Duloxetine

Registered South African indications:

• Depression (as defined by DSM-IV criteria) 
• Diabetic peripheral neuropathic pain (DPNP)

Contraindications

South African recommendations

Oral (cap)

• Hypersensitivity to duloxetine or to any of its excipients
• Severe impairment of hepatic function (Child-Pugh C)
• Advanced renal impairment (CrCl<30ml/min)
• Concomitant use of monoamine oxidase inhibitors (MAOIs) including linezolid
• Patients under 18 years of age
• Pregnancy
• Lactation

Oral (src)

• Known hypersensitivity to duloxetine or any of the ingredients
• Children under the age of 18 years
• Pregnancy
• Lactation
• Severe hepatic impairment
• Severe renal impairment (CrCl<30ml/min)
• Concomitant use of monoamine oxidase inhibitors (MAOIs) including linezolid
• Uncontrolled narrow angle glaucoma
• Uncontrolled hypertension
• In combination with fluvoxamine, ciprofloxacin or enoxacin (i.e., potent CYP1A2 inhibitors), since the combination results in elevated plasma concentrations of duloxetine

Recommendations in other jurisdictions

• Hypersensitivity to the active substance or to any of the excipients
• Concomitant use of duloxetine with non-selective, irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated
• Liver disease resulting in hepatic impairment
• Should not be used in combination with fluvoxamine, ciprofloxacin or enoxacin (i.e. potent CYP1A2 inhibitors) since the combination results in elevated plasma concentrations of duloxetine
• Severe renal impairment (creatinine clearance<30ml/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

Cautions

South African recommendations

• Mild to moderate renal impairment (CrCl≥30ml/min)
• Mild to moderate hepatic impairment
• Elderly
  - Recent history of, or condition predisposing to, altered fluid balance
  - Use of maximum dose
• History of bleeding disorders
  - Von Willebrand disease
  - Haemophilia A
  - Deficiency in F VIII
  - Haemophilia B
• Comorbid bleeding disorders
  - Multiple pregnancy
  - Gestational hypertension
  - Preeclampsia
• History of suicide-related events or exhibiting a significant degree of suicidal thoughts
• Other psychiatric and non-psychiatric disorders
• Known bleeding tendencies
• Increased intraocular pressure
• Risk of acute narrow angle glaucoma
• History of mania
• Bipolar disorder
• Seizures
• Known hypertension and/or other cardiac diseases
• Uncontrolled hypertension
• Abrupt withdrawal
• Substantial alcohol use
• Smoking
• Increased risk for hyponatraemia
  - Elderly
  - Cirrhotic patients
  - Dehydration
  - Coadministration with diuretics
• Conditions that may be compromised by an increased heart rate or by an increase in blood pressure
• Coadministration with other serotonergic agents, agents which impair metabolism of serotonin, antipsychotics, other dopamine antagonists 
• Coadministration with anticoagulants and/ or agents known to affect platelet function
• Coadministration with medicines that may impair its metabolism
• Coadministration with other duloxetine containing medicines (different trademarks)
• Coadministration with other medicines associated with hepatic injury
• Fructose intolerance
• Glucose-galactose malabsorption
• Sucrase-isomaltase insufficiency
• May impair ability to drive and operate machinery

Recommendations in other jurisdictions

• Pregnancy
• Breastfeeding
• Elderly
  - Recent history of, or condition predisposing to, altered fluid balance
  - Use of maximum dose
• History of mania
• Bipolar disorder
• Seizures
• Increased intraocular pressure
• Risk of acute narrow-angle glaucoma
• Known hypertension and/or other cardiac diseases
• Conditions that may be compromised by an increased heart rate or by an increase in blood pressure
• History of suicide-related events or exhibiting a significant degree of suicidal thoughts
• Other psychiatric disorders
• Children
  - Prolonged use
• Known bleeding tendencies
• Abrupt withdrawal
• Smoking
• Increased risk for hyponatraemia
  - Elderly
  - Cirrhotic patients
  - Dehydration
  - Coadministration with diuretics
• Coadministration with medicines that may impair its metabolism
• Coadministration with other serotonergic agents, agents which impair metabolism of serotonin, antipsychotics, other dopamine antagonists
• Coadministration with anticoagulants and/ or agents known to affect platelet function
• Coadministration with other duloxetine containing medicines (different trademarks)
• Coadministration with other medicines associated with hepatic injury
• Fructose intolerance
• Glucose-galactose malabsorption
• Sucrase-isomaltase insufficiency
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: cap, src

