BALTAXINE

Duloxetine delayed-release capsules, USP are a selective serotonin and norepinephrine reuptake inhibitor (SNRI) for oral administration.

Its chemical designation is (+)-( S ).

• N -methyl-γ-(1-naphthyloxy)-2-thiophenepropylamine hydrochloride.

The empirical formula is

C 18 H 19 NOS∙HCl, which corresponds to a molecular weight of 333.88.

The structural formula is

Duloxetine hydrochloride is a white to slightly brownish white solid, which is slightly soluble in water.

Each capsule contains enteric-coated pellets of 20, 30, 40 or 60 mg of duloxetine (equivalent to 22.4, 33.7, 44.9 or 67.3 mg of duloxetine hydrochloride, respectively).

These enteric-coated pellets are designed to prevent degradation of the drug in the acidic environment of the stomach.

Inactive ingredients include ammonium hydroxide, black iron oxide, hypromellose, methacrylic acid copolymer dispersion (methacrylic acid-ethyl acrylate copolymer, polysorbate 80, sodium lauryl sulfate), potassium hydroxide, propylene glycol, shellac, sucrose, sugar spheres (maize starch, sucrose), talc, titanium dioxide, triethylcitrate, and hard gelatin capsules (gelatin, titanium dioxide).

The 20 mg hard gelatin capsule colorant is yellow iron oxide.

The 30 mg hard gelatin capsule colorants are FD&C Blue No. 1, FD&C Yellow No. 6, and FD&C Yellow No. 10.

The 40 mg hard gelatin capsule colorants are FD&C Blue No. 2, red iron oxide, and yellow iron oxide.

The 60 mg hard gelatin capsule colorants are FD&C Blue No. 1, FD&C Yellow No. 6, FD&C Yellow No.10, and yellow iron oxide.

Duloxetine delayed-release capsules is indicated for the treatment of: Major depressive disorder in adults Generalized anxiety disorder in adults and pediatric patients 7 years of age and older Diabetic peripheral neuropathic pain in adults Fibromyalgia in adults and pediatric patients 13 years of age and older Chronic musculoskeletal pain in adults Duloxetine delayed-release capsules are a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of the following conditions: Major depressive disorder (MDD) in adults Generalized anxiety disorder (GAD) in adults and pediatric patients 7 years of age and older Diabetic peripheral neuropathic pain (DPNP) in adults Fibromyalgia (FM) in adults and pediatric patients 13 years of age and older Chronic musculoskeletal pain in adults.

Manic access, history (d) Lactation Cardiopathies Cirhrosis Convulsions Dehydration Pregnancy Hypertension Intraocular hypertension Suicidal ideation, history (of) Newborn exposed in utero to the medicine Suicidal-prone patient Dialysis patient Elderly Subject at risk of hyponatraemia Subject at risk of glaucoma Subject at risk of bleeding Subject under 18 Subject between and 25 years Bipolar disorder.

Although the exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions of duloxetine in humans are unknown, these actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS. 12.2 Pharmacodynamics Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake.

Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro.

Duloxetine does not inhibit monoamine oxidase (MAO).

Duloxetine delayed-release capsules are in a class of drugs known to affect urethral resistance.

Cardiac Electrophysiology The effect of

Duloxetine delayed-release capsules 160 mg and 200 mg administered twice daily (2.7 and 3.3 times the maximum recommended dosage, respectively) to steady state was evaluated in a randomized, double-blinded, two-way crossover study in 117 healthy female adult subjects.

No QT interval prolongation was detected.

Duloxetine delayed-release capsules appears to be associated with concentration-dependent but not clinically meaningful QT shortening. 12.3 Pharmacokinetics Duloxetine has an elimination half-life of about 12 hours (range to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic range.

Steady-state plasma concentrations are typically achieved after 3 days of dosing.

Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP1A2 and CYP2D6.

Absorption After oral

Duloxetine delayed-release capsules administration, duloxetine hydrochloride is well absorbed.

There is a median 2 hour lag until absorption begins (T lag ), with maximal plasma concentrations (C max ) of duloxetine occurring 6 hours post dose.

