Cymbalta

Duloxetine hydrochloride.

The active ingredient in CYMBALTA is duloxetine.
Each capsule contains 30 mg of duloxetine as duloxetine hydrochloride.
Each capsule contains 60 mg of duloxetine as duloxetine hydrochloride.
Excipients/Inactive ingredients: Capsule content: Hypromellose, Hydroxypropyl methylcellulose acetate succinate, Sucrose, Sugar spheres, Talc, Titanium dioxide (E171), Triethyl citrate.
Capsule Shell: 30 mg: Gelatin, Sodium Lauryl Sulfate, Titanium Dioxide (E171), Indigo Carmine (E132), Edible Green Ink.
60 mg: Gelatin, Sodium Lauryl Sulfate, Titanium Dioxide (E171), Indigo Carmine (E132), Yellow Iron Oxide (E172), Edible White Ink.
Edible Green Ink contains: Black Iron Oxide-Synthetic (E172), Yellow Iron Oxide-Synthetic (E172), Propylene glycol, Shellac.
Edible White Ink contains: Titanium Dioxide (E171), Propylene glycol, Shellac, Povidone.

Pharmacotherapeutic Group: Other antidepressants. ATC Code: N06AX21.
Pharmacology: Pharmacodynamics: 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. Duloxetine dose-dependently increases extracellular levels of serotonin and noradrenaline in various brain areas of animals.
Duloxetine normalised pain thresholds in several preclinical models of neuropathic and inflammatory pain and attenuated pain behaviour in a model of persistent pain. The pain inhibitory action of duloxetine is believed to be a result of potentiation of descending inhibitory pain pathways within the central nervous system.
Major Depressive Episodes: CYMBALTA was studied in a clinical programme involving 2951 patients (1,259 patient-years of exposure) meeting DSM-IV criteria for major depression. The efficacy of CYMBALTA at the recommended dose of 60 mg once a day was demonstrated in two out of two randomized, double-blind, placebo-controlled, fixed dose acute studies in adult outpatients with major depressive disorder. Overall, CYMBALTA's efficacy has been demonstrated at daily doses between 60 and 120 mg in a total of four out of six randomized, double-blind, placebo-controlled, fixed dose acute studies in adult outpatients with major depressive disorder.
CYMBALTA demonstrated statistical superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale (HAM-D) total score (including both the emotional and somatic symptoms of depression). Response and remission rates were also statistically significantly higher with CYMBALTA compared with placebo. Only a small proportion of patients included in pivotal clinical trials had severe depression (baseline HAM-D>25).
In a relapse prevention study, patients responding to 12-weeks of acute treatment with open-label CYMBALTA 60 mg once daily were randomised to either CYMBALTA 60 mg once daily or placebo for a further 6-months. CYMBALTA 60 mg once daily demonstrated a statistically significant superiority compared to placebo (p=0.004) on the primary outcome measure, the prevention of depressive relapse, as measured by time to relapse. The incidence of relapse during the 6-months double-blind follow-up period was 17% and 29% for duloxetine and placebo, respectively.
The effect of CYMBALTA 60 mg once a day in elderly depressed patients (≥ 65 years) was specifically examined in a study that showed a statistically significative difference in the reduction of the HAMD17 score for duloxetine-treated patients compared to placebo. Tolerability of CYMBALTA 60 mg once day in elderly patients was comparable to that seen in the younger adults. However, data on elderly patients exposed to the maximum dose (120mg per day) are limited and thus, caution is recommended when treating this population.
Diabetic Peripheral Neuropathic Pain: The efficacy of duloxetine as a treatment for diabetic neuropathic pain was established in 2 randomised, 12-week, double-blind, placebo-controlled, fixed dose studies in adults (22 to 88 years) having diabetic neuropathic pain for at least 6 months. Patients meeting diagnostic criteria for major depressive disorder were excluded from these trials. The primary outcome measure was the weekly mean of 24-hour average pain, which was collected in a daily diary by patients on an 11-point Likert scale.
In both studies, duloxetine 60 mg once daily and 60 mg twice daily significantly reduced pain compared with placebo. The effect in some patients was apparent in the first week of treatment. The difference in mean improvement between the two active treatment arms was not significant. At least 30% reported pain reduction was recorded in approximately 65% of duloxetine treated patients versus 40% for placebo. The corresponding figures for at least 50% pain reduction were 50% and 26% respectively. Clinical response rates (50% or greater improvement in pain) were analysed according to whether or not the patient experienced somnolence during treatment. For patients not experiencing somnolence, clinical response was observed in 47% of patients receiving duloxetine and 27% patients on placebo. Clinical response rates in patients experiencing somnolence were 60% on duloxetine and 30% on placebo. Patients not demonstrating a pain reduction of 30% within 60 days of treatment were unlikely to reach this level during further treatment.
In an open label long-term uncontrolled study, the pain reduction in patients responding to 8-weeks of acute treatment of CYMBALTA 60 mg once daily was maintained for a further 6-months as measured by change on the Brief Pain Inventory (BPI) 24-hour average pain item.
Pharmacokinetics: 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.
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. 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.
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 5hydroxy,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.
The elimination half-life of duloxetine ranges from 8 to 17 hours (mean of 12 hours). After an intravenous dose the plasma clearance of duloxetine ranges from 22 l/hr to 46 l/hr (mean of 36 l/hr). After an oral dose the apparent plasma clearance of duloxetine 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 approximatively 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 (see Dosage & Administration and Precautions).
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.
Therefore, a lower dose should be considered for patients with clinically significant renal impairment. (See Dosage & Administration.)
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.
Nursing 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.
Toxicology: 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 (45 mg/kg/day) 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 prenatal/postnatal toxicity studies in the rat, duloxetine induced adverse behavioural effects in the offspring at exposures below maximum clinical exposure (AUC).