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Depression (as defined by DSM-IV criteria) 
Diabetic peripheral neuropathic pain (DPNP)

• Oral (cap, src): Initial: 60mg, dly without regard to meals; Maintenance: 60-120mg, dly; Max: 120mg/24hrs

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Although doses up to 120mg per day have been used, the efficacy of the 120mg dose was not statistically different from that of the 60mg once daily dose and the adverse event rate was higher with the 12 mg dose

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Depression (cap): Therapeutic response is usually seen after 2-4 weeks of treatment

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DPNP (cap): 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 3 months)

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Gradually taper dose over at least 1-2 weeks when discontinuing
See additional prescribing points

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Indications and dosages registered in other jurisdictions

Major depressive disorder

• Oral (cap): Initial: 60mg, dly without regard to meals; Maintenance: 60-120mg, dly; Max: 120mg/24hrs 

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Dosages >60mg, dly, up to a max dose of 120mg/day have been evaluated from a safety perspective in clinical trials. However, there is no clinical evidence suggesting that patients not responding to the initial recommended dose may benefit from dose up-titrations

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Therapeutic response usually seen after 2-4 weeks of treatment

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After consolidation of the antidepressive response, it is recommended to continue treatment for several months, in order to avoid relapse. In patients responding to duloxetine, and with a history of repeated episodes of major depression, further long-term treatment at a dose of 60-120mg/day could be considered

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Diabetic peripheral neuropathy pain

• Oral (cap): Initial: 60mg, dly without regard to meals; Titrate up to 120mg in evenly divided doses; Maintenance: 60-120mg, dly; Max: 120mg/24hrs 

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Dosages above 60mg, dly, up to a max dose of 120mg/day administered in evenly divided doses, have been evaluated from a safety perspective in clinical trials. The plasma concentration of duloxetine displays large inter-individual variability. Hence, some patients that respond insufficiently to 60mg may benefit from a higher dose

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Response to treatment should be evaluated after 2 months. In patients with inadequate initial response, additional response after this time is unlikely

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The therapeutic benefit should be reassessed regularly (at least every 3 months)

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Generalised anxiety disorder

• Oral (cap): Initial: 30mg, dly without regard to meals; If insufficient response: Increase to 60mg, dly 

- Co-morbid major depressive disorder

• Oral (cap): Initial: 60mg, dly without regard to meals; If insufficient response: Increase to 90-120mg based upon clinical response and tolerability; Max: 120mg/24hrs
  (Also see: Major depressive disorder recommendations above)

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Doses up to 120mg/day have been shown to be efficacious and have been evaluated from a safety perspective in clinical trials

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Dose escalation should be based upon clinical response and tolerability

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After consolidation of the response, it is recommended to continue treatment for several months, in order to avoid relapse

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

• Contraindicated

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Duloxetine should not be used in the treatment of children and adolescents under the age of 18 years

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Indications and dosages registered in other jurisdictions

• Not established for use in patients below 18 years

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Duloxetine should not be used in children and adolescents under the age of 18 years for the treatment of major depressive disorder because of safety and efficacy concerns

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The safety and efficacy of duloxetine for the treatment of generalised anxiety disorder in paediatric patients aged 7-17 years have not been established

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The safety and efficacy of duloxetine for the treatment of diabetic peripheral neuropathic pain has not been studied. No data are available

Pregnancy

South African recommendations

• Contraindicated
• Safety of duloxetine in pregnant women has not been established
• Observational data have provided evidence of an increased risk (less than 2-fold) of postpartum haemorrhage following exposure to duloxetine within the month prior to birth
• Epidemiological data have suggested that the use of SSRIs 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 duloxetine, taking into account the related mechanism of action (inhibition of the re-uptake of serotonin)
• Discontinuation symptoms may occur in the neonate after maternal duloxetine use near term. Discontinuation symptoms seen with duloxetine may include hypotonia, tremor, jitteriness, feeding difficulty, respiratory distress and seizures. The majority of cases have occurred either at birth or within a few days of birth
• Postpartum haemorrhage (PPH) is a leading cause of maternal mortality. Treatment with SSRIs and SNRIs within one month prior to birth may increase the risk of PPH
• Observational data indicate an increased risk of PPH following SSRI/ SNRI exposure within the month prior to delivery. Healthcare professionals should be aware of the potential risk of PPH while making treatment decisions for prescribing SSRI/ SNRI towards the end of pregnancy

