Duloxetine

Duloxetine is an active ingredient that is administered to treat depression, anxiety disorders and pain. It belongs to the group of SSNRIs (selective serotonin and noradrenaline reuptake inhibitors). It is found in medicines as S-duloxetine hydrochloride, is a white to brownish powder and is only slightly soluble in water. Duloxetine is broken down racemically and only the left-turned enantiomer is used. A racemate is an active substance that consists of 2 molecules that occur in a 1:1 ratio and behave like image and mirror image. One speaks of the R-(dextrorotatory) enantiomer and S-(levorotatory) enantiomer. Enantiomers do NOT differ in their physical properties such as melting or boiling point. However, they can behave in opposite ways in terms of their effects. For example, (S)-carvone smells like caraway and (R)-carvone smells like mint. The amino acid (S)-valine tastes bitter, while (R)-valine tastes sweet. For these reasons, both enantiomers are always tested in today's approval procedures for new active ingredients. Sometimes one enantiomer can be converted into the other in the body.

Duloxetine works by increasing the concentration of serotonin and noradrenaline in the synaptic cleft. It occupies the receptors that are responsible for reuptake into the presynapse. Since depression is thought to be caused by a lack of serotonin and noradrenaline in the synaptic cleft, duloxetine causes an increased concentration. By inhibiting the reuptake receptors, the serotonin content increases. In addition, the increased concentrations lead to a reduction in pain.

Duloxetine is metabolized in the liver, primarily by the enzymes CYP1A2 and CYP2D6. The bioavailability, i.e. the percentage of the active substance available in the blood, is 50% on average, but can range from 30% to 80%. The half-life of duloxetine, i.e. the time it takes for the body to excrete half of the active substance, is around 12 hours, but like bioavailability has a range of 8-17 hours. The maximum plasma concentration (Cmax), i.e. the maximum concentration of the active substance in the blood plasma (liquid cell-free part of the blood), is reached after 6 hours.

Always take duloxetine exactly as described in the package leaflet or as advised by your doctor.

Adults:

The usual recommended dose depends on the underlying condition and ranges between 30 mg and 120 mg daily .

The maximum daily dose is 120 mg .

The following side effects may occur:

Very common:

• Headache
• drowsiness
• nausea
• Dry mouth

Frequent:

• Weight loss
• Fatigue
• Falls
• Erectile dysfunction
• Ejaculation disorders
• Delayed ejaculation
• Dysuria
• Pollakiuria
• Musculoskeletal pain
• Muscle cramps
• Increased sweating
• skin rash
• constipation
• diarrhea
• abdominal pain
• vomiting
• dyspepsia
• flatulence
• yawning
• flushing
• Increase in blood pressure
• palpitations
• Ringing in the ears
• Blurred vision
• Trembling
• paralysis
• abnormal dreams
• abnormal orgasm
• anxiety
• loss of libido
• agitation
• insomnia
• decreased appetite
• lethargy

Occasionally:

• Atrial fibrillation
• high blood pressure
• fainting
• Cold extremities
• Tightness in the throat
• nosebleeds
• Gastrointestinal bleeding
• Gastrointestinal inflammation
• belching
• Stomach inflammation
• Dysphagia
• Liver inflammation
• Elevated liver enzymes
• Liver damage
• Night sweats
• Hives
• Skin rashes
• Cold sweats
• Hypersensitivity of the skin to light
• Increased tendency to bruise
• Muscle stiffness
• Muscle twitching
• Urinary retention
• Urinary delay
• Increased urination at night
• polyuria
• Decreased urine flow
• Gynecological bleeding
• menstrual disorders
• sexual dysfunction
• testicular pain
• breast pain
• discomfort
• feeling cold
• thirst
• chills
• malaise
• feeling of heat
• gait disturbances
• Weight gain
• Increase in creatine phosphokinase in the blood
• Increased blood potassium level
• laryngitis
• hyperglycemia
• suicidal thoughts
• sleep disorders
• teeth grinding
• confusion
• apathy
• myoclonus
• akathisia
• nervousness
• attention deficit disorder
• taste disturbances
• dyskinesia
• Restless legs syndrome
• Poor sleep
• Mydriasis
• Visual disturbances
• dizziness
• earache
• High heart rate
• Supraventricular arrhythmias

Rarely:

• Increased blood cholesterol levels
• Increased bleeding after childbirth
• Hyperprolactinemia
• Galactorrhea
• Menopausal symptoms
• Abnormal urine odor
• spasm of the masticatory muscles
• angioedema
• Stevens-Johnson syndrome
• jaundice
• liver failure
• stomatitis
• hematochezia
• bad breath
• intestinal inflammation
• pneumonia
• interstitial lung diseases
• Hypertensive crisis
• glaucoma
• serotonin syndrome
• seizures
• Psychomotor agitation
• Extrapyramidal symptoms
• Hallucinations, aggression and anger
• mania
• Suicidal tendencies
• Syndrome of adequate ADH secretion
• Hyponatremia
• dehydration
• Hypothyroidism
• Hypersensitivity reaction
• Allergic reactions

Very rare:

• Cutaneous vasculitis

Interactions may occur if the following medicines are taken at the same time:

• Monoamine oxidase inhibitors (MAO inhibitors)
• Drugs that inhibit the enzyme CYP1A2
• serotonergic drugs
• antidepressants
• St. John's wort
• triptans
• buprenorphine
• tramadol
• pethidine
• tryptophan
• benzodiazepines
• opioids
• antipsychotics
• phenobarbital
• sedatives
• alcohol
• Sedative antihistamines
• Drugs that are broken down by the enzymes CYP1A2 or CYP2D6
• risperidone
• Tricyclic antidepressants
• flecainide
• propafenone
• Metoprolol
• Medications that interfere with blood thinning or blood clotting
• Smoking

Duloxetine must NOT be taken in the following cases

• in case of allergy to duloxetine
• when using MAO inhibitors
• in the case of liver disease
• when taking fluvoxamine, ciprofloxacin and enoxacin
• severe renal dysfunction
• for untreated blood pressure problems

Duloxetine should NOT be taken under the age of 18, as studies have shown growth disorders and weight fluctuations.

Duloxetine should only be used during pregnancy if the benefit outweighs the risk. However, this decision is made by your doctor. Animal studies have shown malformations in unborn babies. Two observational studies (from the USA and Europe) found no increased risk of congenital malformations in babies. Especially when taken in late pregnancy (from the 20th week of pregnancy), adaptation disorders and withdrawal symptoms were observed in newborns.

As an alternative, the better-tested antidepressants sertraline and citalopram can be taken.

During breastfeeding, duloxetine is only recommended after consultation with your doctor. Duloxetine only passes into breast milk in very small quantities and has been observed to be well tolerated. However, as the data only includes eight mother-child pairs, the observations must be viewed very critically.

While duloxetine received European marketing authorization in August 2004, the US FDA rejected marketing authorization in the USA in 2005. The reason for this was safety concerns in connection with the suicide of a test subject. The active ingredient is marketed jointly by the pharmaceutical companies Eli Lilly and Boehringer Ingelheim and is disappointing in terms of sales in Europe.