi were achieved within 2 weeks.

The efficacy of Deloxi has not been evaluated for longer than 3 months in placebo-controlled studies. The clinical benefit of Deloxi compared with placebo has not been demonstrated in women with mild SUI, defined in randomised trials as those with IEF < 14 per week. In these women, Deloxi may provide no benefit beyond that afforded by more conservative behavioural interventions.

Quality of Life: Incontinence Quality of Life (I-QOL) questionnaire scores were significantly improved in the Deloxi-treated patient group compared with the placebo-treated group (9.2 versus 5.9 score improvement, p<0.001). Using a global improvement scale (PGI), significantly more women using Deloxi considered their symptoms of stress incontinence to be improved with treatment compared with women using placebo (64.6% versus 50.1%, p<0.001).

Deloxi and Prior Continence Surgery: There are limited data that suggest that the benefits of Deloxi are not diminished in women with stress urinary incontinence who have previously undergone continence surgery.

Deloxi and Pelvic Floor Muscle Training (PFMT): During a 12-week blinded, randomised, controlled study, Deloxi demonstrated greater reductions in IEF compared with either placebo treatment or with PFMT alone. Combined therapy (Deloxi + PFMT) showed greater improvement in both pad use and condition-specific quality of life measures than Deloxi alone or PFMT alone.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Deloxi in all subsets of the paediatric population in the treatment of stress urinary incontinence.

Pharmacokinetic properties

Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic range. Steady-state plasma concentrations are typically achieved after 3 days of dosing. Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP1A2 and CYP2D6.

Orally administered duloxetine hydrochloride is well absorbed. There is a median 2 hour lag until absorption begins (Tlag), with maximal plasma concentrations (Cmax) of duloxetine occurring 6 hours post dose. Food does not affect the Cmax of duloxetine, but delays the time to reach peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (AUC) by about 10%. There is a 3 hour delay in absorption and a one-third increase in apparent clearance of duloxetine after an evening dose as compared to a morning dose.

The apparent volume of distribution averages about 1640 L. Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and α1-acid glycoprotein. The interaction between duloxetine and other highly protein bound drugs has not been fully evaluated. Plasma protein binding of duloxetine is not affected by renal or hepatic impairment.

Biotransformation and disposition of duloxetine in humans have been determined following oral administration of 14C-labeled duloxetine. Duloxetine comprises about 3% of the total radiolabeled material in the plasma, indicating that it undergoes extensive metabolism to numerous metabolites. The major biotransformation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP1A2 and CYP2D6 catalyze the oxidation of the naphthyl ring in vitro. Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate. Many additional metabolites have been identified in urine, some representing only minor pathways of elimination. Only trace (<1% of the dose) amounts of unchanged duloxetine are present in the urine. Most (about 70%) of the duloxetine dose appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces. Duloxetine undergoes extensive metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine.

Duloxetine steady-state plasma concentration was comparable in children (7 to 12 years of age), adolescents (13 to 17 years of age) and adults. The average steady-state duloxetine concentration was approximately 30% lower in the pediatric population (children and adolescents) relative to the adults. The model-predicted duloxetine steady state plasma concentrations in children and adolescents were mostly within the concentration range observed in adult patients and did not exceed the concentration range in adults.

Duloxetine is administered as a single enantiomer. Duloxetine is extensively metabolised by oxidative enzymes (CYP1A2 and the polymorphic CYP2D6), followed by conjugation. The pharmacokinetics of duloxetine demonstrate large intersubject variability (generally 50 - 60%), partly due to gender, age, smoking status and CYP2D6 metaboliser status.

Absorption

Duloxetine is well absorbed after oral administration with a Cmax occurring 6 hours post dose. The absolute oral bioavailability of duloxetine ranged from 32% to 80% (mean of 50%). Food delays the time to reach the peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (approximately 11%). These changes do not have any clinical significance.

Distribution

Duloxetine is approximately 96% bound to human plasma proteins. Duloxetine binds to both albumin and alpha-l acid glycoprotein. Protein binding is not affected by renal or hepatic impairment.

Biotransformation

Duloxetine is extensively metabolised and the metabolites are excreted principally in urine. Both cytochromes P450-2D6 and 1A2 catalyse the formation of the two major metabolites glucuronide conjugate of 4-hydroxy duloxetine and sulphate conjugate of 5-hydroxy 6-methoxy duloxetine. Based upon in vitro studies, the circulating metabolites of duloxetine are considered pharmacologically inactive. The pharmacokinetics of duloxetine in patients who are poor metabolisers with respect to CYP2D6 has not been specifically investigated. Limited data suggest that the plasma levels of duloxetine are higher in these patients.

