Cymbalta 30mg. 60mg Capsule

CYMBALTA is indicated for:

• The treatment of depression (as defined by DSM-IV criteria)
• The treatment of Diabetic Peripheral Neuropathic Pain (DPNP)

Posology

Depression

CYMBALTA should be initiated and maintained at a dose of 60 mg once daily without regard to meals. Although doses up to 120 mg per day have been used the efficacy of the 120 mg dose was not statistically different from that of the 60 mg once daily dose and the adverse event rate was higher with the 120 mg dose. Therapeutic response is usually seen after 2 to 4 weeks of treatment.

Diabetic peripheral neuropathic pain

CYMBALTA should be administered at a dose of 60 mg once daily without regard to meals. Although doses up to 120 mg per day have been used the efficacy of the 120 mg dose was not statistically significantly different from that of the 60 mg once daily dose and the adverse event rate was higher with the 120 mg dose. 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 section 5.1).

Special populations

Renal impairment

Initial dose should be 30 mg once daily in patients with mild to moderate impairment of renal function (see sections 4.3, 4.4 and 5.2).

Hepatic impairment

Initial dose should be 30 mg once daily in patients with mild to moderate impairment of hepatic function (see sections 4.3, 4.4 and 5.2).

Elderly

No dosage adjustment is recommended for elderly patients 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 depression, for which data are limited (see sections 4.4 and 5.2).

Paediatric population

CYMBALTA is not indicated for use in patients under 18 years of age.

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 sections 4.4 and 4.8). 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 medical practitioners may continue decreasing the dose, but at a more gradual rate.

Method of administration

For oral use.

CYMBALTA is contraindicated in patients with a known hypersensitivity to the active substance, duloxetine, or to any of the excipients, listed in section 6.1. Pregnancy and lactation (see section 4.6). Severe impairment of hepatic function (Child-Pugh C). Advanced renal impairment (creatinine clearance < 30 ml/min). Concomitant use of monoamine oxidase inhibitors (MAOIs) including linezolid (see section 4.4 and 4.5). Patients under 18 years of age.

Suicide

The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. Close supervision of high-risk patients should accompany initial medicine therapy. Cases of suicidal ideation and suicidal behaviours have been reported during CYMBALTA therapy or early after treatment discontinuation. CYMBALTA is not indicated for use in patients under the age of 18. Analyses from pooled studies of antidepressants such as CYMBALTA in psychiatric disorders found an increased risk for suicidal ideation and/or suicidal behaviours in paediatric and young adult (< 25 years of age) patients compared to placebo.

Medical practitioners should encourage patients to report any distressing thoughts or feelings at any time.

Activation of mania/hypomania

CYMBALTA should be used cautiously in patients with a history of mania or a diagnosis of bipolar disorder.

Seizures

CYMBALTA should be used cautiously in patients with a history of a seizure disorder.

Mydriasis

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

Renal or hepatic impairment

Increased plasma concentrations of CYMBALTA occur in patients with renal impairment or hepatic impairment. An initial dose of 30 mg once daily should be used in patients with renal impairment and those with mild to moderate hepatic impairment (Child-Pugh A and B) (see sections 4.2, 4.2 and 5.2).

Hepatitis/elevated liver enzymes

Elevations in liver enzymes, hepatitis and jaundice have been reported in patients treated with CYMBALTA. Severe elevations of liver enzymes (> 10 x upper limit of normal) or liver injury with a cholestatic or mixed pattern have been reported, in some cases associated with excessive alcohol use or pre-existing liver disease. CYMBALTA should be used with caution in patients with substantial alcohol use or pre-existing liver disease.

Blood pressure and heart rate

CYMBALTA is associated with an increase in blood pressure. In patients with known hypertension and/or other cardiac disease, blood pressure monitoring is recommended as appropriate. CYMBALTA 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 (see section 4.5). For patients who experience a sustained increase in blood pressure while receiving duloxetine either dose reduction or gradual discontinuation should be considered (see section 4.8). In patients with uncontrolled hypertension CYMBALTA should not be initiated.

Hyponatraemia

Cases of hyponatraemia (some with serum sodium lower than 110 mmol/litre) have been reported. 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. Hyponatraemia 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.

Haemorrhage

CYMBALTA, may increase the risk of bleeding events, such as ecchymoses, purpura and gastrointestinal bleeding (see section 4.8). CYMBALTA may increase the risk of postpartum haemorrhage (see section 4.6). Therefore, caution is advised in patients taking CYMBALTA concomitantly with anticoagulants and/or medicines known to affect platelet function (e.g. NSAIDs, aspirin) and in patients with known bleeding tendencies.