Treatment of major depressive episodes in adults.
Treatment of diabetic peripheral neuropathic pain in adults.
Treatment of generalized anxiety disorder (GAD) in adults.
Treatment of fibromyalgia (FM) with depression in adults.
Duloxetine is indicated for the treatment of chronic pain (CP) states associated with Diabetic Peripheral Neuropathic Pain (DPNP), Fibromyalgia (FM), Chronic Lower Back Pain (CLBP) and Osteoarthritis (OA).
Guidelines for diagnosis of Fibromyalgia using the American College of Rheumatology (ACR) 1990 Criteria for the Classification of Fibromyalgia: History of widespread pain.
Definition. Pain is considered widespread when all of the following are present: pain in the left side of the body, pain in the right side of the body, pain above the waist, and pain below the waist. In addition, axial skeletal pain (cervical spine or anterior chest or thoracic spine or low back) must be present. In this definition, shoulder and buttock pain is considered as pain for each involved side. "Low back" pain is considered lower segment pain.
Pain in 11 of 18 tender point sites on digital palpation.
Definition. Pain, on digital palpation, must be present in at least 11 of the following 18 sites: Occiput: Bilateral, at the suboccipital muscle insertions.
Low cervical: bilateral, at the anterior aspects of the intertransverse spaces at C5-C7.
Trapezius: bilateral, at the midpoint of the upper border.
Supraspinatus: bilateral, at origins, above the scapula spine near the medial border.
Second rib: bilateral, at the second costochondral junctions, just lateral to the junctions on upper surfaces.
Lateral epicondyle: bilateral, 2 cm distal to the epicondyles.
Gluteal: bilateral, in upper outer quadrants of buttocks in anterior fold of muscle.
Greater trochanter: bilateral, posterior to the trochanteric prominence.
Knee: bilateral, at the medial fat pad proximal to the joint line.
Digital palpation should be performed with an approximate force of 4 kg.
For a tender point to be considered "positive" the subject must state that the palpation was painful. "Tender is not to be considered "painful."
*For classification purposes, patients will be said to have fibromyalgia if both criteria are satisfied. Widespread pain must have been present for at least 3 months. The presence of a second clinical disorder does not exclude the diagnosis of fibromyalgia.