Elimination

The elimination half-life of duloxetine ranges from 8 to 17 hours (mean of 12 h). After an intravenous dose the plasma clearance of duloxetine ranges from 22 l/h to 46 l/h (mean of 36 l/h). After an oral dose the apparent plasma clearance of duloxetine ranges from 33 to 261 l/h (mean 101 l/h).

Special populations

Gender

Pharmacokinetic differences have been identified between males and females (apparent plasma clearance is approximately 50% lower in females). Based upon the overlap in the range of clearance, gender-based pharmacokinetic differences do not justify the recommendation for using a lower dose for female patients.

Age

Pharmacokinetic differences have been identified between younger and elderly females (> 65 years) (AUC increases by about 25% and half-life is about 25% longer in the elderly), although the magnitude of these changes is not sufficient to justify adjustments to the dose. As a general recommendation, caution should be exercised when treating the elderly.

Renal impairment

End stage renal disease (ESRD) patients receiving dialysis had 2-fold higher duloxetine Cmax and AUC values compared with healthy subjects. Pharmacokinetic data on duloxetine is limited in patients with mild or moderate renal impairment.

Hepatic impairment

Moderate liver disease (Child Pugh Class B) affected the pharmacokinetics of duloxetine. Compared with healthy subjects, the apparent plasma clearance of duloxetine was 79% lower, the apparent terminal half-life was 2.3 times longer, and the AUC was 3.7-times higher in patients with moderate liver disease. The pharmacokinetics of duloxetine and its metabolites have not been studied in patients with mild or severe hepatic insufficiency.

Breast-feeding mothers

The disposition of duloxetine was studied in 6 lactating women who were at least 12-weeks postpartum. Duloxetine is detected in breast milk, and steady-state concentrations in breast milk are about one-fourth those in plasma. The amount of duloxetine in breast milk is approximately 7 μg/day while on 40 mg twice daily dosing. Lactation did not influence duloxetine pharmacokinetics.

Deloxi is administered as a single enantiomer. Deloxi is extensively metabolised by oxidative enzymes (CYP1A2 and the polymorphic CYP2D6), followed by conjugation. The pharmacokinetics of Deloxi demonstrate large intersubject variability (generally 50-60%), partly due to gender, age, smoking status and CYP2D6 metaboliser status.

Absorption: Deloxi is well absorbed after oral administration with a Cmax occurring 6 hours post dose. The absolute oral bioavailability of Deloxi ranged from 32% to 80% (mean of 50%). Food delays the time to reach the peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (approximately 11 %). These changes do not have any clinical significance.

Distribution: Deloxi is approximately 96% bound to human plasma proteins. Deloxi binds to both albumin and alpha-l acid glycoprotein. Protein binding is not affected by renal or hepatic impairment.

Biotransformation: Deloxi is extensively metabolised and the metabolites are excreted principally in urine. Both cytochromes P450-2D6 and 1A2 catalyse the formation of the two major metabolites glucuronide conjugate of 4-hydroxy Deloxi and sulphate conjugate of 5-hydroxy 6-methoxy Deloxi. Based upon in vitro studies, the circulating metabolites of Deloxi are considered pharmacologically inactive. The pharmacokinetics of Deloxi in patients who are poor metabolisers with respect to CYP2D6 has not been specifically investigated. Limited data suggest that the plasma levels of Deloxi are higher in these patients.

Elimination: The elimination half-life of Deloxi ranges from 8 to 17 hours (mean of 12 hours). After an intravenous dose the plasma clearance of Deloxi ranges from 22 l/hr to 46 l/hr (mean of 36 l/hr). After an oral dose the apparent plasma clearance of Deloxi ranges from 33 to 261 l/hr (mean 101 l/hr).

Special populations

Gender: Pharmacokinetic differences have been identified between males and females (apparent plasma clearance is approximately 50% lower in females). Based upon the overlap in the range of clearance, gender-based pharmacokinetic differences do not justify the recommendation for using a lower dose for female patients.

Age: Pharmacokinetic differences have been identified between younger and elderly females (>65 years) (AUC increases by about 25% and half-life is about 25% longer in the elderly), although the magnitude of these changes is not sufficient to justify adjustments to the dose. As a general recommendation, caution should be exercised when treating the elderly.

