NEWS - The Journal of Clinical Endocrinology & Metabolism

JCEMTM 

THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 

Volume 93 • Number 4 • April 2008 • jcem.endojournals.org

Sandostatin LAR ® Depot 

(octreotide acetate for injectable suspension) 

Rx only 

BRIEF SUMMARY: Please see package insert for full prescribing information. 

INDICATIONS AND USAGE: Acromegaly: Sandostatin LAR ® Depot (octreotide acetate for injectable suspension) is indicated for 

long-term maintenance therapy in acromegalic patients for whom medical treatment is appropriate and who have been shown to 

respond to and can tolerate Sandostatin ® (octreotide acetate) Injection. The goal of treatment in acromegaly is to reduce GH and 

IGF-1 levels to normal. Sandostatin LAR ® Depot can be used in patients who have had an inadequate response to surgery or in 

those for whom surgical resection is not an option. It may also be used in patients who have received radiation and have had an 

inadequate therapeutic response (see CLINICAL TRIALS and DOSAGE AND ADMINISTRATION in the full prescribing information). 

Carcinoid Tumors: Sandostatin LAR ® Depot is indicated for long-term treatment of the severe diarrhea and flushing episodes 

associated with metastatic carcinoid tumors in patients in whom initial treatment with Sandostatin ® Injection has been shown to 

be effective and tolerated. 

Vasoactive Intestinal Peptide Tumors (VIPomas): Sandostatin LAR ® Depot is indicated for long-term treatment of the profuse 

watery diarrhea associated with VIP-secreting tumors in patients in whom initial treatment with Sandostatin ® Injection has been 

shown to be effective and tolerated. 

In patients with acromegaly, carcinoid syndrome and VIPomas, the effect of Sandostatin ® Injection and Sandostatin LAR ® Depot 

on tumor size, rate of growth and development of metastases, has not been determined. 

CONTRAINDICATIONS: Sensitivity to this drug or any of its components. 

WARNINGS: Adverse events that have been reported in patients receiving Sandostatin ® (octreotide acetate) Injection can also 

be expected in patients receiving Sandostatin LAR ® Depot (octreotide acetate for injectable suspension). Incidence figures in 

the WARNINGS and ADVERSE REACTIONS sections, below, are those obtained in clinical trials of Sandostatin ® Injection and 

Sandostatin LAR ® Depot. 

Gallbladder and Related Events: Single doses of Sandostatin ® Injection have been shown to inhibit gallbladder contractility and 

decrease bile secretion in normal volunteers. In clinical trials with Sandostatin ® Injection (primarily patients with acromegaly or 

psoriasis) in patients who had not previously received octreotide, the incidence of biliary tract abnormalities was 63% (27% gallstones, 

24% sludge without stones, 12% biliary duct dilatation). The incidence of stones or sludge in patients who received 

Sandostatin ® Injection for 12 months or longer was 52%. The incidence of gallbladder abnormalities did not appear to be related 

to age, sex or dose but was related to duration of exposure. 

In clinical trials 52% of acromegalic patients, most of whom received Sandostatin LAR ® Depot for 12 months or longer, developed 

new biliary abnormalities including gallstones, microlithiasis, sediment, sludge and dilatation. The incidence of new cholelithiasis 

was 22%, of which 7% were microstones. 

In clinical trials 62% of malignant carcinoid patients who received Sandostatin LAR ® Depot for up to 18 months developed new 

biliary abnormalities including gallstones, sludge and dilatation. New gallstones occurred in a total of 24% of patients. 

Across all trials, a few patients developed acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic hepatitis, 

or pancreatitis during octreotide therapy or following its withdrawal. One patient developed ascending cholangitis during 

Sandostatin ® Injection therapy and died. Despite the high incidence of new gallstones in patients receiving octreotide, 1% of 

patients developed acute symptoms requiring cholecystectomy. 

PRECAUTIONS (See ADVERSE REACTIONS): General: Growth hormone secreting tumors may sometimes expand and cause 

serious complications (e.g., visual field defects). Therefore, all patients with these tumors should be carefully monitored. 

Octreotide alters the balance between the counter-regulatory hormones, insulin, glucagon and growth hormone, which may result 

in hypoglycemia or hyperglycemia. Octreotide also suppresses secretion of thyroid stimulating hormone, which may result in 

hypothyroidism. Cardiac conduction abnormalities have also occurred during treatment with octreotide. 

Glucose Metabolism: The hypoglycemia or hyperglycemia which occurs during octreotide therapy is usually mild, but may result 

in overt diabetes mellitus or necessitate dose changes in insulin or other hypoglycemic agents. Severe hyperglycemia, subsequent 

pneumonia, and death following initiation of Sandostatin ® (octreotide acetate) Injection therapy was reported in one patient with 

no history of hyperglycemia (see ADVERSE REACTIONS). 

In patients with concomitant Type I diabetes mellitus, Sandostatin Injection and Sandostatin LAR ® Depot (octreotide acetate for 

injectable suspension) are likely to affect glucose regulation, and insulin requirements may be reduced. Symptomatic hypoglycemia, 

which may be severe, has been reported in these patients. In non-diabetics and Type II diabetics with partially intact 

insulin reserves, Sandostatin Injection or Sandostatin LAR Depot administration may result in decreases in plasma insulin levels 

and hyperglycemia. It is recommended that glucose tolerance and antidiabetic treatment be periodically monitored during therapy 

with these drugs. 

Thyroid Function: Hypothyroidism has been reported in acromegaly and carcinoid patients receiving octreotide therapy. Baseline 

and periodic assessment of thyroid function (TSH, total and/or free T4) is recommended during chronic octreotide therapy (see 

ADVERSE REACTIONS). 

Cardiac Function: In both acromegalic and carcinoid syndrome patients, bradycardia, arrhythmias and conduction abnormalities 

have been reported during octreotide therapy. Other EKG changes were observed such as QT prolongation, axis shifts, early repolarization, 

low voltage, R/S transition, early R wave progression, and non-specific ST-T wave changes. The relationship of these 

events to octreotide acetate is not established because many of these patients have underlying cardiac disease (see PRECAU- 

TIONS). Dose adjustments in drugs such as beta-blockers that have bradycardia effects may be necessary. In one acromegalic 

patient with severe congestive heart failure, initiation of Sandostatin ® Injection therapy resulted in worsening of CHF with improvement 

when drug was discontinued. Confirmation of a drug effect was obtained with a positive rechallenge (see ADVERSE REACTIONS). 

Nutrition: Octreotide may alter absorption of dietary fats in some patients. 

Depressed vitamin B12 levels and abnormal Schilling’s tests have been observed in some patients receiving octreotide therapy, and 

monitoring of vitamin B12 levels is recommended during therapy with Sandostatin LAR ® Depot. 

Octreotide has been investigated for the reduction of excessive fluid loss from the G.I. tract in patients with conditions producing 

such a loss. If such patients are receiving total parenteral nutrition (TPN), serum zinc may rise excessively when the fluid loss is 

reversed. Patients on TPN and octreotide should have periodic monitoring of zinc levels. 

Information for Patients: Patients with carcinoid tumors and VIPomas should be advised to adhere closely to their scheduled 

return visits for reinjection in order to minimize exacerbation of symptoms. 

Patients with acromegaly should also be urged to adhere to their return visit schedule to help assure steady control of GH and 

IGF-1 levels. 

Laboratory Tests: Laboratory tests that may be helpful as biochemical markers in determining and following patient response 

depend on the specific tumor. Based on diagnosis, measurement of the following substances may be useful in monitoring the 

progress of therapy: 

Acromegaly: Growth Hormone, IGF-1 (somatomedin C) 

Responsiveness to octreotide may be evaluated by determining growth hormone levels at 1-4 hour intervals for 8-12 hours 

after subcutaneous injection of Sandostatin ® Injection (not Sandostatin LAR ® Depot). Alternatively, a single measurement 

of IGF-1 (somatomedin C) level may be made two weeks after initiation of Sandostatin ® Injection or dosage change. After 

patients are switched from Sandostatin ® Injection to Sandostatin LAR ® Depot, GH and IGF-1 determinations may be made 

after 3 monthly injections of Sandostatin LAR ® Depot. (Steady-state serum levels of octreotide are reached only after a period 

of 3 months of monthly injections.) Growth hormone can be determined using the mean of 4 assays taken at 1-hour intervals. 

Somatomedin C can be determined with a single assay. All GH and IGF-1 determinations should be made 4 weeks after 

the previous Sandostatin LAR ® Depot. 

Carcinoid: 5-HIAA (urinary 5-hydroxyindole acetic acid), plasma serotonin, plasma Substance P 

VIPoma: VIP (plasma vasoactive intestinal peptide) 

Baseline and periodic total and/or free T4 measurements should be performed during chronic therapy (see PRECAUTIONS - General). 