There is a 3 hour delay in absorption and a one-third increase in apparent clearance of duloxetine after an evening dose as compared to a morning dose.

Food does not affect the C max of duloxetine, but delays the time to reach peak concentration from to 10 hours and it marginally decreases the extent of absorption (AUC) by about 10%.

The apparent volume of distribution averages about 1640 L. Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and α 1 -acid glycoprotein.

The interaction between duloxetine and other highly protein bound drugs has not been fully evaluated.

Plasma protein binding of duloxetine is not affected by renal or hepatic impairment.

Biotransformation and disposition of duloxetine in humans have been determined following oral administration of 14 C-labeled duloxetine.

Duloxetine comprises about 3% of the total radiolabeled material in the plasma, indicating that it undergoes extensive metabolism to numerous metabolites.

The major biotransformation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation.

CYP1A2 and CYP2D6 catalyze the oxidation of the naphthyl ring in vitro.

Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate.

Many additional metabolites have been identified in urine, some representing only minor pathways of elimination.

Only trace (<1% of the dose) amounts of unchanged duloxetine are present in the urine.

Most (about 70%) of the duloxetine dose appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces.

Duloxetine undergoes extensive metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine.

Duloxetine steady-state plasma concentration was comparable in pediatric patients to 17 years of age and adult patients.

The average steady-state duloxetine concentration was approximately 30% lower in this pediatric population relative to adult patients.

The model-predicted duloxetine steady state plasma concentrations in pediatric patients to 17 years of age were mostly within the concentration range observed in adult patients and did not exceed the concentration range in adults.

Mechanism of action

Duloxetine is an inhibitor of both serotonin (5-HT) and noradrenaline (NA) reuptake.

It inhibits dopamine reuptake weakly and has no significant affinity for histamine, dopamine, cholinergic, and adrenergic receptors.

Duloxetine increases the extracellular levels of serotonin and noradrenaline in different areas of the animal brain dose-dependently.