Serotonin syndrome

A potentially life-threatening condition may occur with CYMBALTA treatment, particularly with concomitant use of other serotonergic medicine (including SSRIs, SNRIs tricyclic antidepressants or triptans), with medicines that impair metabolism of serotonin such as MAOIs, or with antipsychotics or other dopamine antagonists that may affect the serotonergic neurotransmitter systems (see sections 4.3 and 4.5). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea). If concomitant treatment with CYMBALTA and other serotonergic medicines that may affect the serotonergic and/or dopaminergic neurotransmitter systems is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

St Johnu2019s wort

Adverse reactions may be more common during concomitant use of CYMBALTA and herbal preparations containing St Johnu2019s wort (Hypericum perforatum).

Discontinuation of treatment

Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8). 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 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 section 4.8. 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 to 3 months or more). It is therefore advised that CYMBALTA should be gradually tapered when discontinuing treatment over a period of no less than 2 weeks, according to the patientu2019s needs (see section 4.2).

Elderly

Data on the use of CYMBALTA 120 mg in elderly patients with depression are limited. Therefore, caution should be exercised when treating the elderly with the maximum dosage (see sections 4.2 and 5.2).

Akathisia/psychomotor restlessness

The use of CYMBALTA has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

Other 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.

Sexual dysfunction

CYMBALTA may cause symptoms of sexual dysfunction (see section 4.8). There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of CYMBALTA.

CYMBALTA contains sucrose

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially u2018sodium-freeu2019.

MAOIs (Monoamine Oxidase Inhibitors)

Due to the risk of serotonin syndrome, CYMBALTA should not be used concomitantly with a monoamine oxidase inhibitor (MAOI) including linezolid and moclobemide or within at least 14 days of discontinuing treatment with a MAOI. Based on the half-life of CYMBALTA, at least 5 days should be allowed after stopping CYMBALTA, before starting a MAOI (see section 4.3).

Inhibitors of CYP1A2

Because CYP1A2 is involved in CYMBALTA metabolism, concomitant use of CYMBALTA with inhibitors of CYP1A2 will result in higher concentrations of CYMBALTA. Fluvoxamine (100 mg once daily), a potent inhibitor of CYP1A2, decreased the apparent plasma clearance of CYMBALTA by about 77 %. Caution is advised if administering CYMBALTA with inhibitors of CYP1A2 (e.g. quinolone antibiotics) and a lower CYMBALTA dose should be used.

Inhibitors of CYP2D6

Because CYP2D6 is involved in CYMBALTA metabolism, concomitant use of CYMBALTA with inhibitors of CYP2D6 may result in higher concentrations of CYMBALTA. Paroxetine (20 mg once daily) decreased the apparent plasma clearance of CYMBALTA by about 37 %. Caution is advised if administering CYMBALTA with inhibitors of CYP2D6 (e.g. SSRIs).

CNS medicines

Caution is advised when CYMBALTA is taken in combination with other centrally acting medicines and substances, including alcohol and sedative medicinal products (e.g. benzodiazepines, morphinomimetics, antipsychotics, phenobarbital, sedative antihistamines).

Serotonergic medicines

Concomitant use of other medicines with serotonergic activity like SNRIs, SSRIs, tricyclic antidepressants like clomipramine or amitriptyline, MAOIs like moclobemide and linezolid, St Johnu2019s wort (Hypericum perforatum) or triptans, tramadol, pethidine and tryptophan may result in serotonin syndrome (see section 4.4).

Medicines highly bound to plasma protein

CYMBALTA is highly bound to plasma proteins (> 90 %). Therefore, administration of CYMBALTA to a patient taking another medicine that is highly protein bound may cause an increase in free concentrations of either medicine.

Effect of CYMBALTA on other medicines

Medicines metabolised by CYP1A2: In a clinical study, the pharmacokinetics of theophylline, a CYP1A2 substrate, were not significantly affected by co-administration with CYMBALTA (60 mg twice daily). These results suggest that CYMBALTA is unlikely to have a clinically significant effect on the metabolism of CYP1A2 substrates.