Drug Interactions: Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption 

of orally administered drugs. Concomitant administration of octreotide injection with cyclosporine may decrease blood levels of 

cyclosporine and result in transplant rejection. 

Patients receiving insulin, oral hypoglycemic agents, beta-blockers, calcium channel blockers, or agents to control fluid and electrolyte 

balance, may require dose adjustments of these therapeutic agents. 

Concomitant administration of octreotide and bromocriptine increases the availability of bromocriptine. Limited published data 

indicate that somatostatin analogs might decrease the metabolic clearance of compounds known to be metabolized by cytochrome 

P450 enzymes, which may be due to the suppression of growth hormones. Since it cannot be excluded that octreotide may have 

this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g., quinidine, terfenadine) 

should therefore be used with caution. 

Drug Laboratory Test Interactions: No known interference exists with clinical laboratory tests, including amine or peptide 

determinations. 

Carcinogenesis/Mutagenesis/Impairment of Fertility: Studies in laboratory animals have demonstrated no mutagenic potential of 

Sandostatin ®. No mutagenic potential of the polymeric carrier in Sandostatin LAR ® Depot, D,L-lactic and glycolic acids copolymer, 

was observed in the Ames mutagenicity test. 

No carcinogenic potential was demonstrated in mice treated subcutaneously with octreotide for 85-99 weeks at doses up to 

2000 mcg/kg/day (8x the human exposure based on body surface area). In a 116-week subcutaneous study in rats administered 

octreotide, a 27% and 12% incidence of injection site sarcomas or squamous cell carcinomas was observed in males and females, 

respectively, at the highest dose level of 1250 mcg/kg/day (10x the human exposure based on body surface area) compared to an 

incidence of 8%-10% in the vehicle-control groups. The increased incidence of injection site tumors was most probably caused 

by irritation and the high sensitivity of the rat to repeated subcutaneous injections at the same site. Rotating injection sites would 

prevent chronic irritation in humans. There have been no reports of injection site tumors in patients treated with Sandostatin ® 

Injection for at least 5 years. There was also a 15% incidence of uterine adenocarcinomas in the 1250 mcg/kg/day females compared 

to 7% in the saline-control females and 0% in the vehicle-control females. The presence of endometritis coupled with the 

absence of corpora lutea, the reduction in mammary fibroadenomas, and the presence of uterine dilatation suggest that the uterine 

tumors were associated with estrogen dominance in the aged female rats which does not occur in humans. 

Octreotide did not impair fertility in rats at doses up to 1000 mcg/kg/day, which represents 7x the human exposure based on body 

surface area. 

Pregnancy Category B: Reproduction studies have been performed in rats and rabbits at doses up to 16 times the highest human 

dose based on body surface area and have revealed no evidence of impaired fertility or harm to the fetus due to octreotide. There 

are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always 

predictive of human response, this drug should be used during pregnancy only if clearly needed. 

Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in milk, caution 

should be exercised when Sandostatin LAR ® Depot is administered to a nursing woman. 

Pediatric Use: The efficacy and safety of Sandostatin LAR Depot were examined in a randomized, double-blind, placebo-controlled 

six-month study in 60 pediatric patients aged 6-17 years with hypothalamic obesity resulting from cranial insult. Mean BMI 

increased 0.1 kg/m 2 in Sandostatin LAR Depot-treated subjects compared to 0.0 kg/m 2 in saline control-treated subjects. Diarrhea 

occurred in 11 of 30 (37%) patients treated with Sandostatin LAR Depot. No unexpected adverse events were observed. However, 

with Sandostatin LAR Depot 40 mg once a month, the incidence of new cholelithiasis in this pediatric population (33%) was higher 

than that seen in other adult indications such as acromegaly (22%) or malignant carcinoid syndrome (24%), where Sandostatin LAR 

Depot dosing was 10 to 30 mg once a month. 

Experience with Sandostatin Injection in the pediatric population is limited. Its use has been primarily in patients with congenital 

hyperinsulinism (also called nesidioblastosis). The youngest patient to receive the drug was 1 month old. At doses of 1-40 mcg/kg 

body weight/day, the majority of side effects observed were gastrointestinal- steatorrhea, diarrhea, vomiting and abdominal distention. 

Poor growth has been reported in several patients treated with Sandostatin ® Injection for more than 1 year; catch-up growth 

occurred after Sandostatin ® Injection was discontinued. A 16-month-old male with enterocutaneous fistula developed sudden 

abdominal pain and increased nasogastric drainage and died 8 hours after receiving a single 100 mcg subcutaneous dose of 

Sandostatin ® Injection. 

Geriatric Use: Clinical studies of Sandostatin did not include sufficient numbers of subjects aged 65 and over to determine 

whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in 

responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually 

starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and 

of concomitant disease or other drug therapy. 

ADVERSE REACTIONS (See WARNINGS and PRECAUTIONS): Gallbladder abnormalities, especially stones and/or biliary sludge, 

frequently develop in patients on chronic octreotide therapy (see WARNINGS). Few patients, however, develop acute symptoms 

requiring cholecystectomy. 

Cardiac: In acromegalics, sinus bradycardia (

Sandostatin LAR ® Depot (octreotide acetate for injectable suspension) 

is indicated for long-term maintenance therapy in acromegalic 

patients for whom medical treatment is appropriate and who have 

been shown to respond to and can tolerate immediate release 

Sandostatin ® (octreotide acetate) Injection. The goal of treatment in 

acromegaly is to reduce GH and IGF-I levels to normal. Sandostatin 

LAR ® Depot can be used in patients who have had an inadequate 

response to surgery or in those for whom surgical resection is not an 

option. It may also be used in patients who have received radiation 

and have had an inadequate therapeutic response. 

As with immediate release Sandostatin ® Injection, the most 

frequently reported drug-related adverse events were biliary 

disorders (52%), gastrointestinal disorders (7% to 36%), and injection- 

Please see Brief Summary of Prescribing Information on adjacent page. 

©2007 Novartis 12/07 C-SDS-100010 

FOR PROVEN EFFICACY 

IN THE MEDICAL TREATMENT OF ACROMEGALY 

Face the Facts 

57-68 %* of patients experienced 

GH

SOM230 (pasireotide): Our next generation in somatostatin analogue therapy 

Now Enrolling Adult Patients in a 

Phase III Clinical Trial for Cushing’s Disease 

Protocol No. CSOM230B2305 

SIG-CUSHINGS Study Title: 

A randomized, double-blind study to assess the safety and effi cacy of different dose levels of Pasireotide (SOM230) s.c. 

over a 6 month treatment period in patients with de novo, persistent or recurrent Cushing’s disease 

Study Design: 

Screening/ 

washout 

Randomization 

600 µg pasireotide bid 

900 µg pasireotide bid 

Primary End Point: 

Assess the effi cacy in terms of response to pasireotide 600 µg SC bid and 900 µg SC bid independently in intent-to-treat 

patients with Cushing’s disease, as measured by mean UFC ≤1.0 x ULN from baseline after 6 months of treatment 

Key Inclusion Criteria*: 

Diagnosis of ACTH-dependent Cushing’s disease as defi ned by: 

a. Mean UFC of four 24-hour urine samples collected within 2 weeks, at least 1.5 times the ULN 

b. Morning plasma ACTH within the normal or above normal range 

c. Either MRI confi rmation of pituitary macroadenoma (≥1 cm), or inferior petrosal sinus gradient >3 after 

CRH stimulation for those patients with a microadenoma (tumor

JCEMTM 

THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 

Editor-in-Chief 

Paul W. Ladenson 

Deputy Editors 

David S. Cooper 

Steven E. Kahn 

Editors 

Robert L. Barbieri 

Shalender Bhasin 

George S. Eisenbarth 

Charis E. L. Eng 

Abhimanyu Garg 

Sally Radovick 

Janet A. Schlechte 

Dolores M. Shoback 

William F. Young, Jr. 