Renal impairment: End stage renal disease (ESRD) patients receiving dialysis had 2-fold higher Deloxi Cmax and AUC values compared with healthy subjects. Pharmacokinetic data on Deloxi is limited in patients with mild or moderate renal impairment.

Hepatic impairment: Moderate liver disease (Child Pugh Class B) affected the pharmacokinetics of Deloxi. Compared with healthy subjects, the apparent plasma clearance of Deloxi was 79% lower, the apparent terminal half-life was 2.3 times longer, and the AUC was 3.7 times higher in patients with moderate liver disease. The pharmacokinetics of Deloxi and its metabolites have not been studied in patients with mild or severe hepatic insufficiency.

Breast-feeding mothers: The disposition of Deloxi was studied in 6 lactating women who were at least 12-weeks postpartum. Deloxi is detected in breast milk, and steady-state concentrations in breast milk are about one-fourth those in plasma. The amount of Deloxi in breast milk is approximately 7 μg/day while on 40 mg twice daily dosing. Lactation did not influence Deloxi pharmacokinetics.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Included as part of the "PRECAUTIONS" Section

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

Table 1

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that discontinuation can be associated with certain symptoms.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Deloxi should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Deloxi is not approved for use in treating bipolar depression.

There have been reports of hepatic failure, sometimes fatal, in patients treated with Deloxi. These cases have presented as hepatitis with abdominal pain, hepatomegaly, and elevation of transaminase levels to more than twenty times the upper limit of normal with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. Deloxi should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established.

Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported. Other postmarketing reports indicate that elevated transaminases, bilirubin, and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis.

Deloxi increased the risk of elevation of serum transaminase levels in development program clinical trials. Liver transaminase elevations resulted in the discontinuation of 0.3% (92/34,756) of Deloxi-treated patients. In most patients, the median time to detection of the transaminase elevation was about two months. In adult placebo-controlled trials in any indication, for patients with normal and abnormal baseline ALT values, elevation of ALT >3 times the upper limit of normal occurred in 1.25% (144/11,496) of Deloxi-treated patients compared to 0.45% (39/8716) of placebo-treated patients. In adult placebo-controlled studies using a fixed dose design, there was evidence of a dose response relationship for ALT and AST elevation of >3 times the upper limit of normal and >5 times the upper limit of normal, respectively.

Because it is possible that Deloxi and alcohol may interact to cause liver injury or that Deloxi may aggravate pre-existing liver disease, Deloxi should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.

Orthostatic hypotension, falls and syncope have been reported with therapeutic doses of Deloxi. Syncope and orthostatic hypotension tend to occur within the first week of therapy but can occur at any time during Deloxi treatment, particularly after dose increases. The risk of falling appears to be related to the degree of orthostatic decrease in blood pressure as well as other factors that may increase the underlying risk of falls.

In an analysis of patients from all placebo-controlled trials, patients treated with Deloxi reported a higher rate of falls compared to patients treated with placebo. Risk appears to be related to the presence of orthostatic decrease in blood pressure. The risk of blood pressure decreases may be greater in patients taking concomitant medications that induce orthostatic hypotension (such as antihypertensives) or are potent CYP1A2 inhibitors and in patients taking Deloxi at doses above 60 mg daily. Consideration should be given to dose reduction or discontinuation of Deloxi in patients who experience symptomatic orthostatic hypotension, falls and/or syncope during Deloxi therapy.

Risk of falling also appeared to be proportional to a patient’s underlying risk for falls and appeared to increase steadily with age. As elderly patients tend to have a higher underlying risk for falls due to a higher prevalence of risk factors such as use of multiple medications, medical comorbidities and gait disturbances, the impact of increasing age by itself is unclear. Falls with serious consequences including bone fractures and hospitalizations have been reported.

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Deloxi, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of Deloxi with MAOIs intended to treat psychiatric disorders is contraindicated. Deloxi should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Deloxi. Deloxi should be discontinued before initiating treatment with the MAOI.

If concomitant use of Deloxi with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with Deloxi and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

SSRIs and SNRIs, including Deloxi, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the risk of bleeding associated with the concomitant use of Deloxi and NSAIDs, aspirin, or other drugs that affect coagulation.

Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur with Deloxi. The reporting rate of SJS associated with Deloxi use exceeds the general population background incidence rate for this serious skin reaction (1 to 2 cases per million person years). The reporting rate is generally accepted to be an underestimate due to underreporting.

Deloxi should be discontinued at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified.

Discontinuation symptoms have been systematically evaluated in patients taking Deloxi. Following abrupt or tapered discontinuation in adult placebo-controlled clinical trials, the following symptoms occurred at 1% or greater and at a significantly higher rate in Deloxi-treated patients compared to those discontinuing from placebo: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue.

During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe.

Patients should be monitored for these symptoms when discontinuing treatment with Deloxi. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

In adult placebo-controlled trials in patients with major depressive disorder, activation of mania or hypomania was reported in 0.1% (4/3779) of Deloxi-treated patients and 0.04% (1/2536) of placebo-treated patients. No activation of mania or hypomania was reported in DPNP, GAD, fibromyalgia, or chronic musculoskeletal pain placebo-controlled trials. Activation of mania or hypomania has been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs effective in the treatment of major depressive disorder. As with these other agents, Deloxi should be used cautiously in patients with a history of mania.

The pupillary dilation that occurs following use of many antidepressant drugs including Deloxi may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

Deloxi has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. In adult placebo-controlled clinical trials, seizures/convulsions occurred in 0.02% (3/12,722) of patients treated with Deloxi and 0.01% (1/9513) of patients treated with placebo. Deloxi should be prescribed with care in patients with a history of a seizure disorder.

In adult placebo-controlled clinical trials across indications from baseline to endpoint, Deloxi treatment was associated with mean increases of 0.5 mm Hg in systolic blood pressure and 0.8 mm Hg in diastolic blood pressure compared to mean decreases of 0.6 mm Hg systolic and 0.3 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure. In a clinical pharmacology study designed to evaluate the effects of Deloxi on various parameters, including blood pressure at supratherapeutic doses with an accelerated dose titration, there was evidence of increases in supine blood pressure at doses up to 200 mg twice daily. At the highest 200 mg twice daily dose, the increase in mean pulse rate was 5.0 to 6.8 beats and increases in mean blood pressure were 4.7 to 6.8 mm Hg (systolic) and 4.5 to 7 mm Hg (diastolic) up to 12 hours after dosing. Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment.

Both CYP1A2 and CYP2D6 are responsible for Deloxi metabolism.

CYP1A2 Inhibitors

Co-administration of Deloxi with potent CYP1A2 inhibitors should be avoided.

CYP2D6 Inhibitors

Because CYP2D6 is involved in Deloxi metabolism, concomitant use of Deloxi with potent inhibitors of CYP2D6 would be expected to, and does, result in higher concentrations (on average of 60%) of Deloxi.

Drugs Metabolized by CYP2D6

Co-administration of Deloxi with drugs that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine), phenothiazines and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution. Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a TCA is co-administered with Deloxi. Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, Deloxi and thioridazine should not be co-administered.

Alcohol

Use of Deloxi concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, Deloxi should not be prescribed for patients with substantial alcohol use.

CNS Acting Drugs

Given the primary CNS effects of Deloxi, it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action.

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Deloxi. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when Deloxi was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of Deloxi should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death.

Clinical experience with Deloxi in patients with concomitant systemic illnesses is limited. There is no information on the effect that alterations in gastric motility may have on the stability of Deloxi’s enteric coating. In extremely acidic conditions, Deloxi, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using Deloxi in patients with conditions that may slow gastric emptying (e.g., some diabetics).

Deloxi has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable coronary artery disease. Patients with these diagnoses were generally excluded from clinical studies during the product’s premarketing testing.

Avoid use in patients with chronic liver disease or cirrhosis.

Avoid use in patients with severe renal impairment, GFR <30 mL/min. Increased plasma concentration of Deloxi, and especially of its metabolites, occur in patients with end-stage renal disease (requiring dialysis).

As observed in DPNP trials, Deloxi treatment worsens glycemic control in some patients with diabetes. In three clinical trials of Deloxi for the management of neuropathic pain associated with diabetic peripheral neuropathy, the mean duration of diabetes was approximately 12 years, the mean baseline fasting blood glucose was 176 mg/dL, and the mean baseline hemoglobin A1c (HbA1c) was 7.8%. In the 12-week acute treatment phase of these studies, Deloxi was associated with a small increase in mean fasting blood glucose as compared to placebo. In the extension phase of these studies, which lasted up to 52 weeks, mean fasting blood glucose increased by 12 mg/dL in the Deloxi group and decreased by 11.5 mg/dL in the routine care group. HbA1c increased by 0.5% in the Deloxi and by 0.2% in the routine care groups.