• Hyperkalaemia (Uncommon)
• Hyperglycaemia (Uncommon)
• KPC (increase) (Uncommon)
• Liver enzymes (increase) (Uncommon)
• Hypercholesterolaemia (Rare)
• Hyperprolactinaemia (Rare)
• Hyponatremia (Rare)
• Blood cholesterol increased
• Alkaline phosphates (increase)
• Increased blood glucose ASAT (increase)
• ALT (increase)
• Urticaria (Uncommon)
• Hypersudation (Common)
• Night sweating (Uncommon)
• Rash (Common)
• Ecchymotic trend (Uncommon)
• Photosensitivity (Uncommon)
• Contact dermatitis (Uncommon)
• Stevens-Johnson Syndrome (Rare)
• Coldness (Uncommon)
• Heat sensation (Uncommon)
• Sexual disorder (Uncommon)
• Cold sweat (Uncommon)
• Fall (Common)
• Frisher (Uncommon)
• Chest pain (Uncommon)
• Fatigue (Common)
• Inappropriate antidiuretic hormone secretion syndrome (IADH) (Rare)
• Hypothyroidism (Rare)
• Galactorrhoea (Rare)
• Abnormal orgasm (Common)
• Orgasmic disorder (Common)
• Genital haemorrhage (Uncommon)
• Menstrual disorder (Uncommon)
• Postpartum haemorrhage (Rare)
• Symptoms of menopause (Rare)
• Echymosis (Uncommon)
• Acute hepatitis (Uncommon)
• Hepatitis (Uncommon)
• Ictery (Rare)
• Hepatic impairment (Rare)
• Oedema of Quincke (Rare)
• Hypersensitivity (Rare)
• Anaphylactic reaction (Rare)
• Polydipsy (Uncommon)
• Appetite decreased (Common)
• Weight (increase) (Uncommon)
• Dysphagia (Uncommon)
• Weight (decrease) (Common)
• Dehydration (Rare)
• Mydriase (Uncommon)
• Vision disorder (Uncommon)
• Blurty vision (Common)
• Glaucoma (Rare)
• Vertigo (Uncommon)
• Epistaxis (Uncommon)
• Oral dryness (Very common)
• Hyposialia (Very common)
• Dysgueusia (Uncommon)
• Feeling dizzy (Common)
• Brussels (Uncommon)
• Otalgia (Uncommon)
• Pharyngeal borehole (Uncommon)
• Tinnitus (Common)
• Laryngitis (Uncommon)
• Stomatitis (Rare)
• Lethargy (Common)
• Suicidal ideation (Uncommon)
• Temporospatial disorientation (Uncommon)
• Libido (decrease) (Common)
• Attention disorder (Uncommon)
• Poor quality sleep (Uncommon)
• Nervousness (Uncommon)
• Insomnia (Common)
• Indifference (Uncommon)
• Anxiety (Common)
• Abnormal dreams (Common)
• Sleep disorder (Uncommon)
• Agitation (Common)
• Anger (Rare)
• Mania (Rare)
• Aggressiveness (Rare)
• Manic access (Rare)
• Hallucination (Rare)
• Suicidal behaviour (Rare)
• Irritability Hot flash (Common)
• Hypertension (Uncommon)
• Cooling of the ends (Uncommon)
• Syncope (Uncommon)
• Palpitation (Common) supraventricular arrhythmia (Uncommon)
• Orthostatic hypotension (Uncommon)
• Tachycardia (Uncommon)
• Blood pressure (increase) (Common)
• Malaise (Uncommon)
• Skin vasculitis (Very rare)
• Hypertensive crisis (Rare)
• Atrial fibrillation Abdominal pain (Common)
• Gastritis (Uncommon)
• Dyspepsia (Common)
• Nausea (Very common)
• Erunation (Uncommon)
• Gastrointestinal haemorrhage (Uncommon)
• Constipation (Common)
• Vomiting (Common)
• Gastroenteritis (Uncommon)
• Diarrhoea (Common)
• Fowl (Uncommon)
• Flatulence (Common)
• Microscopic colitis (Rare)
• Melena (Rare)
• Hematochesis (Rare)
• Halitosis (Rare)
• Muscle contractions (Uncommon)
• Musculoskeletal pain (Common)
• Muscle tension (Uncommon)
• Muscle spasm (Common)
• Trismus (Rare)
• Akathisia (Uncommon)
• Myoclonia (Uncommon)
• Dyskinesia (Uncommon)
• Balance disorder (Common)
• Walking disorder (Uncommon)
• Paraesthesia (Common)
• Headache (Very common)
• Bailing (Common)
• Restless leg syndrome (Uncommon)
• Somnolence (Very common)
• Trembling (Common)
• Psychomotor hyperactivity (Rare)
• Extrapyramidal syndrome (Rare)
• Convulsions (Rare)
• Eosinophilic pneumonia (Rare)
• Interstitial pneumopathy (Rare)
• Serotonin syndrome (Rare)
• Weaning syndrome Time to Micturition (Uncommon)
• Pollakiuria (Common)
• Nycturia (Uncommon)
• Testicular pain (Uncommon)
• Urinary retention (Uncommon)
• Ejaculation disorder (Common)
• Urine flow decreased (Uncommon)
• Erection disorder (Common)
• Polyuria (Uncommon)
• Dysuria (Common)
• Delayed ejaculation (Common)
• Abnormal urine odour (Rare).

In postmarketing experience, fatal outcomes have been reported for acute duloxetine overdoses, primarily with mixed overdoses, but also with duloxetine only, including 1000 mg of duloxetine (approximately 8.3 times the maximum recommended dosage).

Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting. 10.2 Management of Overdose There is no specific antidote to a Duloxetine delayed-release capsules overdosage, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered.

In case of acute overdose with

Duloxetine delayed-release capsules, treatment should consist of those general measures employed in the management of overdose with any drug, such as assuring an adequate airway, oxygenation, and ventilation and monitoring cardiac rhythm and vital signs.

Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients.

Induction of emesis is not recommended.

Activated charcoal may be useful in limiting absorption of duloxetine from the gastrointestinal tract.

Administration of activated charcoal has been shown to decrease duloxetine AUC and C max by an average of one-third, although some patients had a limited effect of activated charcoal.

Due to the large volume of distribution of duloxetine, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial.

In managing overdose, the possibility of multiple drug involvement should be considered.

