Brand name
- CYMBALTA®
Drug Class
- Analgesic
- Anti-depressant
- Anxiolytic
Preparations
- Delayed Release Capsules 30 mg and 60 mg
Indications
- Major Depressive Disorder: (Adults)
- Neuropathic Pain Associated with Diabetic Peripheral Neuropathy
- Fibromyalgia
- Chronic Pain Associated with Osteoarthritis (OA) of the Knee
- Generalized Anxiety Disorder (GAD)
- Chronic Low Back Pain
Pharmacology
1. Mechanism of action: serotonin and nor-epinephrine re-uptake inhibitor + weakly inhibits dopamine uptake
2. Pharmacodynamic:
- Effectiveness in the treatment of depression: inhibition of central nervous system (CNS) neuronal uptake of serotonin and norepinephrine
- Pain inhibitory action: potentiation of descending inhibitory pain pathways within the central nervous system
Metabolism
Absorption:
- Orally
- Maximal plasma concentrations: 6 Hours
Distribution:
- Duloxetine is highly bound (>90%) to proteins in human plasma
Metabolism:
- Both CYP2D6 and CYP1A2 catalyze
Excretion:
- 72% in urine & 19% in feces
- less than 1% remains unchanged in urine.
Dosing
Adults:
- Major Depressive Disorder:
- Initial dose: 30 mg/day
- Maintenance and Max dose: 60 mg/day, Increase within 1-2 weeks. (No benefit more dosage than that)
- Therapeutic response is usually seen after 1-4 weeks of treatment
- Generalized Anxiety Disorder:
- Initial dose: 30 mg/day
- Maintenance dose: 60 mg/day, Increase within 1-2 weeks.
- Therapeutic response is usually seen after 1-4 weeks of treatment
- Max Dose: 120 mg/day
- Neuropathic Pain Associated with Diabetic Peripheral Neuropathy:
- Initial dose: 30 mg/day
- Maintenance dose: 60 mg/day, Increase within 1-2 weeks.
- Therapeutic response is usually seen after 1-4 weeks of treatment
- Max Dose: 120 mg/day
- Fibromyalgia:
- Initial dose: 30 mg/day
- Maintenance dose: 60 mg/day, Increase within 1-2 weeks.
- Therapeutic response is usually seen after 1-4 weeks of treatment
- Max Dose: 120 mg/day >>>> higher than 60 mg/day severe & frequent rate of adverse effects.
- Chronic Pain Associated with Osteoarthritis of the Knee:
- Initial dose: 30 mg/day
- Maintenance dose: 60 mg/day, Increase within 1-2 weeks.
- Therapeutic response is usually seen after 1-4 weeks of treatment
- Max Dose: 120 mg/day
Drug Interactions
- Triptans (5Ht1 Agonists)
- Tramadol
- MAOIs
- Warfarin, ASA, NSAIDs
- SSRIs: fluvoxamine – Paroxetine
- Anti-arrhythmics Flecainide and Encainide
- John’s wort
- Thioridazine
- Tricyclic Antidepressants
- Medications have highly plasma protein binding affinity
- Benzodiazepines
- Smoking
Adverse Effects
More than 10% :
- Nausea
- Dry Mouth
- Headache
- Somnolence
- Fatigue
- Dyspepsia
Less than 10% :
- Constipation
- Diarrhea
- Insomnia
- Dizziness
- Anorexia
- Decreased appetite
- Akathisia/Psychomotor Restlessness: occur within the first few weeks mostly >>> Decrease the dose
- Bone Fracture Risk
- Increases the risk of elevation of serum aminotransferase levels
- Cardiovascular: Significant hypertension
- Sedation
- Dizziness
- Sexual Dysfunction ( Decreased Libido & Ejaculation dysfunction)
- Serious Skin Reactions: Stevens-Johnson Syndrome
- Musculoskeletal pain
Contraindications
- Hypersensitivity
- Monoamine Oxidase Inhibitors (MAOIs): eg; Antibiotic Linezolid + Thiazine dye methylthioninium chloride (methyleneblue)
- Hepatic Impairment
- Uncontrolled Narrow-Angle Glaucoma
- Severe Renal Impairment: Creatinine clearance <30 mL/min
- Thioridazine
- CYP1A2 Inhibitors: fluvoxamine & Quinolone antibiotics >>> Ciprofloxacin or Enoxacin
- Monoamine Oxidase Inhibitors (MAOIs): within at least 14 days of discontinuing treatment with a MAOI
- Hepatic Impairment: CYMBALTA is contraindicated in patients with any liver disease resulting in hepatic impairment
- Thioridazine: prolongation of the QTc interval >>> ventricular arrhythmias >>> torsades de pointes >>> sudden death
- Sucrose: Patients with:
- fructose intolerance,
- glucose-galactose malabsorption
- sucrose-isomaltase insufficiency
Pregnancy and Breastfeeding
- Pregnancy: Category C
- Lactation: Not Recommended in nursing women
Precautions
1. Should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
2. Geriatrics: usage with caution (≥65 years of age)
3. Pediatrics (<18 years of age):
- May be associated with behavioural and emotional changes >>> increased risk of suicidal ideation
4. Monoamine Oxidase Inhibitors (MAOIs):
- Not to use within 14 days of discontinuing treatment with a MAOI >>> increase the risk of Neuroleptic Malignant syndrome and Serotonin syndrome