For oral use.
Major Depressive Episodes: The starting and recommended maintenance dose is 60 mg once daily with or without food.
Therapeutic response is usually seen after 2-4 weeks of treatment.
After consolidation of the antidepressive response, it is recommended to continue treatment for several months, in order to avoid relapse.
Diabetic Peripheral Neuropathic Pain: The starting and recommended maintenance dose is 60 mg daily with or without food.
Response to treatment should be evaluated after 2 months. In patients with inadequate initial response, additional response after this time is unlikely.
The therapeutic benefit should be reassessed regularly (at least every three months) (see Pharmacology: Pharmacodynamics under Actions).
Generalized Anxiety Disorder (GAD): The starting and recommended maintenance dose is 60 mg once daily with or without food.
Some patients may benefit from dosages above the recommended 60 mg once daily up to a maximum dose of 120 mg per day.
Fibromyalgia (FM) with Depression: The starting and recommended maintenance dose is 60 mg once daily with or without food.
Some patients may benefit from dosages above the recommended 60 mg once daily up to a maximum dose of 120 mg per day.
Chronic pain (CP): The starting and recommended maintenance dose is 60 mg once daily with or without food.
Some patients may benefit from dosages above the recommended 60 mg once daily up to a maximum dose of 120 mg per day.
Special Populations and General Information: Hepatic impairment: CYMBALTA should not be used in patients with liver disease resulting in hepatic impairment (see Contraindications and Pharmacology: Pharmacokinetics under Actions).
Renal insufficiency: No dosage adjustment is necessary for patients with mild or moderate renal dysfunction (creatinine clearance 30 to 80 ml/min). See Contraindications for severe renal impairment.
Elderly: Major Depressive Episodes: No dosage adjustment is recommended for elderly patients solely on the basis of age. However, as with any medicine, caution should be exercised when treating the elderly, especially with CYMBALTA 120 mg per day for which data are limited (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Diabetic Peripheral Neuropathic Pain: No dosage adjustment is recommended for elderly patients solely on the basis of age. However, caution should be exercised when treating the elderly (see Pharmacology: Pharmacokinetics under Actions).
Generalized Anxiety Disorder (GAD): CYMBALTA should be initiated 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. The maximum dose studied is 120 mg per day.
Children and adolescents: CYMBALTA is not indicated for use in patients under 18 years of age (see Precautions).
Discontinuation of treatment: Abrupt discontinuation should be avoided. When stopping treatment with CYMBALTA 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 (see Precautions and Adverse 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.

In clinical trials, cases of acute ingestions up to above 3000 mg, alone or in combination with other drugs, were reported with none being fatal. However, in post marketing experience, fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine only, at doses as low as approximately 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) 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.

Hypersensitivity to the active substance or to any of the excipients.
Concomitant use of CYMBALTA with nonselective, irreversible Monoamine Oxidase Inhibitors (MAOIs) is contraindicated (see Interactions).
Liver disease resulting in hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
CYMBALTA should not be used in combination with fluvoxamine, ciprofloxacin or enoxacine (i.e. potent CYP1A2 inhibitors) since the combination results in elevated plasma concentrations of duloxetine (see Interactions).
Severe renal impairment (creatinine clearance <30 ml/min).

Suicidality in Children and Adolescents: Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Cymbalta or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Cymbalta is not approved for use in pediatric patients. (See previous text and Precautions.)
Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials.