Editorial Board 

John S. Adams 

Beverley Adams Huet 

Anil K. Agarwal 

Micheala A. Aldred 

Erik K. Alexander 

Bruno Allolio 

Bradley D. Anawalt 

Aydin M. Arici 

Wiebke Arlt 

Ricardo Azziz 

Ashok Balasubramanyam 

Douglas W. Ball 

Lars F. Berglund 

Bernadette Biondi 

Ezio Bonifacio 

Glenn D. Braunstein 

Matthew A. Brown 

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Hong-Wen Deng 

14A 

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Hang Lee 

Phillip D. K. Lee 

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Deborah J. Marsh 

Enio Martino 

Norman A. Mazer 

Michael T. McDermott 

T. Joseph McKenna 

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Long Ngo 

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Elif Oral 

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Annabelle Rodriguez 

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John A. H. Wass 

Nelson B. Watts 

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Group Managing Editor, 

Associate Director 

Scott C. Herman 

Assistant Managing Editor 

Chris Forsberg 

Medical Writer 

Jacqueline Ruttimann 

Manuscript Coordinators 

Rebecca Kelly 

Liliana Medel

A simply effective way to go 

Somatuline ® Depot is the only 28-day acromegaly 

therapy available in a ready-to-use, prefilled syringe 1,2 

• 80% less volume than long-acting octreotide (0.2 – 0.5 mL vs 2.5 mL) 1-3* 

• 20-mm, 18-gauge needle 1 

• Simple-to-prepare, deep subcutaneous injection with no reconstitution required 1 

• Significant, long-term reductions in IGF-1 and GH levels of 55% and 76%, respectively, after 52 weeks 1† 

• Generally well-tolerated therapy with a low 1.9% treatment-related discontinuation rate 1,3‡ 

A simply e fective way to go 

Please see full Prescribing Information or visit www.somatulinedepot.com for additional important information. 

*Comparative clinical relevance is unknown. 

† From a 52-week study of 108 patients with acromegaly. 

‡ Pooled data from 7 safety studies with Somatuline® Depot in 416 patients with acromegaly. 

Volume (mL) 

2.5 mL 

Long-acting octreotide 

Somatuline ® Depot 

0.2 – 0.5 mL 

Shown actual size.

Indication and safety information 

Somatuline ® Depot (lanreotide) Injection is a somatostatin analog 

indicated for the long-term treatment of patients with acromegaly 

who have had an inadequate response to or cannot be treated with 

surgery and/or radiotherapy. 

Lanreotide may reduce gallbladder motility and lead to gallstone 

formation. Periodic monitoring may be needed. Patients treated with 

Somatuline ® Depot may experience hypoglycemia or hyperglycemia. 

Glucose level monitoring is recommended and antidiabetic treatment 

adjusted accordingly. Lanreotide may lead to a decrease in heart 

rate. Use with caution in at-risk patients. 

Patients with moderate and severe renal impairment or moderate and 

severe hepatic impairment should begin treatment with Somatuline ® 

Depot 60 mg. 

There are no adequate and well-controlled studies in pregnant 

women. Because animal reproduction studies are not always 

predictive of human responses, Somatuline ® Depot should be used 

during pregnancy only if the potential benefit justifies risk to the 

fetus. A decision should be made whether to discontinue nursing 

or discontinue the drug taking into account the importance of the 

drug to the mother. 

Somatuline ® Depot may decrease the bioavailability of cyclosporine. 

Cyclosporine dose may need to be adjusted to maintain levels. 

Patients receiving beta-blockers, calcium channel blockers, or other 

drugs that affect heart rate may need dose adjustments. Somatuline ® 

Depot may reduce the intestinal absorption of coadministered drugs. 

Caution should be used. 

The most common adverse reactions (incidence >5%) are diarrhea, 

cholelithiasis, abdominal pain, nausea, injection-site reaction, 

flatulence, arthralgia, and loose stools. 

Please see full Prescribing Information or visit 

www.somatulinedepot.com for additional important information. 

References: 1. Somatuline ® Depot (lanreotide) Injection [prescribing information]. Paris, France: Beaufour Ipsen Pharma; 2007. 

2. Sandostatin LAR ® Depot [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2006. 3. Data on 

file. Brisbane, Calif: Tercica, Inc.; 2007. 

Somatuline ® Depot is manufactured by Ipsen Pharma Biotech (Signes, France) for Beaufour Ipsen Pharma and 

distributed in the United States by Tercica, Inc. 

www.somatulinedepot.com 

©2008 Tercica, Inc. January 2008. DEP030US 

A simply effective way to go 

HIGHLIGHTS OF PRESCRIBING INFORMATION 

These highlights do not include all the information needed to use 

Somatuline Depot safely and effectively. See full prescribing information 

for Somatuline Depot. 

SOMATULINE ® DEPOT (lanreotide) INJECTION 

Initial U.S. Approval: 2007 

Somatuline Depot (lanreotide) Injection is a somatostatin analog indicated for: 

• The long-term treatment of acromegalic patients who have had an inadequate 

response to or cannot be treated with surgery and/or radiotherapy (1) 

----------------------DOSAGE AND ADMINISTRATION------------------------ 

• Dose range of 60 mg to 120 mg every 4 weeks (2) 

• Recommended dose is 90 mg every 4 weeks for 3 months. Adjust thereafter 

based on GH and/or IGF-1 levels (2) 

• Renal and Hepatic Impairment: Initial dose is 60 mg every 4 weeks for 3 

months in moderate and severe renal or hepatic impairment. Adjust thereafter 

based on GH and/or IGF-1 levels. (2, 12.3) 

• Injected in the superior external quadrant of the buttock. Injection site should 

be alternated (2) 

• Store at 2-8°C (36-46°F) in the original package (16.2) 

----------------------DOSAGE FORMS AND STRENGTHS---------------------- 

Single use syringe: 60, 90, and 120 mg (3) 

-----------------------------CONTRAINDICATIONS------------------------------ 

None 

------------------------WARNINGS AND PRECAUTIONS----------------------- 

• Gallbladder: Gallstones may occur; consider periodic monitoring (5.1) 

• Glucose Metabolism: Hypo- and/or hyperglycemia may occur. Glucose 

monitoring is recommended and anti-diabetic treatment adjusted accordingly 

(5.2) 

• Cardiac Function: Decrease in heart rate may occur. Use with caution in 

at-risk patients (5.3) 

-------------------------------ADVERSE REACTIONS---------------------------- 

Most common adverse reactions are diarrhea, cholelithiasis, abdominal pain, 

nausea, and injection-site reactions (6) 

To report SUSPECTED ADVERSE REACTIONS, contact Tercica at 1-866- 

837-2422 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 

-------------------------------DRUG INTERACTIONS---------------------------- 

• Hypoglycemia agents: Hypo- and/or hyperglycemia may occur. Glucose 

monitoring is recommended and anti-diabetic treatment adjusted accordingly 

(7.1) 

• Cyclosporine: Somatuline ® Depot may decrease the bioavailability of 

cyclosporine. Cyclosporine dose may need to be adjusted (7.2) 

• Drugs affecting heart rate: Somatuline ® Depot may decrease heart rate. 

Dose adjustment of coadministered drugs that decrease heart rate may 

be necessary (7.3) 

---------------------------USE IN SPECIFIC POPULATIONS-------------------- 

• Renal Impairment: Start dose is 60 mg in moderate and severe renal 

impairment (2, 8.6, 12.3) 

• Hepatic Impairment: Start dose is 60 mg in moderate and severe hepatic 

impairment (2, 8.6, 12.3) 

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved 

patient labeling. 

Revised: 08/2007

NDOCRINOLOGY & METABOLISM NEWS 

NEWSE 

Endocrine Discovery 

Central precocious puberty in a girl was found 

to be associated with a mutation in GPR54, a 

G protein–coupled receptor recently associated 

with its ligand, kisspeptin, which, in turn, 

stimulates the neuroregulatory system for gonadotropin-releasing 

hormone secretion. In vitro functional 

studies showed this mutation prolonged 

kisspeptin-mediated activation of its intracellular 

signaling pathways. (N Engl J Med [February 14, 

2008] 358(7):709) 

Patients receiving levothyroxine therapy after 

undergoing near-total or total thyroidectomy 

achieved normal T 3 levels without T 3 supplementation, 

suggesting that combination therapy 

may not be warranted. (JAMA [February 20, 2008] 

299(7):769) 

In the Diabetes Prevention Project cohort of 

3,187 individuals at risk for the development 

of diabetes, the presence of depression initially 

or later during the study was unassociated 

with diabetes risk. While antidepressant use 

was associated with diabetes risk in the placebo and 

lifestyle arms of the study, it was not in those on 

metformin. (Diabetes Care [March 2008] 31(3):420) 

In overweight Hispanic children and adolescents 

with normal glucose tolerance, plasma 

markers of endothelial dysfunction and subclinical 

inflammation increased in parallel with 

their degrees of excess body fat and increased 

insulin resistance, possibly contributing to their 

greater risk of developing type 2 diabetes and cardiovascular 

disease. (Diabetes Care [March 2008] 

31(3):576) 

In a prospective study of 50 individuals undergoing 

total thyroidectomy, normal serum T 3 

levels similar to the patients’ baseline values 

were achieved with L-thyroxine therapy alone 

in most patients, suggesting that T 3 administration 

would be of no additional benefit. (JAMA [February 

20, 2008] 299(7):769) 

In a meta analysis of 42 trials assessing statin 

therapy for all-stroke prevention (n � 

121,285), the relative risk (RR) for stroke was 

reduced (RR � 0.84; 95% CI, 0.79–0.91). The RR 

of statin therapy for all-cause mortality (n � 

116,080) was also less (0.88; 95% CI, 0.83–0.93). 