A specific caution involves patients who overdose with Duloxetine delayed-release capsules and tricyclic antidepressants.

In such a case, decreased clearance of the parent tricyclic and/or its active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation.

Consider contacting a poison control center (1-800-222-1222 or for additional information on the treatment of overdosage.

The use of MAOIs intended to treat psychiatric disorders with Duloxetine delayed-release capsules or within 5 days of stopping treatment with Duloxetine delayed-release capsules is contraindicated because of an increased risk of serotonin syndrome.

The use of

Duloxetine delayed-release capsules within 14 days of stopping an MAOI intended to treat psychiatric disorders is contraindicated.

Duloxetine delayed-release capsules in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome.

Concomitant use of an MAOI antidepressant with Duloxetine delayed-release capsules is contraindicated Use of Duloxetine delayed-release capsules within 14 days of stopping an MAOI antidepressant is contraindicated In linezolid.

• or intravenous methylene blue-treated patients, initiation of Duloxetine delayed-release capsules is contraindicated.

Duloxetine delayed-release capsules once daily, with or without food.

Swallow whole; do not crush, chew, or open capsule Indication Starting Dose Target Dose Maximum Dose MDD 40 mg/day to 60 mg/day Acute Treatment: 40 mg/day (20 mg twice daily) to 60 mg/day (once daily or as 30 mg twice daily); Maintenance Treatment: 60 mg/day 120 mg/day GAD Adults 60 mg/day 60 mg/day (once daily) 120 mg/day Geriatric 30 mg/day 60 mg/day (once daily) 120 mg/day Pediatrics (7 to 17 years of age) 30 mg/day to 60 mg/day (once daily) 120 mg/day DPNP 60 mg/day 60 mg/day (once daily) 60 mg/day FM Adults and Pediatrics (13 to 17 years of age) 30 mg/day 60 mg/day (once daily) 60 mg/day Chronic Musculoskeletal Pain 30 mg/day 60 mg/day (once daily) 60 mg/day Discontinuing Duloxetine delayed-release capsules: Gradually reduce dosage to avoid discontinuation symptoms 2.1 Important Administration Instructions Administer Duloxetine delayed-release capsules orally (with or without meals) and swallow whole.

Do not chew or crush, and do not open the delayed-release capsule and sprinkle its contents on food or mix with liquids because these actions might affect the enteric coating.

If a dose of

Duloxetine delayed-release capsules is missed, take the missed dose as soon as it is remembered.

If it is almost time for the next dose, skip the missed dose and take the next dose at the regular time.

Do not take two doses of

Duloxetine delayed-release capsules at the same time. 2.2 Dosage for Treatment of Major Depressive Disorder in Adults The recommended starting dosage in adults with MDD is 40 mg/day (given as 20 mg twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily).

For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to Duloxetine delayed-release capsules before increasing to 60 mg once daily.

While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer any additional benefits.

Periodically reassess to determine the need for maintenance treatment and the appropriate dosage for such treatment. 2.3 Dosage for Treatment of Generalized Anxiety Disorder Recommended Dosage in Adults Less than 65 Years of Age For most adults less than 65 years of age with GAD, initiate Duloxetine delayed-release capsules 60 mg once daily.

While a 120 mg once daily dosage was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit.

Nevertheless, if a decision is made to increase the dosage beyond 60 mg once daily, increase dosage in increments of 30 mg once daily.

Periodically reassess to determine the continued need for maintenance treatment and the appropriate dosage for such treatment.

Recommended Dosage in Geriatric Patients In geriatric patients with GAD, initiate Duloxetine delayed-release capsules at a dosage of 30 mg once daily for 2 weeks before considering an increase to the target dose of 60 mg/day. Thereafter, patients may benefit from doses above 60 mg once daily.

If a decision is made to increase the dose beyond 60 mg once daily, increase dose in increments of 30 mg once daily.

The maximum dose studied was 120 mg per day. Recommended Dosage in Pediatric Patients to 17 Years of Age Initiate Duloxetine delayed-release capsules in pediatric patients to 17 years of age with GAD at a dosage of 30 mg once daily for 2 weeks before considering an increase to 60 mg once daily.

The recommended dosage range is to 60 mg once daily.