Medicines metabolised by CYP2D6: CYMBALTA is a moderate inhibitor of CYP2D6. When CYMBALTA was administered at the dose of 60 mg twice daily with a single dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold. The co-administration of CYMBALTA (40 mg twice daily) increased steady-state AUC of tolterodine (2 mg twice daily) by 71 % but did not affect the pharmacokinetics of the 5-hydroxyl metabolite. Therefore, caution should be used if CYMBALTA is co-administered with medications that are predominantly metabolised by the CYP2D6 system (risperidone and tricyclic antidepressants such as nortriptyline, amitriptyline and imipramine), and which have a narrow therapeutic index (such as flecainide, propafenone and metoprolol).

Oral contraceptives and other steroidal medicines: Results of in vitro studies demonstrate that CYMBALTA does not induce the catalytic activity of CYP3A. Specific in vivo medicine interaction studies have not been performed.

Anticoagulants and antiplatelet medicines: Caution should be exercised when CYMBALTA is combined with oral anticoagulants or antiplatelet medicines due to a potential increased risk of bleeding attributable to a pharmacodynamic interaction. Furthermore, increases in INR values have been reported when duloxetine was co-administered to patients treated with warfarin. However, concomitant administration of CYMBALTA with warfarin under steady state conditions, in healthy volunteers, as part of a clinical pharmacology study, did not result in a clinically significant change in INR from baseline or in the pharmacokinetics of R- or S-warfarin.

Pregnancy

Safety in pregnant women has not been established. CYMBALTA should not be used during pregnancy. Discontinuation symptoms (e.g. hypotonia, tremor, jitteriness, feeding difficulty, respiratory distress and seizures) may occur in the neonate after maternal CYMBALTA use near term (see section 4.3). In a study, maternal exposure to duloxetine during late pregnancy (at any time from 20 weeks gestational age to delivery) was associated with an increased risk for preterm birth (less than 2-fold, corresponding to approximately 6 additional premature births per 100 women treated with duloxetine late in pregnancy). The majority occurred between 35 and 36 weeks of gestation. Observational data have provided evidence of an increased risk (less than 2-fold) of postpartum haemorrhage following CYMBALTA exposure within the month prior to birth. Epidemiological data have suggested that the use of SSRIs, such as CYMBALTA, in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although no studies have investigated the association of PPHN to SNRI treatment, this potential risk cannot be ruled out with CYMBALTA taking into account the related mechanism of action (inhibition of the re-uptake of serotonin).

Breastfeeding

The safety of CYMBALTA has not been established in women who are breastfeeding their infants. CYMBALTA is excreted into the milk of lactating women. Women who are taking CYMBALTA should not breastfeed their infants (see section 4.3).

Fertility

In animal studies, CYMBALTA had no effect on male fertility, and effects in females were only evident at doses that caused maternal toxicity.

CYMBALTA may be associated with undesirable effects, such as sedation and dizziness. Therefore, patients should be cautioned about operating hazardous machinery, including automobiles, while taking CYMBALTA.

a. Summary of the safety profile

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

b. Tabulated summary of adverse reactions

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

Table 1: Adverse reactions

Frequency estimate: Very common ( u2265 1/10), common ( u2265 1/100 to < 1/10), uncommon ( u2265 1/1 000 to < 1/100), rare ( u2265 1/10 000 to < 1/1 000), very rare (< 1/10 000).

Very common

Common

Uncommon

Rare

Very Rare

Infections and infestations

Laryngitis

Immune system disorders

Anaphylactic reaction; Hyper-sensitivity disorder

Endocrine disorders

Hypothyroidism

Metabolism and nutrition disorders

Decreased appetite

Hyperglycaemia (reported especially in diabetic patients)

Dehydration; Hyponatraemia SIADH

Psychiatric disorders

Insomnia; Suicidal ideation; Suicidal

Agitation; Libido decreased; Anxiety; Orgasm abnormal; Abnormal dreams

Sleep disorder; Bruxism; Disorientation; Apathy behaviour; Mania; Hallucinations; Aggression and anger

Nervous system disorders

Headache; Somnolence; Dizziness; Lethargy; Tremor; Paraesthesia

Myoclonus; Akathisia; Nervousness; Disturbance in attention; Dysgeusia; Dyskinesia; Restless leg syndrome; Poor quality sleep

Serotonin syndrome; Convulsion; Psychomotor restlessness; Extra-pyramidal symptoms

Eye disorders

Vision blurred; Mydriasis; Glaucoma; Visual impairment

Ear and labyrinth disorders

Tinnitus; Vertigo; Ear pain

Cardiac disorders

Palpitations; Tachycardia; Supra-ventricular arrhythmia, mainly atrial fibrillation