(Am J Med [January 2008] 121(1):24) 

NALP5 appears to be a tissue-specific autoantigen 

involved in hypoparathyroidism in patients 

with APS-1. Autoantibodies against NALP5 

appear to be highly specific and may be diagnostic 

Readers are encouraged to suggest items for Endocrinology and 

Metabolism News by email (sherman@endo-society.org). Submissions 

will be considered based on their significance and 

timeliness. 

for this prominent component of APS-1. (N Engl 

J Med [March 6, 2008] 358(10):1018) 

In both insulin-deficient and insulin-resistant 

mice, diabetes-related impairment of hippocampus-dependent 

memory—as well as 

neurogenesis, synaptic plasticity, and learning—were 

all associated with elevated circulating 

corticosterone. These hippocampal 

changes in both models were reversed by maintenance 

of physiological corticosterone levels, suggesting 

that diabetes-related cognitive impairment 

might be glucocorticoid-mediated. (Nat Neurosci 

[March 2008] 11(3):309) 

� cell progenitors in the pancreatic duct lining 

of adult mice can be activated in the injured 

pancreas, a process dependent on neurogenin 

3 expression, and one that generates � cells as 

well as all other islet cell types, implying that 

pluripotent progenitor cells do exist in the adult 

mouse pancreas and can be autonomously activated 

to expand � cell mass. (Cell [January 25, 2008] 

132(2): 197) 

A novel phosphoinositide-binding domain in 

O-GlcNAc transferase (OGT) has been shown 

to modify the insulin signaling pathway, with 

hepatic overexpression of OGT inhibiting expression 

of insulin-responsive genes and causing insulin resistance 

and dyslipidemia. This represents a new 

molecular mechanism for nutritional signals to regulate 

insulin signalling through O-GlcNAc. (Nature 

[February 21, 2007] 451(7181):964) 

Osteoblast-specific Notch function gain increased 

proliferation of immature osteoblasts, 

causing osteosclerosis, an action mediated by 

up-regulation of the cyclin D, cyclin E, and Sp7 

(osterix) genes; loss of osteoblastic Notch signaling 

was associated with age-related osteoporosis. 

(Nat Med [March 2008] 14(3):299) 

Intermittent TSH administration to mice and 

rats exerted antiresorptive actions in vivo, preventing 

bone loss and restoring previously 

lost bone after ovariectomy. Inhibition of osteoclast 

action was also observed in cells overexpressing 

a constitutively active TSH receptor, whereas a 

mouse model with a dysfunction TSH receptor mutant 

showed increased osteoclast differentiation–all 

implying that TSH receptors play a role in regulation 

of bone remodeling. (Proc Natl Acad Sci USA 

[March 18, 2008] 105(11):4289) 

Unliganded thyroid hormone receptor �1 in 

maternal mice causes locomotor deficiencies 

and aberrant development of parvalbuminimmunoreactive 

GABAergic interneurons in 

the neocortex of their offspring, implying there 

may be a previously unknown basis for endemic 

cretinism and untreated congenital hypothyroidism. 

(J Neurosci [Feb. 20, 2008] 28(8):1904) 

“. . .as 

endocrinologists, we 

are going to have to 

do a better job of 

individualizing A1c 

targets—different 

populations handle 

A1c levels 

differently,” Irl Hirsch, 

M.D., on the latest 

ADVANCE trial results 

that, unlike those 

from the ACCORD 

trial, affirm aggressive 

serum glucose 

treatment in type 2 

diabetes patients. 

NEWS 

J Clin Endocrinol Metab, April 2008, 93(4):17A–20A jcem.endojournals.org 17A

ENDOCRINOLOGY & METABOLISM NEWS 

“The take-home 

message is that there 

are risks while you’re 

taking it and most of 

those risks appear to 

go away when you 

stop,” Elizabeth 

Barrett-Connor, M.D., 

summarizing the 

latest WHI findings 

on women who stop 

estrogen-plusprogestin 

treatment 

after 3 years. 


In patients with chronic hepatitis C, insulin resistance 

is associated with viral genotypes 1 

and 4, high serum HCV RNA level, and significant 

liver fibrosis. (Gastroenterology [Feb. 2008] 

134:416) 

In a meta-analysis of studies examining the 

relationship between body mass index and 

risk of cancers (141 articles with 282,137 subjects), 

the risks of several common and less 

common cancers—including thyroid, endometrial, 

and renal cancer—increased with higher 

body mass index, with the degree of risk differing 

among genders and different ethnic groups. (Lancet 

[Feb. 16, 2008] 317:569) 

Calcitriol treatment of patients with chronic 

kidney disease not yet receiving dialysis was 

associated with better short-term survival in a 

study of 520 male patients with chronic renal disease 

stages 3 to 5 followed for 2 years. (Arch Intern 

Med [Feb. 25, 2008] 168(4):397) 

Largest Type 2 Diabetes Trial Affirms 

Aggressive Serum Glucose Treatment 

New data from an international trial has heightened 

controversy about the cardiovascular value 

and risks of very tight glycemic control for individuals 

with type 2 diabetes. In February, the ACCORD 

trial run by the U.S. National Heart, Lung, and Blood 

Institute revealed that lowering A1c levels to 6.0% 

was associated with excess deaths—257, compared 

to 203 in the standard treatment group—resulting 

in premature termination of that study arm. 

Now results recently released from the ADVANCE 

(Action in Diabetes and Vascular Disease: Preterax 

and Diamicron MR Controlled Evaluation) trial finds 

no evidence that aggressive treatment increases 

their risk of death. ADVANCE is a randomized control 

study that enrolled 11,140 type 2 diabetes patients 

at high risk for heart disease from about 200 

clinical centers in 20 countries in Asia, Australia, Europe, 

and North America. As in the ACCORD trial, 

this study aimed to reduce hemoglobin A1c levels, 

but only to less than 6.5%, through an intensive, 

modified-release glicazide-based regimen. This 

study has longer follow-up time than the ACCORD 

trial. 

Due to the similar treatment arms of both studies, 

the ADVANCE mortality data was reviewed by the 

Data and Safety Monitoring Committee to determine 

if similar increase in mortality would also have 

been seen. “At this stage, the Data Monitoring and 

Safety Committee have reviewed results that are 

more than 99% complete, so we are confident that 

the interim findings are a reliable guide to the final 

results,” said Anushka Patel, FRACP, ADVANCE 

study leader at The George Institute in Sydney, cautioning 

that “until we have the final results of both 

studies, it would be most reasonable to advise patients 

and doctors to continue to follow current 

guidelines.” 

18A jcem.endojournals.org J Clin Endocrinol Metab. April 2008, 93(4):17A–20A 

The final results of the ADVANCE trial will be presented 

this June at the American Diabetes Association 

annual meeting, with a resulting publication 

to follow soon thereafter. In the meantime, endocrinologists 

can only speculate as to what will be the 

final resolution of the controversy arising from these 

conflicting trial results. 

“It appears, from the data now available, that 

hypoglycemia has a different impact on different 

populations. For those with advanced vascular disease, 

it seems that hypoglycemia is more dangerous 

than those without,” said Irl Hirsch, M.D., professor 

at the University of Washington School of Medicine 

in Seattle. “Furthermore, for this population, it appears 

that control of blood pressure and cholesterol 

seems more important.” 

Some research clinicians have postulated that the 

differences seen between the two studies could be 

due to the American patients being heavier and thus 

more at risk for heart disease, or that the ADVANCE 

trial patients received gliclazide, a drug unavailable 

in the United States. Most, however, agree that for 

the time being, patients should have treatments developed 

with an eye toward their personal medical 

history. 

“As medical professionals, but especially as endocrinologists, 

we are going to have to do a better 

job of individualizing A1c targets– different populations 

handle A1c levels differently,” said Hirsch. 

Women’s Health Initiative Study Shows 

Overall Risks Outweigh Benefits in Short- 

Term Combined Hormone Replacement 

Therapy 

The latest results from the Women’s Health Initiative 

(WHI) indicate that even halting combination 

hormone therapy after a couple of years following 

menopause, overall risks still outweigh the benefits. 

Launched in 1991 and sponsored by the National 

Heart, Lung, and Blood Institute at the National Institutes 

of Health, the WHI consisted of a set of 

clinical trials and an observational study investigating 

the quality of life and risk for cardiovascular disease, 

cancer, stroke, and bone fractures on generally 

healthy postmenopausal women either on 

placebo, estrogen, or a combination of estrogen 

and progestin. The combined therapy trial was limited 

to 16,608 women with a uterus. 