Deloxi is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with Deloxi, 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 Deloxi use, hospitalization and/or catheterization has been needed.

No specific laboratory tests are recommended.

See FDA-approved patient labeling (PATIENT INFORMATION).

• Information on Medication Guide - Inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Deloxi and counsel them in its appropriate use. A patient Medication Guide is available for Deloxi. Instruct patients, their families, and their caregivers to read the Medication Guide before starting Deloxi and each time their prescription is renewed, and assist them in understanding its contents. Give patients the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
  Advise patients of the following issues and ask them to alert their prescriber if these occur while taking Deloxi.
• Suicidal Thoughts and Behaviors - Encourage patients, their families, and their caregivers to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down.
  Advise families and caregivers of patients to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
• Deloxi should be swallowed whole and should not be chewed or crushed, nor should the capsule be opened and its contents be sprinkled on food or mixed with liquids. All of these might affect the enteric coating.
• Continuing the Therapy Prescribed - While patients may notice improvement with Deloxi therapy in 1 to 4 weeks, advise patients to continue therapy as directed.
• Hepatotoxicity - Inform patients that severe liver problems, sometimes fatal, have been reported in patients treated with Deloxi. Instruct patients to talk to their healthcare provider if they develop itching, right upper belly pain, dark urine, or yellow skin/eyes while taking Deloxi, which may be signs of liver problems. Instruct patients to talk to their healthcare provider about their alcohol consumption. Use of Deloxi with heavy alcohol intake may be associated with severe liver injury.
• Alcohol - Although Deloxi does not increase the impairment of mental and motor skills caused by alcohol, use of Deloxi concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, Deloxi should not be prescribed for patients with substantial alcohol use.
• Orthostatic Hypotension, Falls and Syncope - Advise patients of the risk of orthostatic hypotension, falls and syncope, especially during the period of initial use and subsequent dose escalation, and in association with the use of concomitant drugs that might potentiate the orthostatic effect of Deloxi.
• Serotonin Syndrome —Caution patients about the risk of serotonin syndrome with the concomitant use of Deloxi and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort.
  Advise patients of the signs and symptoms associated with serotonin syndrome that may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Caution patients to seek medical care immediately if they experience these symptoms.
• Abnormal Bleeding - Caution patients about the concomitant use of Deloxi and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.
• Severe Skin Reactions - Caution patients that Deloxi may cause serious skin reactions. This may need to be treated in a hospital and may be life-threatening. Counsel patients to call their doctor right away or get emergency help if they have skin blisters, peeling rash, sores in their mouth, hives, or any other allergic reactions.
• Discontinuation of Treatment - Instruct patients that discontinuation of Deloxi may be associated with symptoms such as dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue, and should be advised not to alter their dosing regimen, or stop taking Deloxi without consulting their physician.
• Activation of Mania or Hypomania - Adequately screen patients with depressive symptoms for risk of bipolar disorder (e.g. family history of suicide, bipolar disorder, and depression) prior to initiating treatment with Deloxi. Advise patients to report any signs or symptoms of a manic reaction such as greatly increased energy, severe trouble sleeping, racing thoughts, reckless behavior, talking more or faster than usual, unusually grand ideas, and excessive happiness or irritability.
• Angle-Closure Glaucoma - Advise patients that taking Deloxi can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle-closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible..
• Seizures - Advise patients to inform their physician if they have a history of seizure disorder.
• Effects on Blood Pressure - Caution patients that Deloxi may cause an increase in blood pressure.
• Concomitant Medications - Advise patients to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter medications, since there is a potential for interactions.
• Hyponatremia - Advise patients that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs, including Deloxi. Advise patients of the signs and symptoms of hyponatremia.
• Concomitant Illnesses - Advise patients to inform their physicians about all of their medical conditions.
• Deloxi is in a class of medicines that may affect urination. Instruct patients to consult with their healthcare provider if they develop any problems with urine flow.
• Pregnancy and Nursing Mothers

  Advise patients to notify their physician if they:

  • become pregnant during therapy
  • intend to become pregnant during therapy
  • are nursing.
• Pediatric Use - Safety and efficacy of Deloxi in patients 7 to 17 years of age have been established for the treatment of GAD. The types of adverse reactions observed with Deloxi in children and adolescents were generally similar to those observed in adults. The safety and effectiveness of Deloxi have not been established in pediatric patients less than 18 years of age with other indications..
• Interference with Psychomotor Performance - Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies Deloxi has not been shown to impair psychomotor performance, cognitive function, or memory, it may be associated with sedation and dizziness. Therefore, caution patients about operating hazardous machinery including automobiles, until they are reasonably certain that Deloxi therapy does not affect their ability to engage in such activities.