Recommendations in other jurisdictions

• Caution
• Studies in animals have shown reproductive toxicity at systemic exposure levels (AUC) of duloxetine lower than the maximum clinical exposure
• Two large observational studies do not suggest an overall increased risk of major congenital malformation (one from the US including 2,500 exposed to duloxetine during the first trimester and one from the EU including 1,500 exposed to duloxetine during the first trimester). The analysis on specific malformations such as cardiac malformations shows inconclusive results
• In the EU 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. This association was not seen in the US study
• The US observational data have provided evidence of an increased risk (less than 2-fold) of postpartum haemorrhage following duloxetine exposure within the month prior to birth
• Epidemiological data have suggested that the use of SSRIs 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 duloxetine taking into account the related mechanism of action (inhibition of the re-uptake of serotonin)
• As with other serotonergic medicinal products, discontinuation symptoms may occur in the neonate after maternal duloxetine use near term. Discontinuation symptoms seen with duloxetine may include hypotonia, tremor, jitteriness, feeding difficulty, respiratory distress and seizures. The majority of cases have occurred either at birth or within a few days of birth
• Duloxetine 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

Breastfeeding

South African recommendations

• Contraindicated
• Safety of duloxetine during breastfeeding has not been established
• Duloxetine and/or its metabolites are excreted into the milk

Recommendations in other jurisdictions

• Caution; not recommended
• Duloxetine is very weakly excreted into human milk based on a study of 6 lactating patients, who did not breastfeed their children. The estimated daily infant dose on a mg/kg basis is approximately 0.14% of the maternal dose. As the safety of duloxetine in infants is not known, the use of duloxetine while breastfeeding is not recommended

Fertility

South African recommendations

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

Recommendations in other jurisdictions

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

Renal Impairment

South African recommendations

• Mild to moderate (CrCl≥30ml/min): Caution; dose adjustment recommended 
  Oral (cap): Initial: 30mg, dly
• Severe (CrCl<30ml/min): Contraindicated 

Recommendations in other jurisdictions

• Mild to moderate: No dose adjustment recommended
• Severe: Contraindicated

Hepatic Impairment

South African recommendations

• Mild to moderate: Caution; dose adjustment recommended 
  The initial dose should be lower or less frequent
• Severe: Contraindicated 

Recommendations in other jurisdictions

• Contraindicated

Elderly

South African recommendations

• Caution; no dose adjustment recommended 
  Caution should be exercised when treating elderly patients, especially with a dose of 120mg, dly for depressive disorder, for which data are limited

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended
  Caution should be exercised when treating the elderly, especially with duloxetine 120mg, dly for major depressive disorder or generalised anxiety disorder, for which data are limited

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Insomnia
• Agitation
• Anxiety
• Abnormal dreams
• Suicidal ideation
• Sleep disorder
• Disorientation
• Apathy
• Suicidal behaviour
• Mania
• Hallucinations
• Aggression
• Headache
• Somnolence
• Dizziness
• Tremor
• Paraesthesia
• Myoclonus
• Disturbances in attention
• Restless legs syndrome
• Serotonin syndrome
• Seizures
• Extrapyramidal symptoms
• Yawning
• Bruxism
• Gait disturbances

Cardiovascular Disorders

• Palpitations
• Tachycardia
• Supraventricular arrhythmias
• Flushing
• Syncope
• Hypertension
• Orthostatic hypotension
• Peripheral coldness
• Hypertensive crisis
• Chest pain

Respiratory Disorders

• Laryngitis
• Throat tightness
• Epistaxis

Gastrointestinal Disorders

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

Hepatobiliary Disorders

• Hepatitis
• Increased hepatic enzymes
• Acute hepatic injury
• Hepatic failure
• Jaundice

Genitourinary Disorders

• Dysuria
• Pollakiuria
• Urinary retention
• Urinary hesitation
• Nocturia
• Polyuria
• Decreased urine flow
• Abnormal urine odour
• Sexual dysfunction
• Ejaculation disorder
• Abnormal orgasm
• Gynaecological haemorrhage
• Menstrual disorder
• Testicular pain
• Decreased libido

Endocrine and Metabolic Disorders

• Decreased weight
• Increased weight
• Galactorrhoea
• Hyperprolactinaemia
• Menopausal symptoms
• Hypothyroidism
• Decreased appetite
• Hyperglycaemia 
• Dehydration
• Hyponatraemia
• Syndrome of inappropriate antidiuretic hormone secretion
• Increased serum creatine phosphokinase
• Hyperkalaemia