The trials looking at the effects of combined therapy 

were stopped in 2002, after it was found that 

women on these treatments had higher risks of 

breast cancer, stroke, blood clots, and heart disease, 

while the risk of colorectal cancer and hip fractures 

were lower compared to women who did not take 

the therapy. Since then, the U.S. Food and Drug 

Administration have emphasized that those who 

are prescribed this type of medication should only 

take it at the smallest effective dose for the shortest 

time possible. 

The latest study, published in the March 5, 2008 

issue of JAMA, followed 15,730 women, aged 50 to

NDOCRINOLOGY & METABOLISM NEWS 

NEWSE 

70 years with an intact uterus, for approximately 3 

years after they stopped taking estrogen-plus-progestin. 

The participants underwent a yearly health 

exam and mammogram, with biopsies performed 

as needed. After three years, the previously established 

risk of heart disease was diminished, but overall 

risks, including that of stroke, blood clots, and 

cancer, remained. Specifically, the risk of breast cancer 

continued at a rate similar to that seen during 

treatment; women who had stopped taking combined 

therapy were 27% more likely to develop 

breast cancer than those on placebo. The study also 

found that other effects of combined therapy, such 

as decreased risk of colorectal cancer and hip fractures, 

also stopped when therapy ended. In sum, the 

global risk index was 12% higher in women assigned 

to combined hormonal therapy than 

placebo. 

Elizabeth G. Nabel, M.D., NHLBI director, said the 

article “confirms the study’s primary conclusion that 

combination hormone therapy should not be used 

to prevent disease in healthy, premenopausal 

women.” Added Michael Lauer, M.D., director of 

the NHLBI Division of Prevention and Population Sciences: 

“All the accumulated risks do not simply 

disappear.” 

Yet outside physicians did not draw as negative a 

conclusion. “The take-home message is that there 

are risks while you’re taking it and most of those 

risks appear to go away when you stop,” said Elizabeth 

Barrett-Connor, M.D., professor and division 

chief of epidemiology at the University of California 

in San Diego. “The not-so-good news is that the risk 

of cancer doesn’t go away.” The bottom line, she 

said, is that, “The risks of combined hormone therapy 

are very small and the benefits are very small. 

The trick here is how to advise women in the way 

that is best for their health and quality of life and not 

to scare them.” 

Similarly, in his practice, Robert Barbieri, M.D., 

gynecology and reproductive biology professor at 

Harvard Medical School in Boston, Massachusetts, 

takes the age of his patients under consideration. “I 

think the risks are quite modest with someone in 

their 40s and 50s,” he said. “If I see people in their 

60s with hormone replacement therapy, I take a 

more active stance in trying to get them to stop it.” 

(JAMA [March 5, 2008] 299(9):1036) 

Restricting Insulin Doses Increases 

Mortality Risk 

Women with type 1 diabetes who reported taking 

less insulin than prescribed had a three-fold 

greater risk of death and higher rates of complications 

than those who did not skip needed insulin 

shots, researchers at the Joslin Diabetes Center report 

in the March issue of Diabetes Care. This reported 

danger casts further light onto what is referred 

to in the popular press as “diabulimia,” an 

eating disorder in which people with type 1 diabetes 

deliberately take less insulin than they need for the 

purposes of weight loss. The attention to diet, 

weight, and glycemic control associated with diabetes 

management can trigger this behavior, observed 

more often in younger females. 

In their study, 234 women from age 13 to 60 with 

type 1 diabetes were followed for 11 years. At the 

study’s onset, 30% of these women reported taking 

less insulin than they should for a number of reasons, 

including weight concerns and related eating 

disorders, as well as other psychological symptoms 

such as depression, anxiety, or fear of hypoglycemia. 

Researchers found that, compared to those 

who regularly took insulin, the insulin restrictors had 

increased mortality along with higher rates of nephropathy 

and foot problems. This was true even 

though the mean age of death was actually younger 

for insulin restrictors compared to insulin takers: 45 

years versus 58 years. 

“There is a subset of women for whom their fears 

of weight gain and their extreme desire for thinness 

interferes with appropriate diabetes self-care,” said 

lead author, Ann Goebel-Fabbri, Ph.D., psychologist 

and instructor at Harvard Medical School, who 

noted that other studies have shown women with 

diabetes are nearly 2.5 times more likely to develop 

an eating disorder than women without diabetes. 

Goebel-Fabbri and her team propose a screening 

question appropriate for routine diabetes care— 

“Do you take less insulin than you should”—to increase 

the likelihood of earlier detection of this 

problem and improve access to specialty treatment 

referrals for these high-risk patients. 

“Raising awareness of the impact of insulin restriction 

among clinicians who treat type 1 diabetes 

is extremely important so that they can make appropriate 

assessments and referrals to mental 

health professionals who are experienced in the 

treatment of people with diabetes,” said study coauthor 

Katie Weinger, Ed.D., R.N., and assistant 

professor of psychiatry at Harvard Medical School. 

Warning signs of insulin restriction can include 

unexplainable spikes in their hemoglobin A1c; 

weight loss; unusual pattern of intense exercise; 

lack of marks from finger sticks; lack of prescription 

refills for diabetes medications; repeated problems 

with diabetic ketoacidosis; amenorrhea; and blood 

glucose records that do not match hemoglobin A1c. 

Making an eating disorder diagnosis, however, 

can be somewhat tricky cautioned Jennifer Larsen, 

M.D., diabetes, endocrinology, and metabolism 

section chief at the University of Nebraska Medical 

Center. “It’s not so clear cut. Some tools used to 

identify eating disorders can be globally abnormal 

for many patients with diabetes.” (Diabetes Care 

[March 2008] 31(3):415) 

Climate and Metabolic Syndrome 

There may be a predisposition towards metabolic 

disorders and diabetes based on the climate in 

which people live, according to a recent population 

genetics study performed by University of Chicago 

researchers. The notion isn’t too far-fetched. Previ- 

“There is a subset of 

women for whom 

their fears of weight 

gain and their 

extreme desire for 

thinness interferes 

with appropriate 

diabetes self-care,” 

Ann Goebel-Fabbri, 

Ph.D., on her study 

showing that women 

with type 1 diabetes 

who restrict their 

insulin have a threefold 

greater risk of 

death and disease 

complications. 


J Clin Endocrinol Metab, April 2008, 93(4):17A–20A jcem.endojournals.org 19A

ENDOCRINOLOGY & METABOLISM NEWS 

“The same variants 

that allowed humans 

to adapt to different 

climates . . . could 

increase the risk to 

some of these 

diseases,” Anna Di 

Rienzo, Ph.D., 

discussing her study 

that shows a possible 

link between climate 

and metabolic 

syndrome. 


ously scientists have noted that humans inhabiting 

colder regions were stockier and had relatively 

shorter arms and legs compared to their sunnier 

southern and equatorial neighbors. Correlations 

have also been made between colder climates and 

increased body mass index. 

In her study in the February issue of PLoS Genetics, 

genetics professor Anna Di Rienzo, Ph.D., examined 

52 populations from 5 continents—about 

1,000 people—for differences in allele patterning 

from 82 genes associated with energy metabolism. 

The genes were used as “bait” to fish out additional 

genes that may also be implicated. Among the 

“caught” genes, they found several single nucleotide 

polymorphisms associated with phenotypes related 

to cold tolerance such as those from the leptin 

receptor and fatty acid binding protein 2. 

“Climate has been an important selective pressure 

during human evolution,” said Di Rienzo. “Our 

earliest human ancestors lived in a hot, humid climate 

that placed a premium on dispersing heat. As 

some populations migrated out of Africa to much 

cooler climates, there would have been pressure to 

adapt to their new settings by boosting the processes 

that produce and retain heat. . . .The same 

variants that allowed humans to adapt to different 

climates also under some circumstances could increase 

the risk to some of these diseases.” 

Since then, she said, the consequences of climate 

have been attenuated by our modern lifestyle of 

nice heated and air conditioned homes. In short, our 

genes have yet to catch up to this lifestyle change. 

“It’s a very provocative set of findings,” said Nancy 

Cox, Ph.D., fellow geneticist at the University of Chicago 

who was not involved in this study. “We’re seeing 

in today’s genes things that occurred over 10,000 

years ago when climate was a bigger deal.” 