Duloxetine was administered in the diet to mice and rats for 2 years.

In female mice receiving duloxetine at 140 mg/kg/day (6 times the maximum recommended human dose (MRHD

Mania and seizures

Duloxetine should be used with caution in patients with a history of mania or a diagnosis of bipolar disorder, and/or seizures.

Serotonin syndrome

As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with duloxetine treatment, particularly with concomitant use of other serotonergic agents (including SSRIs, SNRIs tricyclic antidepressants 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.

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 duloxetine and other serotonergic agents that may affect the serotonergic and/or dopaminergic neurotransmitter systems in 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 duloxetine and herbal preparations containing St. John's Wort (Hypericum perforatum).

Mydriasis

Mydriasis has been reported in association with duloxetine, therefore, caution should be used when prescribing duloxetine in patients with increased intraocular pressure, or those at risk of acute narrow-angle glaucoma.

Blood pressure and heart rate

Duloxetine 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 duloxetine. Cases of hypertensive crisis have been reported with duloxetine, 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. Duloxetine should be used with caution in patients whose conditions could be compromised by an increased heart rate or by an increase in blood pressure. Caution should also be exercised when duloxetine is used with medicinal products that may impair its metabolism. For patients who experience a sustained increase in blood pressure while receiving duloxetine either dose reduction or gradual discontinuation should be considered. In patients with uncontrolled hypertension duloxetine should not be initiated.

Renal impairment

Increased plasma concentrations of duloxetine occur in patients with severe renal impairment on haemodialysis (creatinine clearance < 30 ml/min).

Haemorrhage

There have been reports of bleeding abnormalities, such as ecchymoses, purpura and gastrointestinal haemorrhage with selective serotonin reuptake inhibitors (SSRIs) and serotonin/noradrenaline reuptake inhibitors (SNRIs), including duloxetine. Caution is advised in patients taking anticoagulants and/or medicinal products known to affect platelet function (e.g. NSAIDs or acetylsalicylic acid (ASA)), and in patients with known bleeding tendencies.

Discontinuation of treatment

Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt. 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 duloxetine should be gradually tapered when discontinuing treatment over a period of no less than 2 weeks, according to the patient's needs.

Hyponatraemia

Hyponatraemia has been reported when administering duloxetine, 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.

Depression, suicidal ideation and behaviour

Although duloxetine is not indicated for the treatment of depression, its active ingredient (duloxetine) also exists as an antidepressant medicinal product. 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. 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 a 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 duloxetine therapy or early after treatment discontinuation. Physicians should encourage patients to report any distressing thoughts or feelings or depressive symptoms at any time. If while on duloxetine therapy, the patient develops agitation or depressive symptoms, specialised medical advice should be sought, as depression is a serious medical condition. If a decision to initiate antidepressant pharmacological therapy is taken, the gradual discontinuation of duloxetine is recommended.

Use in children and adolescents under 18 years of age

Duloxetine 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. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.

Medicinal products containing duloxetine

Duloxetine is used under different trademarks in several indications (treatment of diabetic 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 duloxetine. Most of them occurred during the first months of treatment. The pattern of liver damage was predominantly hepatocellular. Duloxetine should be used with caution in patients treated with other medicinal products associated with hepatic injury.

Akathisia/psychomotor restlessness

The use of duloxetine 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.

Sucrose

Deloxi 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.

Mania and seizures

Deloxi should be used with caution in patients with a history of mania or a diagnosis of bipolar disorder, and/or seizures.

Serotonin syndrome

As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with Deloxi treatment, particularly with concomitant use of other serotonergic agents (including SSRIs, SNRIs tricyclic antidepressants 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.

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 Deloxi and other serotonergic agents that may affect the serotonergic and/or dopaminergic neurotransmitter systems in 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 Deloxi and herbal preparations containing St John's wort (Hypericum perforatum).