Hepatotoxicity: Cymbalta increases the risk of elevation of serum transaminase levels. Liver transaminase elevations resulted in the discontinuation of 0.4% (31/8454) of Cymbalta-treated patients. In these patients, the median time to detection of the transaminase elevation was about two months. In controlled trials in MDD, elevations of alanine transaminase (ALT) to >3 times the upper limit of normal occurred in 0.9% (8/930) of Cymbalta-treated patients and in 0.3% (2/652) of placebo-treated patients. In controlled trials in DPN, elevations of ALT to >3 times the upper limit of normal occurred in 1.68% (8/477) of Cymbalta-treated patients and in 0% (0/187) of placebo-treated patients. In the full cohort of placebo-controlled trials in any indication, 1% (39/3732) of Cymbalta-treated patients had a >3 times the upper limit of normal elevation of ALT compared to 0.2% (6/2568) of placebo-treated patients. In 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.
Elevations in liver enzymes were seen in some patients treated with duloxetine in clinical trials. These were usually transient and self-limiting, or resolved upon discontinuation of duloxetine. Severe elevations of liver enzymes (>10 times the upper limit of normal) or liver injury with a cholestatic or mixed pattern have been rarely reported, in some cases associated with excessive alcohol use or pre-existing liver disease. Duloxetine should be used with caution in patients with substantial alcohol use or pre-existing liver disease.
Postmarketing reports have described cases of 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. Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported. The combination of transaminase elevations and elevated bilirubin, without evidence of obstruction, is generally recognized as an important predictor of severe liver injury. In clinical trials, three Cymbalta patients had elevations of transaminases and bilirubin, but also had elevation of alkaline phosphatase, suggesting an obstructive process; in these patients, there was evidence of heavy alcohol use and this may have contributed to the abnormalities seen. Two placebo-treated patients also had transaminase elevations with elevated bilirubin.
Postmarketing reports indicate that elevated transaminases, bilirubin and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis. Because it is possible that duloxetine and alcohol may interact to cause liver injury or that duloxetine may aggravate preexisting liver disease, Cymbalta should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.
Although Cymbalta does not increase the impairment of mental and motor skills caused by alcohol, use of Cymbalta concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, Cymbalta should ordinarily not be prescribed for patients with substantial alcohol use.
Mania and seizures: CYMBALTA should be used with caution in patients with a history of mania or a diagnosis of bipolar disorder, and/or seizures.
Mydriasis: Mydriasis has been reported in association with duloxetine, therefore, caution should be used when prescribing CYMBALTA to patients with increased intraocular pressure, or those at risk of acute narrow-angle glaucoma.
Blood pressure and heart rate: Duloxetine is associated with an increase in blood pressure in some patients. This may be due to the noradrenergic effect of duloxetine. In patients with known hypertension and/or other cardiac disease, blood pressure monitoring is recommended, especially at the beginning 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.
Renal impairment: Increased plasma concentrations of duloxetine occur in patients with severe renal impairment on haemodialysis (creatinine clearance <30 ml/min). For patients with severe renal impairment, see Contraindications. See Dosage & Administration for information on patients with mild or moderate renal dysfunction.
Use with antidepressants: Caution should be exercised when using CYMBALTA in combination with antidepressants. In particular the combination with selective reversible MAOIs is not recommended.
St John's wort: Undesirable effects may be more common during concomitant use of CYMBALTA and herbal preparations containing St John's wort (Hypericum perforatum).
Suicide: Major Depressive Episodes: Depression is associated with an increased risk of suicidal thoughts, self harm and suicide. 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 with all antidepressant therapies that the risk of suicide may increase in the early stages of recovery. Cases of suicidal ideation and suicidal behaviours have been reported during duloxetine therapy or early after treatment discontinuation. Close supervision of high-risk patients should accompany drug therapy. Patients, (and caregivers of patients) should be alerted about the need to monitor for the emergence of suicidal ideation/behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present.
Diabetic Peripheral Neuropathic Pain: As with other medicinal products with similar pharmacological action (antidepressants), isolated cases of suicidal ideation and suicidal behaviours have been reported during duloxetine therapy or early after treatment discontinuation. Physicians should encourage patients to report any distressing thoughts or feelings at any time.
Sucrose: CYMBALTA hard gastro-resistant capsules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine.
Haemorrhage: There have been reports of bleeding abnormalities, such as ecchymoses, purpura, gastrointestinal haemorrhage and postpartum haemorrhage (see Use in Pregnancy & Lactation) with selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs). Caution is advised in patients taking anticoagulants and/or medicinal products known to affect platelet function, and in patients with known bleeding tendencies.
Hyponatremia: Hyponatremia has been reported rarely, predominantly in the elderly, when administering CYMBALTA. Caution is required in patients at increased risk for hyponatremia; such as elderly, cirrhotic, or dehydrated patients or patients treated with diuretics. Hyponatremia may be due to a syndrome of inappropriate anti-diuretic hormone secretion (SIADH).
Cases of hyponatremia (some with serum sodium lower than 110mmol/Liter) have been reported very rarely. The majority of these cases occurred in elderly patients, especially when coupled with a recent history of altered fluid balance or conditions pre-disposing to altered fluid balance. Hyponatremia may present with nonspecific signs and symptoms (such as dizziness, weakness, nausea, vomiting, confusion, somnolence, and lethargy). Signs and symptoms associated with more severe cases have included syncopal episodes, falls, and seizure.
Discontinuation of treatment: Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see Adverse Reactions). In clinical trials adverse events seen on abrupt treatment discontinuation occurred in approximately 45% of patients treated with CYMBALTA and 23% of patients taking placebo. The risk of withdrawal symptoms seen with SSRI's and SNRI's may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction. The most commonly reported reactions are listed in Adverse Reactions. Generally these symptoms are mild to moderate, however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that duloxetine should be gradually tapered when discontinuing treatment over a period of no less than 2 weeks, according to the patient's needs (see Dosage & Administration).
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 and it may be necessary to review the use of duloxetine.
Medicinal products containing duloxetine: Duloxetine is used under different trademarks in several indications (treatment of diabetic neuropathic pain, major depressive episodes as well as stress urinary incontinence). The use of more than one of these products concomitantly should be avoided.
Effects on ability to drive and use machines: Although in controlled studies duloxetine has not been shown to impair psychomotor performance, cognitive function, or memory, it may be associated with sedation and dizziness. Patients should be cautioned about their ability to drive a car or operate hazardous machinery.
Use in Children: CYMBALTA is not indicated for use in patients under the age of 18. Although a causal role for duloxetine in inducing such events has not been established, some analyses from pooled studies of antidepressants in psychiatric disorders found an increased risk for suicidal ideation and/or suicidal behaviors in pediatric and young adult (<25 years of age) patients compared to placebo. 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.
Use in the Elderly: Major Depressive Episodes: Data on the use of CYMBALTA 120mg in elderly patients with major depressive disorders are limited. Therefore, caution should be exercised when treating the elderly with the maximum dosage (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).