Some patients may benefit from dosages above 60 mg once daily.

If a decision is made to increase the dose beyond 60 mg once daily, increase dosage in increments of 30 mg once daily.

The maximum dose studied was 120 mg per day. 2.4 Dosage for Treatment of Diabetic Peripheral Neuropathic Pain in Adults Administer 60 mg once daily in adults with diabetic peripheral neuropathic pain.

There is no evidence that doses higher than 60 mg once daily confer additional significant benefit and the higher dosage is clearly less well tolerated.

For patients for whom tolerability is a concern, a lower starting dose may be considered.

Since diabetes is frequently complicated by renal disease, consider a lower starting dosage and gradual increase in dosage for patients with renal impairment. 2.5 Dosage for Treatment of Fibromyalgia Recommended Dosage in Adults The recommended Duloxetine delayed-release capsules dosage is 60 mg once daily in adults with fibromyalgia.

Begin treatment at 30 mg once daily for 1 week, to allow patients to adjust to Duloxetine delayed-release capsules before increasing to 60 mg once daily.

Some patients may respond to the starting dosage.

There is no evidence that dosages greater than 60 mg/day confer additional benefit, even in patients who do not respond to a 60 mg/day dosage, and higher dosages were associated with a higher rate of adverse reactions.

Patients to 17 Years of Age The recommended starting Duloxetine delayed-release capsules dosage in pediatric patients 13-17 years of age with fibromyalgia is 30 mg once daily.

The dosage may be increased to 60 mg once daily based on response and tolerability. 2.6 Dosage for Treatment of Chronic Musculoskeletal Pain in Adults The recommended Duloxetine delayed-release capsules dosage is 60 mg once daily in adults with chronic musculoskeletal pain.

Begin treatment at 30 mg once daily for one week, to allow patients to adjust to Duloxetine delayed-release capsules before increasing to 60 mg once daily.

There is no evidence that higher dosages confer additional benefit, even in patients who do not respond to a 60 mg once daily dosage, and higher dosages are associated with a higher rate of adverse reactions. 2.7 Dosage in Patients with Hepatic Impairment or Severe Renal Impairment Avoid use in patients with chronic liver disease or cirrhosis.

Avoid use in patients with severe renal impairment, GFR <30 mL/minute. 2.8 Discontinuing Duloxetine delayed-release capsules Adverse reactions after discontinuation of Duloxetine delayed-release capsules, after abrupt or tapered discontinuation, include: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue.

A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible. 2.9 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric.

Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Duloxetine delayed-release capsules.

Conversely, at least 5 days should be allowed after stopping Duloxetine delayed-release capsules before starting an MAOI intended to treat psychiatric disorders. 2.10 Use of Duloxetine delayed-release capsules with Other MAOIs such as Linezolid or Methylene Blue Do not start duloxetine in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome.

In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered.

In some cases, a patient already receiving Duloxetine delayed-release capsules therapy may require urgent treatment with linezolid or intravenous methylene blue.

If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Duloxetine delayed-release capsules should be stopped promptly, and linezolid or intravenous methylene blue can be administered.

The patient should be monitored for symptoms of serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first.

Therapy with

Duloxetine delayed-release capsules may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue.

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Duloxetine delayed-release capsules is unclear.

The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use.

Duloxetine delayed-release capsules, USP are available in the following strengths, colors, imprints, and presentations: Features Strengths 20 mg equivalent to duloxetine base 30 mg 40 mg 60 mg Body color Opaque ochre Opaque white Opaque orange Opaque ochre Cap color Opaque ochre Opaque green Opaque blue Opaque green Cap imprint B B B B Body imprint 746 747 750 748 Presentations and NDC Codes Bottles of 30 NA 51407-818-30 NA 51407-819-30 Bottles of 60 51407-817-60 NA NA NA Bottles of 90 NA 51407-818-90 NA NA Bottles of 500 NA NA NA NA Bottles of 1000 NA NA NA 51407-819-10 16.2 Storage and Handling Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) .

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) .

Data from a postmarketing retrospective cohort study indicate that use of duloxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage.