Mydriasis

Mydriasis has been reported in association with Deloxi, therefore, caution should be used when prescribing Deloxi in patients with increased intraocular pressure, or those at risk of acute narrow-angle glaucoma.

Blood pressure and heart rate

Deloxi 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 Deloxi. Cases of hypertensive crisis have been reported with Deloxi, 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. Deloxi should be used with caution in patients whose conditions could be compromised by an increased heart rate or by an increase in blood pressure. Caution should also be exercised when Deloxi is used with medicinal products that may impair its metabolism. For patients who experience a sustained increase in blood pressure while receiving Deloxi either dose reduction or gradual discontinuation should be considered. In patients with uncontrolled hypertension Deloxi should not be initiated.

Renal impairment

Increased plasma concentrations of Deloxi occur in patients with severe renal impairment on haemodialysis (creatinine clearance <30 ml/min).

Haemorrhage

There have been reports of bleeding abnormalities, such as ecchymoses, purpura and gastrointestinal haemorrhage with selective serotonin reuptake inhibitors (SSRIs) and serotonin/noradrenaline reuptake inhibitors (SNRIs), including Deloxi. Caution is advised in patients taking anticoagulants and/or medicinal products known to affect platelet function (e.g. NSAIDs or acetylsalicylic acid (ASA)), and in patients with known bleeding tendencies.

Discontinuation of treatment

Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt. 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 Deloxi should be gradually tapered when discontinuing treatment over a period of no less than 2 weeks, according to the patient's needs.

Hyponatraemia

Hyponatraemia has been reported when administering Deloxi, 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.

Depression, suicidal ideation and behaviour

Although Deloxi is not indicated for the treatment of depression, its active ingredient (Deloxi) also exists as an antidepressant medicinal product. 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. 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 a 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 Deloxi therapy or early after treatment discontinuation. Physicians should encourage patients to report any distressing thoughts or feelings or depressive symptoms at any time. If while on Deloxi therapy, the patient develops agitation or depressive symptoms, specialised medical advice should be sought, as depression is a serious medical condition. If a decision to initiate antidepressant pharmacological therapy is taken, the gradual discontinuation of Deloxi is recommended.

Use in children and adolescents under 18 years of age

Deloxi 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. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.

Medicinal products containing Deloxi

Deloxi is used under different trademarks in several indications (treatment of diabetic 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 Deloxi. Most of them occurred during the first months of treatment. The pattern of liver damage was predominantly hepatocellular. Deloxi should be used with caution in patients treated with other medicinal products associated with hepatic injury.

Akathisia/psychomotor restlessness

The use of Deloxi 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.

Sucrose

Deloxi contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-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. Duloxetine 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.

No studies on the effects on the ability to drive and use machines have been performed. Deloxi 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.

Dosage (Posology) and method of administration

Swallow Deloxi whole. Do not chew or crush. Do not open the capsule and sprinkle its contents on food or mix with liquids. All of these might affect the enteric coating. Deloxi can be given without regard to meals. If a dose of Deloxi is missed, take the missed dose as soon as it is remembered. If it is almost time for the next dose, skip the missed dose and take the next dose at the regular time. Do not take two doses of Deloxi at the same time.

Administer Deloxi at a total dose of 40 mg/day (given as 20 mg twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily). For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer any additional benefits. The safety of doses above 120 mg/day has not been adequately evaluated. Periodically reassess to determine the need for maintenance treatment and the appropriate dose for such treatment.

For most patients, initiate Deloxi 60 mg once daily. For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg once daily dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. Nevertheless, if a decision is made to increase the dose beyond 60 mg once daily, increase dose in increments of 30 mg once daily. The safety of doses above 120 mg once daily has not been adequately evaluated. Periodically reassess to determine the continued need for maintenance treatment and the appropriate dose for such treatment.

Initiate Deloxi at a dose of 30 mg once daily for 2 weeks before considering an increase to the target dose of 60 mg. Thereafter, patients may benefit from doses above 60 mg once daily. If a decision is made to increase the dose beyond 60 mg once daily, increase dose in increments of 30 mg once daily. The maximum dose studied was 120 mg per day. Safety of doses above 120 mg once daily has not been adequately evaluated.