Pregnancy: There are no data on the use of duloxetine in pregnant women. Studies in animals have shown reproductive toxicity at systemic exposure levels (AUC) of duloxetine lower than the maximum clinical exposure (see Pharmacology: Toxicology: Preclinical safety data under Actions).
The potential risk for humans is unknown. As with other serotoninergic drugs, discontinuation symptoms (e.g. hypotonia, tremor, jitteriness, feeding difficulty, respiratory distress and seizures) may occur in the neonate after maternal duloxetine use near term. The majority of cases have occurred either at birth or within a few days of birth.
Using observational data, there is evidence of an increased risk (less than 2-fold) for postpartum haemorrhage following duloxetine exposure close to delivery.
CYMBALTA should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus. Women should be advised to notify their physician if they become pregnant, or intend to become pregnant, during therapy.
Breast feeding: Duloxetine is excreted into the milk of lactating women. The estimated daily infant dose on a mg/kg basis is approximately 0.14% of the maternal dose (see Pharmacology: Pharmacokinetics under Actions). Adverse behavioural effects were seen in offspring in a peri-post natal toxicity study in rats (see Pharmacology: Toxicology: Preclinical safety data under Actions). As the safety of duloxetine in infants is not known, the use of CYMBALTA while breast-feeding is not recommended.