Vascular disorders

Blood pressure increase; Flushing; Syncope; Hypertension; Orthostatic hypotension; Peripheral coldness; Hypertensive crisis

Respiratory, thoracic and mediastinal disorders

Yawning; Throat tightness; Epistaxis; Interstitial lung disease; Eosinophilic pneumonia

Gastrointestinal disorders

Nausea; Dry mouth; Constipation; Diarrhoea; Abdominal pain; Vomiting; Dyspepsia; Flatulence; Gastrointestinal haemorrhage; Gastroenteritis; Eructation; Gastritis; Dysphagia; Stomatitis; Haematochezia; Breath odour; Microscopic colitis

Hepato-biliary disorders

Hepatitis; Elevated liver enzymes (ALT, AST, alkaline phosphatase); Acute liver injury; Hepatic failure; Jaundice

Skin and subcutaneous disorders

Sweating increased; Rash; Night sweats; Urticaria; Dermatitis contact; Cold sweat; Photosensitivity reaction; Increased tendency to bruise; Stevens-Johnson Syndrome; Angio-neurotic oedema; Cutaneous vasculitis

Musculoskeletal and connective tissue disorders

Musculoskeletal pain; Muscle spasm; Muscle tightness; Muscle twitching; Trismus

Renal and urinary disorders

Dysuria; Pollakiuria; Urinary retention; Urinary hesitation; Nocturia; Polyuria; Urine flow decreased; Urine odour abnormal

Reproductive system and breast disorders

Erectile dysfunction; Ejaculation disorder; Ejaculation delayed; Gynaecological haemorrhage; Menstrual disorder; Sexual dysfunction; Testicular pain; Menopausal symptoms; Galactorrhoea; Hyperprolactinaemia; Postpartum haemorrhage

General disorders and administration site conditions

Falls; Fatigue; Chest pain; Feeling abnormal; Feeling cold; Thirst; Chills; Malaise; Feeling hot; Gait disturbance

Investigations

Weight decreased; Weight increased; Blood creatine phosphokinase increased; Blood potassium increased; Blood cholesterol increased

Cases of convulsion and cases of tinnitus have also been reported after treatment discontinuation. Cases of orthostatic hypotension and syncope have been reported especially at the initiation of treatment. See section 4.4. Cases of aggression and anger have been reported particularly early in treatment or after treatment discontinuation. Cases of suicidal ideation and suicidal behaviours have been reported during duloxetine therapy or early after treatment discontinuation (see section 4.4). Estimated frequency of post-marketing surveillance reported adverse reactions; not observed in placebo-controlled clinical trials.

Not statistically significantly different from placebo. Falls were more common in the elderly (u2265 65 years old). Estimated frequency based on all clinical trial data. Estimated frequency based on placebo-controlled clinical trials.

c. Description of selected adverse reactions

Discontinuation symptoms have been reported when stopping CYMBALTA. The most commonly reported symptoms following abrupt or tapered discontinuation of CYMBALTA in clinical trials have included dizziness, nausea and or vomiting, headache, paraesthesia or electric shock-like sensations particularly in the head, fatigue, vomiting, irritability, nightmares, insomnia, fatigue, somnolence, diarrhoea, agitation or anxiety, tremor, 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 sections 4.2 and 4.4). CYMBALTA treatment in placebo-controlled clinical trials was associated with mean increases from baseline to endpoint in ALT, AST and CPK and potassium. In some cases, abnormal values were observed for these analytes in CYMBALTA-treated patients compared with placebo-treated patients.

Glucose regulation: In three clinical trials of CYMBALTA for the treatment of diabetic neuropathic pain, the mean duration of diabetes was approximately 12 years, the mean baseline fasting blood glucose was 9,048 mmol/l (176 mg/dl) and the mean baseline haemoglobin A1c (HbA1C) was 7,81 %.

In the 12-week acute treatment phase of these studies, increases in fasting blood glucose were observed in CYMBALTA-treated patients. HbA1c was stable in both CYMBALTA-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 CYMBALTA and the routine care groups, but the mean increase was 0,3 % greater in the CYMBALTA treated group. There was also an increase in fasting blood glucose and in total cholesterol in CYMBALTA-treated patients.

Signs and symptoms

Fatal outcomes have been reported for acute overdoses at doses as low as approximately 1000 mg. Signs and symptoms of overdose (CYMBALTA alone or with mixed medicines) included somnolence, coma, serotonin syndrome, seizures, vomiting and tachycardia.

Management of overdose

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