Data from published literature and from a postmarketing retrospective cohort study have not identified a clear drug-associated risk of major birth defects or other adverse developmental outcomes.

There are risks associated with untreated depression and fibromyalgia in pregnancy, and with exposure to SNRIs and SSRIs, including Duloxetine delayed-release capsules, during pregnancy.

In rats and rabbits treated with duloxetine during the period of organogenesis, fetal weights were decreased but there was no evidence of developmental effects at doses up to and 6 times, respectively, the maximum recommended human dose (MRHD) of 120 mg/day given to adolescents on a mg/m 2 basis.

When duloxetine was administered orally to pregnant rats throughout gestation and lactation, pup weights at birth and pup survival to 1 day postpartum were decreased at a dose 2 times the MRHD given to adolescents on a mg/m 2 basis.

At this dose, pup behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity were observed.

Post-weaning growth was not adversely affected.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

Maternal and/or Embryo/Fetal Risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants.

This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy.

Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.

Pregnant women with fibromyalgia are at increased risk for adverse maternal and infant outcomes including preterm premature rupture of membranes, preterm birth, small for gestational age, intrauterine growth restriction, placental disruption, and venous thrombosis.

It is not known if these adverse maternal and fetal outcomes are a direct result of fibromyalgia or other comorbid factors.

Use of duloxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage.

Fetal/Neonatal Adverse Reaction Neonates exposed to Duloxetine delayed-release capsules and other SNRIs or SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding.

Such complications can arise immediately upon delivery.

Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying.

These findings are consistent with either a direct toxic effect of the SNRIs or SSRIs, or possibly, a drug discontinuation syndrome.

It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome.

Data from a postmarketing retrospective claims-based cohort study found an increased risk for postpartum hemorrhage among 955 pregnant women exposed to duloxetine in the last month of pregnancy compared to 4,128,460 unexposed pregnant women (adjusted relative risk: 1.53; 95% CI: 1.08-2.18).

The same study did not find a clinically meaningful increase in the risk for major birth defects in the comparison of 2532 women exposed to duloxetine in the first trimester of pregnancy to 1,284,827 unexposed women after adjusting for several confounders.

Methodologic limitations include possible residual confounding, misclassification of exposure and outcomes, lack of direct measures of disease severity, and lack of information about alcohol use, nutrition, and over-the-counter medication exposures.

In animal reproduction studies, duloxetine has been shown to have adverse effects on embryo/fetal and postnatal development.

When duloxetine was administered orally to pregnant rats and rabbits during the period of organogenesis, there was no evidence of malformations or developmental variations at doses up to 45 mg/kg/day [3 and 6 times, respectively, the MRHD of 120 mg/day given to adolescents on a mg/m 2 basis.

However, fetal weights were decreased at this dose, with a no-effect dose of 10 mg/kg/day (approximately equal to the MRHD in rats and 2 times the MRHD in rabbits).

When duloxetine was administered orally to pregnant rats throughout gestation and lactation, the survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were decreased at a dose of 30 mg/kg/day (2 times the MRHD given to adolescents on a mg/m 2 basis); the no-effect dose was 10 mg/kg/day. Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups following maternal exposure to 30 mg/kg/day. Post-weaning growth and reproductive performance of the progeny were not affected adversely by maternal duloxetine treatment.

The safety and effectiveness of

Duloxetine delayed-release capsules have been established for treatment of generalized anxiety disorder (GAD) in patients to 17 years of age and for treatment of juvenile fibromyalgia syndrome in patients to 17 years of age.

Duloxetine delayed-release capsules have not been established in pediatric patients with major depressive disorder (MDD), diabetic peripheral neuropathic pain, or chronic musculoskeletal pain.

Antidepressants increased the risk of suicidal thoughts and behavior in pediatric patients.

Monitor all pediatric patients being treated with antidepressants for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of treatment, or at times of dosage changes.

Perform regular monitoring of weight and growth in pediatric patients treated with Duloxetine delayed-release capsules.

Generalized Anxiety Disorder Use of

Duloxetine delayed-release capsules for the treatment of GAD in patients to 17 years of age is supported by one 10-week, placebo.

• controlled trial (GAD-6).