Summary of the safety profile: The most commonly reported adverse reactions in patients treated with CYMBALTA were nausea, dry mouth and headache. However, the majority of common adverse reactions were mild to moderate, they usually started early in therapy, and most tended to subside even as therapy was continued.
Tabulated summary of adverse reactions: The tables give the adverse reactions observed from clinical trial data for all indication. (See Tables A and B.)

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Click on icon to see table/diagram/image

SPONTANEOUS DATA: Adverse drug reactions for all indications: The following list of undesirable effects (adverse drug reactions) is based on post-marketing spontaneous reports, and corresponding reporting rates have been provided.
Cardiac disorders: Very rarely (< 0.01%): Supraventricular arrhythmia.
Ear and Labyrinth Disorders: Very rarely (< 0.01%): Tinnitus upon treatment discontinuation.
Endocrine disorders: Very rarely (< 0.01%): Syndrome of Inappropriate Antidiuretic Hormone (SIADH).
Eye disorders: Very rarely (< 0.01%): Glaucoma.
Gastrointestinal Disorders: Very rarely (< 0.01%): Microscopic colitis.
Hepatobiliary disorders: Very rarely (< 0.01%): Hepatitis, jaundice.
Immune system disorders: Very rarely (< 0.01%): Anaphylactic reaction, hypersensitivity.
Investigations: Very rarely (< 0.01%): Alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, bilirubin increased.
Metabolism and nutrition disorders: Very rarely (< 0.01%): Hyponatremia, hyperglycemia (reported especially in diabetic patients).
Musculoskeletal and connective tissue disorders: Very rarely (< 0.01%): Trismus.
Nervous system disorders: Very rarely (< 0.01%): Extrapyramidal disorder, paraesthesia (including electric shock-like sensation) upon treatment discontinuation, restless legs syndrome, serotonin syndrome, seizures, seizures upon treatment discontinuation.
Psychiatric disorders: Rarely (≥ 0.01% -<0.1%): Hallucinations.
Very rarely (< 0.01%): Mania, aggression and anger, (particularly early in treatment or after treatment discontinuation).
Renal and urinary disorders: Rarely (≥ 0.01% -<0.1%): Urinary retention.
Reproductive system and breast disorders: Very rarely (< 0.01%): Gynecological bleeding, galactorrhea, hyperprolactinemia.
Skin and subcutaneous tissue disorders: Rarely (≥ 0.01% -<0.1%): Rash.
Very rarely (< 0.01%): Angioneurotic edema, contusion, cutaneous vasculitis (sometimes associated with systemic involvement), ecchymosis, Stevens-Johnson Syndrome, urticarial.
Vascular disorders: Very rarely (< 0.01%): Orthostatic hypotension (especially at the initiation of treatment), syncope (especially at initiation of treatment), hypertensive crisis.
Description of selected adverse reactions: Discontinuation symptoms have been reported when stopping duloxetine. The most commonly reported symptoms following abrupt or tapered discontinuation of duloxetine in clinical trials have include dizziness, nausea, headache, paresthesia, fatigue, vomiting, irritability, nightmares, insomnia, diarrhea, anxiety, hyperhidrosis, vertigo, somnolence and myalgia.
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 (see Dosage & Administration and Precautions).
Duloxetine treatment in placebo-controlled clinical trials was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, and potassium; infrequent, transient, abnormal values were observed for these analytes in duloxetine-treated patients, compared with placebo-treated patients.
Glucose Regulation: In three clinical trials of duloxetine for the treatment of diabetic peripheral neuropathic pain, the mean duration of diabetes was approximately 12 years, the mean baseline fasting blood glucose was 176 mg/dL, and the mean baseline hemoglobin A_1c (HbA_1c) was 7.81%. 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.
Electrocardiograms were obtained from 1139 duloxetine treated patients and 777 placebo-treated patients in 8-week clinical trials in major depressive disorder, and from 528 duloxetine-treated and 205 placebo-treated patients with diabetic neuropathic pain in clinical trials lasting up to 13-weeks. 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.
Effect on Blood Pressure: Cymbalta treatment, for up to 9-weeks in MDD placebo-controlled clinical trials of 40 to 120 mg daily doses caused increases in blood pressure, averaging 2 mm Hg systolic and 0.5 mm Hg diastolic compared to placebo and an increase in the incidence of at least one measurement of systolic blood pressure over 140 mm Hg.
Cymbalta treatment, for up to 9-weeks in MDD placebo-controlled clinical trials and for up to 13-weeks in DPN placebo-controlled trials caused a small increase in heart rate compared to placebo of about 2 beats per minute.