5. Potential Association with Behavioural and Emotional Changes, Including Self-Harm >>> Suicidal / Homicidal ideation.
6. Akathisia/Psychomotor Restlessness:
- Occur within the first few weeks mostly.
7. Discontinuation Symptoms:
- Should be discontinued abruptly if:
- Dizziness, Nausea, Headache, Paresthesia, Fatigue, Vomiting, Irritability, Nightmare, Insomnia, Diarrhea, Anxiety, Hyperhidrosis, Vertigo, Somnolence, & myalgia.
8. Increases the risk of elevation of serum aminotransferase levels:
- Be aware of the signs and symptoms of liver damage:
- Pruritus, dark urine, jaundice, right upper quadrant tenderness/ unexplained “flu-like” symptoms >>>> CYMBALTA should be discontinued and should not be restarted in patients with jaundice.
9. Concomitant use with Thioridazine:
- Prolongation of the QTc interval >>> ventricular arrhythmias >>> torsade de pointes >>> sudden death
10. CYMBALTA capsules contain sucrose:
- Patients fructose intolerance, glucose-galactose malabsorption / sucrose-isomaltase insufficiency >>> should not take this medicine.
11. Bone Fracture Risk:
- Elderly patients & patients with important risk factors for bone fractures: >>> should be advised of possible adverse events which increase the risk of falls:
- Dizziness and orthostatic hypotension, especially at the early stages of treatment & soon after withdrawal.
12. Cardiovascular:
- Might increase in blood pressure & clinically significant hypertension (Cause: noradrenergic effect):
- Use with caution in patients with uncontrolled hypertension
- Blood pressure & heart rate should be evaluated prior to initiating treatment & throughout treatment.
13. Diabetic gastroparesis:
- Caution should be exercised in using CYMBALTA in patients with conditions that slow gastric emptying like Diabetic gastroparesis.
14. Dependence Liability:
- Carefully evaluate patients for a history of drug abuse & follow them closely:
- Duloxetine abuse/misuse>>> Drug seeking behaviours
15. Glycemic control:
- CYMBALTA treatment may worsen glycemic control in diabetic patients >>> HbA1C may increase by 0.5%.
16. Abnormal Bleeding:
- SNRIs, including CYMBALTA, may increase the risk of bleeding events >>> abnormal platelet aggregation:
- Caution in concomitant use with ASA, Warfarin & NSAIDs
17. Reversible Hyponatremia:
- May be the result of Syndrome of Inappropriate ADH (SIADH) >>> Discontinue in symptomatic patients.
18. Seizure:
- Used with caution in patients with a history of a seizure disorder.
19. Avoid driving and / Using Machines:
- Because of psychomotor impairment effect
20. Activation of Mania/Hypomania:
- Should be used cautiously >>> May be at an increased risk of experiencing manic episodes when treated with antidepressants alone!
21. Urinary Hesitation and Retention:
- Caution in patients who use concomitant medications that may affect voiding (e.g., anticholinergics)
22. Patients With Substantial Alcohol Use:
- May be associated with severe liver injury.
23. Medications have highly plasma protein binding affinity:
- Duloxetine is highly bound to plasma proteins (>90%) >>> Increased free plasma concentration of either drugs.
24. Benzodiazepines:
- Concomitant use >>> Increased Sedation effect. Use with caution!
25. Smoking:
- Bioavailability appears to be about 34% lower in smokers than in non-smokers >>> Dose adjustment not routinely recommended.
26. Administration:
- May be administered with or without food >>>> food may help reduce the incidence of initial nausea.
27. CYMBALTA should be swallowed whole and should not be chewed or crushed.
28. Overdose:
- No specific antidote >>> Supportive therapy.
Section
This document is prepared by the “Mental Health for All” team. This document is provided for information purposes only and does not necessarily represent endorsement by or an official position of the Essentials of Medicine. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient’s medical history.