Musculoskeletal Disorders

• Musculoskeletal pain
• Muscle spasm
• Muscle tightness
• Muscle twitching
• Trismus

Skin and Subcutaneous Tissue Disorders

• Increased sweating
• Rash
• Night sweats
• Urticaria
• Contact dermatitis
• Cold sweat
• Photosensitivity reactions
• Stevens-Johnson Syndrome
• Cutaneous vasculitis

Immune, Blood and Lymphatic System Disorders

• Anaphylactic reactions
• Hypersensitivity disorders
• Angioneurotic oedema
• Fever

Sensory Disorders

• Dysgeusia
• Blurred vision
• Mydriasis
• Visual impairment
• Glaucoma
• Tinnitus
• Vertigo
• Ear pain

• Monoamine oxidase inhibitors
• Linezolid
• Fluvoxamine
• Ciprofloxacin
• Enoxacin
• CYP1A2 inhibitors
• CYP1A2 inducers
• Central nervous system depressants
• Serotonergic agents
• CYP2D6 substrates
• Anticoagulants
• Antiplatelet agents
• Oral contraceptives

Other interactions

• St John's wort

• Blood pressure

Specific cases may require

• Blood glucose
• Renal function
• Hepatic function
• Vital signs

Additional observations

• Blood loss
• Signs of anaemia
  - Fatigue
  - Shortness of breath
  - Chest pain
  - Lactation problems

Risk of postpartum haemorrhage (PPH)

• PPH is a leading cause of maternal mortality. Treatment with SSRIs and SNRIs within one month prior to birth may increase the risk of PPH
• Observational data indicate an increased risk of PPH following SSRI/ SNRI exposure within the month prior to delivery
• Healthcare professionals should be aware of the potential risk of PPH while making treatment decisions for prescribing SSRI/ SNRI towards the end of pregnancy
• Patients should be advised to inform their doctors before taking SSRI/ SNRI containing medicines if they have history of bleeding disorders (e.g von Willebrand disease, haemophilia A, deficiency in F VIII, and haemophilia B); and comorbid bleeding disorders (e.g multiple pregnancy, gestational hypertension or preeclampsia)

Diabetic peripheral neuropathy

• The safety and efficacy of duloxetine for the treatment of diabetic peripheral neuropathic pain has not been studied. No data are available
• Response to treatment should be evaluated after 2 months. In patients with inadequate initial response, additional response after this time is unlikely

Discontinuation of treatment

• Abrupt discontinuation of duloxetine should be avoided. When stopping treatment with duloxetine 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 doctor may continue decreasing the dose, but at a more gradual rate

Duloxetine is a combined serotonin and noradrenaline reuptake inhibitor. It weakly inhibits dopamine reuptake, with no significant affinity for histaminergic, dopaminergic, cholinergic, and adrenergic receptors. This results in an antidepressant and analgesic action due to its potentiation of serotonergic and noradrenergic activity in the central nervous system.

Capsule 30mg

• Cymbalta (Eli Lilly) originator
• Cymgen 30 (Pharmacare) originator
• Deotin 30 (Cipla Medpro)
• DRL Duloxetine (Dr Reddy's)
• Dueloks 30 (Innovata Pharmaceuticals)
• Duleve 30 (Zydus Healthcare SA)
• Duloxetine 30mg Mylan (Mylan)
• Duloxetine DR 30mg Austell (Austell Laboratories)
• Duloxetine MR 30 Unicorn (Unicorn Pharmaceuticals)
• Dulta 30 (Pharma Dynamics)
• Duzela 30 (Ranbaxy Pharmaceuticals)
• Yelate (Dr Reddy's)

Capsule 60mg

• Cymbalta (Eli Lilly) originator
• Cymgen 60 (Pharmacare) originator
• Deotin 60 (Cipla Medpro)
• DRL Duloxetine (Dr Reddy's)
• Dueloks 60 (Innovata Pharmaceuticals)
• Duleve 60 (Zydus Healthcare SA)
• Duloxetine 60mg Mylan (Mylan)
• Duloxetine DR 60mg Austell (Austell Laboratories)
• Duloxetine MR 60 Unicorn (Unicorn Pharmaceuticals)
• Dulta 60 (Pharma Dynamics)
• Duzela 60 (Ranbaxy Pharmaceuticals)
• Yelate (Dr Reddy's)