Endocrinologist Puneet Arora, M.D., at Regions 

Hospital in St. Paul, Minnesota, concurred, and 

added that this study will spur future epidemiological 

studies. “This is mostly a statistical construct at 

this point,” he said. “It would be interesting to see 

if these specific polymorphisms can now be localized 

to populations we already know to be more 

susceptible to metabolic disorders.” (PLoS Genet 

[February 2008] 4(2):e32) 

Endocrine Policy 

The National Institute of Diabetes and Digestive and Kidney 

Diseases released publications containing health information 

to raise awareness about diabetes, digestive 

diseases, and kidney and urologic diseases among 

people not yet diagnosed with the disease. These fact 

sheets, available in Spanish and English, can be 

viewed online at http://www2.niddk.nih.gov/ 

HealthEducation/Awareness � and � Prevention � 

Series.htm 

20A jcem.endojournals.org J Clin Endocrinol Metab. April 2008, 93(4):17A–20A 

Students in the health professions will now be able to 

borrow up to $224,000 total in Stafford loans, an increase 

from the previous $189,125 limit, based on a decreefromtheU.S.DepartmentofEducation;theincrease 

allows students to take on additional unsubsidized loans 

at a 6.8 percent interest rate. (For more information, see: 

http://www.aamc.org/advocacy/library/educ/corres/ 

2008/022808hploanlimits.pdf) 

Endocrine Practice 

FDA approved the first generic formulation of 

the bisphosphonate Fosamax (alendronate sodium 

tablets) in three once-daily dosing strengths (5 

mg, 10 mg, and 40 mg) and two once-weekly dosing 

strengths (35 mg and 70 mg). (For more information, 

see: http://www.fda.gov/bbs/topics/NEWS/ 

2008/NEW01793.html) 

The National Osteoporosis Foundation has released 

a new guideline for treatment of people 

with low bone mass, “Clinician’s Guide to 

Prevention and Treatment of Osteoporosis,” 

The document provides guidance regarding procedures 

for treating minority postmenopausal women 

and, for the first time, for men aged 50 and older. 

It also features the World Health Organization’s 

newly released algorithm on absolute fracture risk 

called FRAX®. (To view this guideline, see: 

http://www.nof.org/professionals/clinical.htm) 

U.S. adults spent nearly $36 billion on prescription 

drugs to lower blood sugar, reduce cholesterol, 

or help manage other metabolic problems 

in 2005, with this class of drugs ranking first in terms 

of total prescription drug expenses, according to the 

latest information from the U.S. Department of Health 

and Human Services’s Agency for Healthcare Research 

and Quality. (For more information, go to: http :// 

www.meps.ahrq.gov/mepsweb/data_files/publications/ 

st198/stat198.pdf) 

Milestones in Endocrinology 

Fifty years ago, Verner-Morrison described the watery 

diarrhea hypokalaemic achlorhydric syndrome. 

In the Journal 25 Years Ago 

Loss of circadian rhythmicity in blood testosterone 

levels with aging in normal men. Bremner WJ, Vitiello 

MV, Prinz PN. J Clin Endocrinol Metab 

1983;56:1278–1281. 

“The circadian rhythm in serum testosterone levels 

found in normal young men were markedly attenuated 

or absent in healthy elderly men; the early 

morning rise in testosterone levels characteristic of 

young men was not present in old age.”

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25A

Important Safety Information 

• Antidepressants increased the risk of suicidal 

thinking and behavior (suicidality) in short-term 

studies in children, adolescents, and young adults 

with major depressive disorder (MDD) and other 

psychiatric disorders. 

• Patients of all ages started on therapy should be 

monitored appropriately and observed closely for clinical 

worsening, suicidality, or unusual changes in behavior. 

• Cymbalta is not approved for use in pediatric patients. 

Cymbalta should not be used concomitantly with monoamine oxidase 

inhibitors (MAOIs) or in patients with uncontrolled narrow-angle glaucoma. 

Clinical worsening and suicide risk: All patients being treated with an 

antidepressant for any indication should be monitored appropriately 

and observed closely for clinical worsening, suicidality, and unusual 

changes in behavior, especially within the fi rst few months of treatment 

and when changing the dose. Consider changing the therapeutic regimen 

if the depression is persistently worse or there are symptoms that are severe, 

sudden, or were not part of the patient’s presentation. If discontinuing 

treatment, taper the medication. Families and caregivers of patients being 

treated with antidepressants for any indication should be alerted about 

the need to monitor patients. 

Postmarketing, severe elevations of liver enzymes or liver injury with 

a hepatocellular, cholestatic, or mixed pattern have been reported. 

Cymbalta should ordinarily not be prescribed to patients with substantial 

alcohol use or evidence of chronic liver disease. 

Cases of orthostatic hypotension and/or syncope as well as cases of 

hyponatremia have been reported. 

Development of a potentially life-threatening serotonin syndrome may 

occur with SNRIs and SSRIs, including Cymbalta treatment, particularly 

with concomitant use of serotonergic drugs, including triptans. 

Concomitant use is not recommended.

In pooled analysis and in individual studies, Cymbalta produced a 

signifi cant separation (P

CYMBALTA� 

(duloxetine hydrochloride) Delayed-release Capsules 

Brief Summary: Consult the package insert for complete prescribing information. 

WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS 

Antidepressants increased the risk compared to placebo of suicidal thinking 

and behavior (suicidality) in children, adolescents, and young adults in short-term 

studies of major depressive disorder (MDD) and other psychiatric disorders. 

Anyone considering the use of Cymbalta or any other antidepressant in a child, 

adolescent, or young adult must balance this risk with the clinical need. 

Short-term studies did not show an increase in the risk of suicidality with 

antidepressants compared to placebo in adults beyond age 24; there was a reduction 

in risk with antidepressants compared to placebo in adults aged 65 and older. 

Depression and certain other psychiatric disorders are themselves associated 

with increases in the risk of suicide. Patients of all ages who are started on 

antidepressant therapy should be monitored appropriately and observed closely for 

clinical worsening, suicidality, or unusual changes in behavior. Families and 

caregivers should be advised of the need for close observation and communication 

with the prescriber. Cymbalta is not approved for use in pediatric patients. [See 

Warnings and Precautions and Use in Specific Populations.] 

INDICATIONS AND USAGE: Major Depressive Disorder—Cymbalta is indicated for the 

acute and maintenance treatment of major depressive disorder (MDD). 

Diabetic Peripheral Neuropathic Pain—Cymbalta is indicated for the management of 

neuropathic pain associated with diabetic peripheral neuropathy. 

Generalized Anxiety Disorder—Cymbalta is indicated for the acute treatment of 

generalized anxiety disorder (GAD). 

CONTRAINDICATIONS: Monoamine Oxidase Inhibitors—Concomitant use in patients 

taking monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of serious, 

sometimes fatal, drug interactions with serotonergic drugs. These interactions may include 

hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of 

vital signs, and mental status changes that include extreme agitation progressing to delirium 

and coma. These reactions have also been reported in patients who have recently 

discontinued serotonin reuptake inhibitors and are then started on an MAOI. Some cases 

presented with features resembling neuroleptic malignant syndrome [see Warnings 

and Precautions]. 

Uncontrolled Narrow-Angle Glaucoma—In clinical trials, Cymbalta use was associated 

with an increased risk of mydriasis; therefore, its use should be avoided in patients with 

uncontrolled narrow-angle glaucoma [see Warnings and Precautions]. 

WARNINGS AND PRECAUTIONS: Clinical Worsening and Suicide Risk—Patients k with 

major depressive disorder (MDD), both adult and pediatric, may experience worsening of 

their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual 

changes in behavior, whether or not they are taking antidepressant medications, and this 

risk may persist until significant remission occurs. Suicide is a known risk of depression and 

certain other psychiatric disorders, and these disorders themselves are the strongest 

predictors of suicide. There has been a long-standing concern, however, that antidepressants 

may have a role in inducing worsening of depression and the emergence of suicidality in 

certain patients during the early phases of treatment. 

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs 

and others) showed that these drugs increase the risk of suicidal thinking and behavior 

(suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive 

disorder (MDD) and other psychiatric disorders. Short-term studies did not show an 

increase in the risk of suicidality with antidepressants compared to placebo in adults 

beyond age 24; there was a reduction with antidepressants compared to placebo in 

adults aged 65 and older. 

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, 

obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 

24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses 

of placebo-controlled trials in adults with MDD or other psychiatric disorders included a 

total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs 

in over 77,000 patients. There was considerable variation in risk of suicidality among 

drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. 

There were differences in absolute risk of suicidality across the different indications, with 

the highest incidence in MDD. The risk of differences (drug vs placebo), however, were 

relatively stable within age strata and across indications. These risk differences (drug-placebo 

difference in the number of cases of suicidality per 1000 patients treated) are provided 

in Table 1. 

Table 1 

Age Range Drug-Placebo Difference in 

Number of Cases of Suicidality 

per 1000 Patients Treated 

Increases Compared to Placebo 

3 times the upper limit of normal occurred in 1.1% (75/6871) 

of Cymbalta-treated patients compared to 0.3% (13/5036) of placebo-treated patients. In 

placebo-controlled studies using a fixed-dose design, there was evidence of a dose-response 

relationship for ALT and AST elevation of >3 times the upper limit of normal and >5 times 

the upper limit of normal, respectively. Postmarketing reports have described cases of 

hepatitis with abdominal pain, hepatomegaly and elevation of transaminase levels to more 

than twenty times the upper limit of normal with or without jaundice, reflecting a mixed 

or hepatocellular pattern of liver injury. Cases of cholestatic jaundice with minimal elevation 

of transaminase levels have also been reported. 