The study included 272 pediatric patients with GAD of which 47% were to 11 years of age (53% were to 17 years of age).

Duloxetine delayed-release capsules demonstrated superiority over placebo as measured by greater improvement in the Pediatric Anxiety Rating Scale (PARS) for GAD severity score.

Duloxetine delayed-release capsules for the treatment of GAD in pediatric patients less than 7 years of age have not been established.

Fibromyalgia Use of

Duloxetine delayed-release capsules for treatment of fibromyalgia in patients to 17 years of age is supported by a 13-week placebo.

• controlled trial in 184 patients with juvenile fibromyalgia syndrome (Study FM-4).

Duloxetine delayed-release capsules showed improvement over placebo on the primary endpoint, change from baseline to end-of-treatment on the Brief Pain Inventory (BPI) – Modified Short Form: Adolescent Version 24-hour average pain severity rating.

Duloxetine delayed-release capsules for the treatment of fibromyalgia in patients less than 13 years of age have not been established.

Major Depressive Disorder The safety and effectiveness of Duloxetine delayed-release capsules have not been established in pediatric patients for the treatment of MDD.

Efficacy of

Duloxetine delayed-release capsules was not demonstrated in two 10-week, placebo-controlled trials with 800 pediatric patients aged to 17 years old with MDD (MDD-6 and MDD-7).

Duloxetine delayed-release capsules nor an active control (approved for treatment of pediatric MDD) was superior to placebo.

The most frequently observed adverse reactions in the MDD pediatric clinical trials included nausea, headache, decreased weight, and abdominal pain.

Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs.

Duloxetine administration to young rats from post-natal day 21 (weaning) through post-natal day 90 (adult) resulted in decreased body weights that persisted into adulthood, but recovered when drug treatment was discontinued; slightly delayed (~1.5 days) sexual maturation in females, without any effect on fertility; and a delay in learning a complex task in adulthood, which was not observed after drug treatment was discontinued.

These effects were observed at the high dose of 45 mg/kg/day (2 times the MRHD, for a child); the no-effect-level was 20 mg/kg/day (≈1 times the MRHD, for a child).

Geriatric Exposure in Premarketing Clinical Trials of Duloxetine delayed-release capsules Of the 2,418 patients in MDD trials, 6% were 65 years of age or over.

Of the 1,041 patients in CLBP trials, 21% were 65 years of age or over.

Of the 487 patients in OA trials, 41% were 65 years of age or over.

Of the 1,074 patients in the DPNP trials, 33% were 65 years of age or over.

Of the 1,761 patients in FM trials, 8% were 65 years of age or over.

In the

MDD, GAD, DPNP, FM, OA, and CLBP studies, no overall differences in safety or effectiveness were generally observed between these patients and younger adult patients, and other reported clinical experience has not identified differences in responses between these geriatric and younger adult patients, but greater sensitivity of some older patients cannot be ruled out.

SSRIs and

SNRIs, including Duloxetine delayed-release capsules have been associated with clinically significant hyponatremia in geriatric patients, who may be at greater risk for this adverse reaction.

In an analysis of data from all placebo-controlled-trials, Duloxetine delayed-release capsules-treated patients reported a higher rate of falls compared to placebo-treated patients.

The increased risk appears to be proportional to a patient's underlying risk for falls.

Underlying risk appears to increase steadily with age.

As geriatric patients tend to have a higher prevalence of risk factors for falls such as medications, medical comorbidities and gait disturbances, the impact of increasing age by itself on falls during Duloxetine delayed-release capsules treatment is unclear.

Falls with serious consequences including bone fractures and hospitalizations have been reported with Duloxetine delayed-release capsules use.

The pharmacokinetics of duloxetine after a single dose of 40 mg were compared in healthy elderly females (65 to 77 years) and healthy middle-age females (32 to 50 years).

There was no difference in the

C max, but the AUC of duloxetine was somewhat (about 25%) higher and the half-life about 4 hours longer in the elderly females.

Population pharmacokinetic analyses suggest that the typical values for clearance decrease by approximately 1% for each year of age between to 75 years of age; but age as a predictive factor only accounts for a small percentage of between-patient variability.

Dosage adjustment based on the age of the adult patient is not necessary.