CNS medicinal products: the risk of using duloxetine in combination with other CNS-active medicinal products has not been systematically evaluated, except in the cases described as follows. Consequently, caution is advised when CYMBALTA is taken in combination with other acting medicinal products and substances including alcohol and sedative medicinal products (e.g. benzodiazepines, morphinomimetics, antipsychotics, phenobarbital, sedative antihistamines).
Monoamine Oxidase Inhibitors (MAOIs): due to the risk of serotonin syndrome, CYMBALTA should not be used in combination with nonselective irreversible monoamine oxidase inhibitors (MAOIs), or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of duloxetine, at least 5 days should be allowed after stopping CYMBALTA before starting an MAOI (see Contraindications).
For selective, reversible MAOIs, like moclobemide, the risk of serotonin syndrome is lower. However, the concomitant use of CYMBALTA with selective, reversible MAOIs is not recommended (see Precautions).
Serotonin syndrome: in rare cases, serotonin syndrome has been reported in patients using SSRIs (e.g. paroxetine, fluoxetine) concomitantly with serotonergic medicinal products. Caution is advisable if CYMBALTA is used concomitantly with serotonergic antidepressants like SSRIs, tricyclics like clomipramine or amitriptyline, St John's wort (Hypericum perforatum), venlafaxine or triptans, tramadol, pethidine and tryptophan may result in serotonin syndrome.
Effect of duloxetine on other drugs: Medicinal products metabolised by CYP1A2: in a clinical study, the pharmacokinetics of theophylline, a CYP1A2 substrate, were not significantly affected by co-administration with duloxetine (60 mg twice daily). The study was performed in males and it can not be excluded that females having a lower CYP1A2 activity and higher plasma concentrations of duloxetine may experience an interaction with a CYP1A2 substrate.
Medicinal products metabolised by CYP2D6: the co-administration of duloxetine (40 mg twice daily) increases steady state AUC of tolterodine (2 mg twice daily) by 71 %, but does not affect the pharmacokinetics of its 5-hydroxyl metabolite and no dosage adjustment is recommended. Caution is advised if CYMBALTA is co-administered with medicinal products that are predominantly metabolised by CYP2D6 if they have a narrow therapeutic index.
Oral contraceptives and other steroidal agents: results of in vitro studies demonstrate that duloxetine does not induce the catalytic activity of CYP3A. Specific in vivo drug interaction studies have not been performed.
Effects of other drugs on duloxetine: Antacids and H2 antagonists: co-administration of duloxetine with aluminium- and magnesium-containing antacids or duloxetine with famotidine had no significant effect on the rate or extent of duloxetine absorption after administration of a 40 mg oral dose.
Inhibitors of CYP 1A2: because CYP1A2 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP1A2 is likely to result in higher concentrations of duloxetine. Fluvoxamine (100 mg once daily), a potent inhibitor of CYP1A2, decreased the apparent plasma clearance of duloxetine by about 77% and increased AUC_o-t 6-fold. Therefore CYMBALTA should not be administered in combination with potent inhibitors of CYP1A2 like fluvoxamine (see Contraindications).
Inducers of CYP1A2: Population pharmacokinetic studies have shown that smokers have almost 50% lower plasma concentrations of duloxetine compared with non-smokers.
Warfarin and INR: Increases in INR have been reported when duloxetine was co-administered with warfarin.

Incompatibilities: Not applicable.

Store in the original package. Do not store above 30°C.

Drugs for Neuropathic Pain / Antidepressants

N06AX21 - duloxetine ; Belongs to the class of other antidepressants.

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