The combination of transaminase elevations and elevated bilirubin, without evidence of 

obstruction, is generally recognized as an important predictor of severe liver injury. In 

clinical trials, three Cymbalta patients had elevations of transaminases and bilirubin, but 

also had elevation of alkaline phosphatase, suggesting an obstructive process; in these 

patients, there was evidence of heavy alcohol use and this may have contributed to the 

abnormalities seen. Two placebo-treated patients also had transaminase elevations with 

elevated bilirubin. Postmarketing reports indicate that elevated transaminases, bilirubin 

and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis. 

Because it is possible that duloxetine and alcohol may interact to cause liver injury or that 

duloxetine may aggravate pre-existing liver disease, Cymbalta should ordinarily not be 

prescribed to patients with substantial alcohol use or evidence of chronic liver disease. 

Orthostatic Hypotension and Syncope—Orthostatic hypotension and syncope have been 

reported with therapeutic doses of duloxetine. Syncope and orthostatic hypotension tend 

to occur within the first week of therapy but can occur at any time during duloxetine 

treatment, particularly after dose increases. The risk of blood pressure decreases may be 

greater in patients taking concomitant medications that induce orthostatic hypotension 

(such as antihypertensives) or are potent CYP1A2 inhibitors [see Warnings and Precautions 

and Drug Interactions] and in patients taking duloxetine at doses above 60 mg daily. 

Consideration should be given to discontinuing duloxetine in patients who experience 

symptomatic orthostatic hypotension and/or syncope during duloxetine therapy. 

Serotonin Syndrome—The development of a potentially life-threatening serotonin 

syndrome may occur with SNRIs and SSRIs, including Cymbalta treatment, particularly 

with concomitant use of serotonergic drugs (including triptans) and with drugs which 

impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms 

may include mental status changes (e.g., agitation, hallucinations, coma), autonomic 

instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular 

aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., 

nausea, vomiting, diarrhea). 

The concomitant use of Cymbalta with MAOIs intended to treat depression is 

contraindicated [see Contraindications]. 

If concomitant treatment of Cymbalta with a 5-hydroxytryptamine receptor agonist 

(triptan) is clinically warranted, careful observation of the patient is advised, particularly 

during treatment initiation and dose increases [see Drug Interactions]. 

The concomitant use of Cymbalta with serotonin precursors (such as tryptophan) is not 

recommended [see Drug Interactions]. 

Cymbalta� (duloxetine hydrochloride) PV 5907 AMP Cymbalta� (duloxetine hydrochloride) PV 5907 AMP

Abnormal Bleeding—SSRIs and SNRIs, including duloxetine, may increase the risk of Use in Patients with Concomitant Illness—Clinical experience with Cymbalta in 

bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, patients with concomitant systemic illnesses is limited. There is no information on the 

warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological effect that alterations in gastric motility may have on the stability of Cymbalta’s enteric 

studies (case-control and cohort design) have demonstrated an association between use coating. In extremely acidic conditions, Cymbalta, unprotected by the enteric coating, may 

of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal undergo hydrolysis to form naphthol. Caution is advised in using Cymbalta in patients 

bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, with conditions that may slow gastric emptying (e.g., some diabetics). 

hematomas, epistaxis, and petechiae to life-threatening hemorrhages. 

Cymbalta has not been systematically evaluated in patients with a recent history of 

Patients should be cautioned about the risk of bleeding associated with the concomitant myocardial infarction or unstable coronary artery disease. Patients with these diagnoses 

use of duloxetine and NSAIDs, aspirin, or other drugs that affect coagulation. 

were generally excluded from clinical studies during the product’s premarketing testing. 

Discontinuation of Treatment with Cymbalta—Discontinuation symptoms have Hepatic p Insufficiencyy—Cymbalta 

should ordinarily not be used in patients with hepatic 

been systematically evaluated in patients taking duloxetine. Following abrupt or tapered insufficiency [see Warnings and Precautions and Use in Specific Populations]. 

discontinuation in placebo-controlled clinical trials, the following symptoms occurred at Severe Renal Impairment p —Cymbalta should ordinarily not be used in patients with 

a rate greater than or equal to 1% and at a significantly higher rate in duloxetine-treated end-stage renal disease or severe renal impairment (creatinine clearance

occurred in 2% or more of patients treated with duloxetine and with an incidence greater than 

placebo were: Cardiac Disorders—palpitations; Eye y Disorders—vision 

blurred; 

Gastrointestinal Disorders—nausea, dry mouth, diarrhea, constipation∗ , abdominal pain 

(includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal 

discomfort, and gastrointestinal pain), vomiting; General Disorders and Administration 

Site Conditions—fatigue (includes asthenia); Investigations g —weight decreased∗ ; 

Metabolism and Nutrition Disorders—decreased appetite (includes anorexia); Nervous 

System y Disorders—dizziness, 

somnolence (includes hypersomnia and sedation), tremor; 

Psychiatric y Disorders—insomnia 

(includes middle insomnia, early morning awakening, 

and initial insomnia), agitation (includes feeling jittery, nervousness, restlessness, tension, and 

psychomotor agitation), anxiety, decreased libido (includes loss of libido), orgasm 

abnormal (includes anorgasmia), abnormal dreams (includes nightmare); Reproductive p 

System y and Breast Disorders—erectile 

dysfunction, ejaculation delayed, ejaculation disorder 

(includes ejaculation failure and ejaculation dysfunction); Respiratory, p y, Thoracic, , and 

Mediastinal Disorders—yawning; Skin and Subcutaneous Tissue Disorders—hyperhidrosis; 

Vascular Disorders—hot flush. ∗ Reactions are categorized by body system according to the following definitions: 

frequent adverse reactions are those occurring in at least 1/100 patients; infrequent 

adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are 

those occurring in fewer than 1/1000 patients. Cardiac Disorders—Frequent: palpitations; 

Events for which there was a significant dose-dependent 

relationship in fixed-dose studies, excluding three MDD studies which did not have a 

placebo lead-in period or dose titration. 

The most commonly observed adverse reactions in duloxetine-treated MDD/GAD 

patients (incidence of 5% or greater and at least twice the incidence in placebo patients) 

were nausea, dry mouth, constipation, somnolence, decreased appetite, and hyperhidrosis. 

Diabetic Peripheral p Neuropathic p Pain—Treatment-emergent 

adverse events that 

occurred in 2% or more of patients treated with Cymbalta in the premarketing acute phase 

of DPN placebo-controlled trials (N=225 Cymbalta 60 mg BID; N=228 Cymbalta 

60 mg QD; N=115 Cymbalta 20 mg QD; N=223 placebo) with an incidence greater than 

placebo were: Gastrointestinal Disorders—nausea, constipation, diarrhea, dry mouth, 

vomiting, dyspepsia, loose stools; General Disorders and Administration Site 

Conditions—fatigue, asthenia, pyrexia; Infections and Infestations—nasopharyngitis; 

Metabolism and Nutrition Disorders—decreased appetite, anorexia; Musculoskeletal and 

Connective Tissue Disorders—muscle cramp, myalgia; Nervous System y Disorders— 

somnolence, headache, dizziness, tremor; Psychiatric y Disorders—insomnia; 

Renal and 

Urinary y Disorders—pollakiuria; 

Reproductive p System y and Breast Disorders—erectile 

dysfunction; Respiratory, p y, Thoracic and Mediastinal Disorders—cough, 

pharyngolaryngeal 

pain; Skin and Subcutaneous Tissue Disorders—hyperhidrosis. 

The following events were reported by at least 2% of patients treated with Cymbalta for 

DPN and had an incidence ≤ placebo: edema peripheral, influenza, upper respiratory tract 

infection, back pain, arthralgia, pain in extremity, and pruritus. 

The most commonly observed adverse events in Cymbalta-treated DPN patients (incidence 

≥5% and at least twice the incidence in placebo patients) were: nausea; somnolence; 

dizziness; constipation; dry mouth; hyperhidrosis; decreased appetite; and asthenia. 

