Pharmacotherapeutic Group: Other antidepressants. ATC Code: N06AX21.
Pharmacology: Pharmacodynamics: Mechanism of action: Cymbalta 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. Cymbalta dose-dependently increases extracellular levels of serotonin and noradrenaline in various brain areas of animals.
Pharmacodynamic effects: Cymbalta 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 Cymbalta is believed to be a result of potentiation of descending inhibitory pain pathways within the central nervous system.
Clinical efficacy and safety: Major Depressive Disorder: Cymbalta was studied in a clinical programme involving 3,158 patients (1,285 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 three out of three randomised, 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 five out of seven randomised, 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 Cymbalta and placebo, respectively.
During 52 weeks of placebo-controlled double blind treatment, Cymbalta-treated patients with recurrent major depressive disorder had a significantly longer symptom free period (p<0.001) compared with patients randomised to placebo. All patients had previously responded to Cymbalta during open-label Cymbalta treatment (28 to 34 weeks) at a dose of 60 to 120 mg/day. During the 52-week placebo-controlled double blind treatment phase 14.4% of the Cymbalta-treated patients and 33.1% of the placebo-treated patients experience a return of their depressive symptoms (p<0.001).
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 significant difference in the reduction of the HAM-D17 score for Cymbalta-treated patients compared to placebo. Tolerability of Cymbalta 60 mg once daily 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.
Generalised Anxiety Disorder: Cymbalta demonstrated statistically significant superiority over placebo in five out of five studies including four randomised, double-blind, placebo-controlled acute studies and a relapse prevention study in adult patients with generalised anxiety disorder.
Cymbalta demonstrated statistically significant superiority over placebo as measured by improvement in the Hamilton Anxiety Scale (HAM-A) total score and by the Sheehan Disability Scale (SDS) global functional impairment score. Response and remission rates were also higher with Cymbalta compared to placebo. Cymbalta showed comparable efficacy results to venlafaxine in terms of improvements on the HAM-A total score.
In a relapse prevention study, patients responding to 6 months of acute treatment with open-label Cymbalta were randomised to either Cymbalta or placebo for a further 6-months. Cymbalta 60 mg to 120 mg once daily demonstrated statistically significant superiority compared to placebo (p<0.001) on the prevention of relapse, as measured by time to relapse. The incidence of relapse during the 6-months double-blind follow-up period was 14% for Cymbalta and 42% for placebo.
The efficacy of Cymbalta 30-120 mg (flexible dosing) once a day in elderly patients (>65 years) with generalised anxiety disorder was evaluated in a study that demonstrated statistically significant improvement in the HAM-A total score for Cymbalta-treated patients compared to placebo-treated patients. The efficacy and safety of Cymbalta 30-120 mg once daily in elderly patients with generalised anxiety disorder was similar to that seen in studies of younger adult patients. However, data on elderly patients exposed to the maximum dose (120 mg per day) are limited and, thus, caution is recommended when using this dose with the elderly population.
Diabetic Peripheral Neuropathic Pain: The efficacy of Cymbalta as a treatment for diabetic peripheral neuropathic pain was established in 2 randomised, 12-weeks, double-blind, placebo-controlled, fixed dose studies in adults (22 to 88 years) having diabetic peripheral 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, Cymbalta 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 Cymbalta-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 Cymbalta and 27% of patients on placebo. Clinical response rates in patients experiencing somnolence were 60% on Cymbalta 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.
Fibromyalgia: The efficacy of Cymbalta was demonstrated in 2 randomised, double-blind, placebo-controlled studies in adult patients with fibromyalgia with or without depression meeting the American College of Rheumatology criteria for fibromyalgia.
In a 3-month study, Cymbalta 60 mg once daily and 60 mg twice daily demonstrated statistical superiority over placebo as measured by improvement on the Brief Pain Inventory (BPI) average pain score. In a 6-month study Cymbalta 60 mg once daily and 120 mg once daily demonstrated statistical superiority over placebo at both 3 and 6 months as measured by improvement in the BPI average pain score. In both studies the pain reduction was apparent after 1 week of treatment. Using pooled data from the two studies at 3 months, approximately 53% of Cymbalta-treated patients versus 27% of placebo treated patients recorded clinically relevant pain relief measured as at least 30% pain reduction. The corresponding figures for at least 50% pain reduction were 39% and 23% respectively. The improvement was irrespective of presence or absence of depression, and depression symptoms, as measured by the HAM-D17, also significantly improved. Confirmation of the clinical relevance of the pain reduction was shown by statistical superiority over placebo in overall patient wellbeing as measured by the Patient rated Global Impression of Improvement (PGI-I) score.
Patients also demonstrated statistically significant improvements compared with placebo in clinician rated overall improvement as measured by the Clinical Global Impression (CGI) Severity Scale, pain interference as measured by the BPI Average Interference score, functioning as measured by the Fibromyalgia Impact Questionnaire (FIQ total score) and mental fatigue as measured by the Multidimensional Fatigue Inventory (MFI) Mental Fatigue Domain.
In a long-term uncontrolled study the safety profile and initial improvement in the BPI average pain score observed after 8 weeks of treatment was maintained for up to one additional year.
Pharmacokinetics: Cymbalta is administered as a single enantiomer. Cymbalta is extensively metabolised by oxidative enzymes (CYP1A2 and the polymorphic CYP2D6), followed by conjugation. The pharmacokinetics of Cymbalta demonstrate large intersubject variability (generally 50-60%), partly due to gender, age, smoking status and CYP2D6 metaboliser status.
Absorption: Cymbalta is well absorbed after oral administration with a Cmax occurring 6 hours post dose. The absolute oral bioavailability of Cymbalta 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: Cymbalta is approximately 96% bound to human plasma proteins. Cymbalta binds to both albumin and alpha-l acid glycoprotein. Protein binding is not affected by renal or hepatic impairment.
Biotransformation: Cymbalta 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 Cymbalta are considered pharmacologically inactive. The pharmacokinetics of Cymbalta in patients who are poor metabolisers with respect to CYP2D6 has not been specifically investigated. Limited data suggest that the plasma levels of Cymbalta are higher in these patients.
Elimination: The elimination half-life of Cymbalta ranges from 8 to 17 hours (mean of 12 hours). After an intravenous dose the plasma clearance of Cymbalta ranges from 22 to 46 l/hr (mean of 36 l/hr). After an oral dose the apparent plasma clearance of Cymbalta ranges from 33 to 261 l/hr (mean 101 l/hr).
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 (see Dosage & Administration and Precautions).
Renal impairment: End stage renal disease (ESRD) patients receiving dialysis had 2-fold higher Cymbalta Cmax and AUC values compared with healthy subjects. Pharmacokinetic data on Cymbalta is limited in patients with mild or moderate renal impairment.
Hepatic impairment: Moderate liver disease (Child Pugh Class B) affected the pharmacokinetics of Cymbalta. Compared with healthy subjects, the apparent plasma clearance of Cymbalta 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 Cymbalta and its metabolites have not been studied in patients with mild or severe hepatic insufficiency.
Breast-feeding mothers: The disposition of Cymbalta was studied in 6 lactating women who were at least 12-weeks postpartum. Cymbalta is detected in breast milk, and steady-state concentrations in breast milk are about one-fourth those in plasma. The amount of Cymbalta in breast milk is approximately 7 μg/day while on 40 mg twice daily dosing. Lactation did not influence Cymbalta pharmacokinetics.
Toxicology: Preclinical safety data: Cymbalta 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 Cymbalta 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 Cymbalta (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, Cymbalta induced adverse behavioural effects in the offspring at exposures below maximum clinical exposure (AUC).