Initiate Deloxi at a dose of 30 mg once daily for 2 weeks before considering an increase to 60 mg. The recommended dose range is 30 to 60 mg once daily. Some patients may benefit from doses above 60 mg once daily. If a decision is made to increase the dose beyond 60 mg once daily, increase dose in increments of 30 mg once daily. The maximum dose studied was 120 mg per day. The safety of doses above 120 mg once daily has not been evaluated.

Administer Deloxi 60 mg once daily. There is no evidence that doses higher than 60 mg confer additional significant benefit and the higher dose is clearly less well tolerated. For patients for whom tolerability is a concern, a lower starting dose may be considered.

Since diabetes is frequently complicated by renal disease, consider a lower starting dose and gradual increase in dose for patients with renal impairment.

Administer Deloxi 60 mg once daily. Begin treatment at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. Some patients may respond to the starting dose. There is no evidence that doses greater than 60 mg/day confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions.

Administer Deloxi 60 mg once daily. Begin treatment at 30 mg for one week, to allow patients to adjust to the medication before increasing to 60 mg once daily. There is no evidence that higher doses confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions.

Avoid use in patients with chronic liver disease or cirrhosis.

Avoid use in patients with severe renal impairment, GFR <30 mL/min.

Adverse reactions after discontinuation of Deloxi, after abrupt or tapered discontinuation, include: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible.

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Deloxi. Conversely, at least 5 days should be allowed after stopping Deloxi before starting an MAOI intended to treat psychiatric disorders.

Do not start Deloxi in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered.

In some cases, a patient already receiving Deloxi therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Deloxi should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Deloxi may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue.

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Deloxi is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use.

Posology

The recommended dose of Deloxi is 40 mg twice daily without regard to meals. After 2 - 4 weeks of treatment, patients should be re-assessed in order to evaluate the benefit and tolerability of the therapy. Some patients may benefit from starting treatment at a dose of 20 mg twice daily for two weeks before increasing to the recommended dose of 40 mg twice daily. Dose escalation may decrease, though not eliminate, the risk of nausea and dizziness.

A 20 mg capsule is also available. However, limited data are available to support the efficacy of Deloxi 20 mg twice daily.

The efficacy of Deloxi has not been evaluated for longer than 3 months in placebo-controlled studies. The benefit of treatment should be re-assessed at regular intervals.

Combining Deloxi with a pelvic floor muscle training (PFMT) programme may be more effective than either treatment alone. It is recommended that consideration be given to concomitant PFMT.

Hepatic impairment

Deloxi must not be used in women with liver disease resulting in hepatic impairment.

Renal impairment

No dosage adjustment is necessary for patients with mild or moderate renal dysfunction (creatinine clearance 30 to 80 ml/min).).

Paediatric population

The safety and efficacy of duloxetine for the treatment of stress urinary incontinence has not been studied. No data are available.

Elderly

Caution should be exercised when treating the elderly.

Discontinuation of treatment

Abrupt discontinuation should be avoided. When stopping treatment with Deloxi the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal reactions. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.

Method of administration

For oral use.

Posology

The recommended dose of Deloxi is 40 mg twice daily without regard to meals. After 2-4 weeks of treatment, patients should be re-assessed in order to evaluate the benefit and tolerability of the therapy. Some patients may benefit from starting treatment at a dose of 20 mg twice daily for two weeks before increasing to the recommended dose of 40 mg twice daily. Dose escalation may decrease, though not eliminate, the risk of nausea and dizziness.

A 20 mg capsule is also available. However, limited data are available to support the efficacy of Deloxi 20 mg twice daily.

The efficacy of Deloxi has not been evaluated for longer than 3 months in placebo-controlled studies. The benefit of treatment should be re-assessed at regular intervals.

Combining Deloxi with a pelvic floor muscle training (PFMT) programme may be more effective than either treatment alone. It is recommended that consideration be given to concomitant PFMT.

Hepatic impairment

Deloxi must not be used in women with liver disease resulting in hepatic impairment.

Renal impairment

No dosage adjustment is necessary for patients with mild or moderate renal dysfunction (creatinine clearance 30 to 80 ml/min).).

Paediatric population

The safety and efficacy of Deloxi for the treatment of stress urinary incontinence has not been studied. No data are available.

Special populations

Elderly

Caution should be exercised when treating the elderly.

Discontinuation of treatment

Abrupt discontinuation should be avoided. When stopping treatment with Deloxi the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal reactions. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.

Method of administration

For oral use.

Special precautions for disposal and other handling

No special requirements.

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.