Infrequent: myocardial infarction and tachycardia; Ear and Labyrinth y Disorders—Frequent: 

vertigo; Infrequent: ear pain and tinnitus; Endocrine Disorders—Infrequent: Hypothyroidism; 

Eye y Disorders—Frequent: 

vision blurred; Infrequent: diplopia and visual disturbance; 

Gastrointestinal Disorders—Frequent: flatulence; Infrequent: eructation, gastritis, halitosis, 

and stomatitis; Rare: gastric ulcer, hematochezia, and melena; General Disorders and 

Administration Site Conditions—Frequent: chills/rigors; Infrequent: feeling abnormal, 

feeling hot and/or cold, malaise, and thirst; Rare: gait disturbance; Infections and 

Infestations—Infrequent: gastroenteritis and laryngitis; Investigations g —Frequent: weight 

increased; Infrequent: blood cholesterol increased; Metabolism and Nutrition Disorders— 

Infrequent: dehydration and hyperlipidemia; Rare: dyslipidemia; Musculoskeletal and 

Connective Tissue Disorders—Frequent: musculoskeletal pain; Infrequent: muscle tightness 

and muscle twitching; Nervous System y Disorders—Frequent: 

dysgeusia, lethargy, and 

parasthesia/hypoesthesia; Infrequent: disturbance in attention, dyskinesia, myoclonus, 

and poor quality sleep; Rare: dysarthria; Psychiatric y Disorders—Frequent: 

abnormal 

dreams and sleep disorder; Infrequent: apathy, bruxism, disorientation/confusional state, 

irritability, mood swings, and suicide attempt; Rare: completed suicide; Renal and Urinary 

Disorders—Infrequent: dysuria, micturition urgency, nocturia, polyuria, and urine odor 

abnormal; Reproductive p System y and Breast Disorders—Frequent: 

anorgasmia/orgasm 

abnormal; Infrequent: menopausal symptoms, and sexual dysfunction; Respiratory, p y, 

Thoracic and Mediastinal Disorders—Frequent: yawning; Infrequent: throat tightness; 

Skin and Subcutaneous Tissue Disorders—Infrequent: cold sweat, dermatitis contact, 

erythema, increased tendency to bruise, night sweats, and photosensitivity reaction; 

Rare: ecchymosis; Vascular Disorders—Frequent: hot flush; Infrequent: flushing, orthostatic 

hypotension, and peripheral coldness. 

Postmarketing Spontaneous Reports—The following adverse reactions have been 

identified during postapproval use of Cymbalta. Because these reactions are reported 

voluntarily from a population of uncertain size, it is not always possible to reliably 

estimate their frequency or establish a causal relationship to drug exposure. 

Adverse reactions reported since market introduction that were temporally related to 

duloxetine therapy and not mentioned elsewhere in labeling include: anaphylactic reaction, 

aggression and anger (particularly early in treatment or after treatment discontinuation), 

angioneurotic edema, erythema multiforme, extrapyramidal disorder, glaucoma, hallucinations, 

hyperglycemia, hypersensitivity, hypertensive crisis, muscle spasm, rash, supraventricular 

arrhythmia, tinnitus (upon treatment discontinuation), trismus, and urticaria. 

Serious skin reactions including Stevens-Johnson Syndrome that have required drug 

discontinuation and/or hospitalization have been reported with duloxetine. 

Effects on Male and Female Sexual Function—Changes in sexual desire, sexual 

performance and sexual satisfaction often occur as manifestations of psychiatric disorders 

or diabetes, but they may also be a consequence of pharmacologic treatment. Because 

adverse sexual reactions are presumed to be voluntarily underreported, the Arizona 

Sexual Experience Scale (ASEX), a validated measure designed to identify sexual side 

effects, was used prospectively in 4 MDD placebo-controlled trials. In these trials, patients 

treated with Cymbalta experienced significantly more sexual dysfunction, as measured by 

the total score on the ASEX, than did patients treated with placebo. Gender analysis 

showed that this difference occurred only in males. Males treated with Cymbalta experienced 

more difficulty with ability to reach orgasm (ASEX Item 4) than males treated with placebo. 

Females did not experience more sexual dysfunction on Cymbalta than on placebo as 

measured by ASEX total score. Physicians should routinely inquire about possible sexual 

side effects. See Table 5 in full PI for specific ASEX results. 

Vital Sign Changes—In clinical trials across indications, relative to placebo, duloxetine 

treatment was associated with mean increases of up to 2.1 mm Hg in systolic blood 

pressure and up to 2.3 mm Hg in diastolic blood pressure. There was no significant 

difference in the frequency of sustained (3 consecutive visits) elevated blood pressure 

[see Warnings and Precautions]. 

Duloxetine treatment, for up to 13-weeks in placebo-controlled trials typically caused 

a small increase in heart rate compared to placebo of up to 3 beats per minute. 

Weight Changes—In placebo-controlled clinical trials, MDD and GAD patients treated 

with Cymbalta for up to 10-weeks experienced a mean weight loss of approximately 

0.5 kg, compared with a mean weight gain of approximately 0.2 kg in placebo-treated 

patients. In DPN placebo-controlled clinical trials, patients treated with Cymbalta for up to 

13-weeks experienced a mean weight loss of approximately 1.1 kg, compared with a 

mean weight gain of approximately 0.2 kg in placebo-treated patients. 

Laboratory Changes—Cymbalta treatment in placebo-controlled clinical trials, was 

associated with small mean increases from baseline to endpoint in ALT, AST, CPK, and 

alkaline phosphatase; infrequent, modest, transient, abnormal values were observed for 

these analytes in Cymbalta-treated patients when compared with placebo-treated patients 

[see Warnings and Precautions]. 

Electrocardiogram Changes—Electrocardiograms were obtained from duloxetinetreated 

patients and placebo-treated patients in clinical trials lasting up to 13-weeks. No 

clinically significant differences were observed for QTc, QT, PR, and QRS intervals between 

duloxetine-treated and placebo-treated patients. There were no differences in clinically 

meaningful QTcF elevations between duloxetine and placebo. In a positive-controlled 

study in healthy volunteers using duloxetine up to 200 mg BID, no prolongation of the 

corrected QT interval was observed. 

Other Adverse Reactions Observed During the Premarketing and Postmarketing 

Clinical Trial Evaluation of Duloxetine—Following is a list of treatment-emergent 

adverse reactions reported by patients treated with duloxetine in clinical trials. In clinical 

trials of all indications, 23,983 patients were treated with duloxetine. Of these, 6,702 took 

duloxetine for at least 6 months, and 3,006 for at least one year. The following listing is 

not intended to include reactions (1) already listed in previous tables or elsewhere in 

labeling, (2) for which a drug cause was remote, (3) which were so general as to be 

uninformative, (4) which were not considered to have significant clinical implications, or 

(5) which occurred at a rate equal to or less than placebo. 

DRUG INTERACTIONS: Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism. 

Inhibitors of CYP1A2—When duloxetine 60 mg was co-administered with fluvoxamine 

100 mg, a potent CYP1A2 inhibitor, to male subjects (n=14) duloxetine AUC was 

increased approximately 6-fold, the Cmax was increased about 2.5-fold, andduloxetine t1/2 

was increased approximately 3-fold. Other drugs that inhibit CYP1A2 metabolism include 

cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin [see 

Warnings and Precautions]. 

Inhibitors of CYP2D6—Concomitant use of duloxetine (40 mg QD) with paroxetine 

(20 mg QD) increased the concentration of duloxetine AUC by about 60%, and greater 

degrees of inhibition are expected with higher doses of paroxetine. Similar effects would 

be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine) [see 


Dual Inhibition of CYP1A2 and CYP2D6—Concomitant administration of duloxetine 

40 mg BID with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to CYP2D6 poor 

metabolizer subjects (n=14) resulted in a 6-fold increase in duloxetine AUC and Cmax. 

Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)— 

Serotonin release by platelets plays an important role in hemostasis. Epidemiological 

studies of the case-control and cohort design that have demonstrated an association 

between use of psychotropic drugs that interfere with serotonin reuptake and the 

occurrence of upper gastrointestinal bleeding. These studies have also shown that 

concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered 

anticoagulant effects, including increased bleeding, have been reported when SSRIs or 

SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be 

carefully monitored when duloxetine is initiated or discontinued [see Warnings 


Lorazepam—Under steady-state conditions for duloxetine (60 mg Q 12 hours) and 

lorazepam (2 mg Q 12 hours), the pharmacokinetics of duloxetine were not affected 

by co-administration. 

Temazepam—Under steady-state conditions for duloxetine (20 mg qhs) and temazepam 

(30 mg qhs), the pharmacokinetics of duloxetine were not affected by co-administration. 

Drugs that Affect Gastric Acidity—Cymbalta has an enteric coating that resists 

dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 

5.5. In extremely acidic conditions, Cymbalta, unprotected by the enteric coating, may 

undergo hydrolysis to form naphthol. Caution is advised in using Cymbalta in patients with 

conditions that may slow gastric emptying (e.g., some diabetics). Drugs that raise the 

gastrointestinal pH may lead to an earlier release of duloxetine. However, co-administration 

of Cymbalta with aluminum- and magnesium-containing antacids (51 mEq) or Cymbalta with 

famotidine, had no significant effect on the rate or extent of duloxetine absorption after 

administration of a 40-mg oral dose. It is unknown whether the concomitant administration of 

proton pump inhibitors affects duloxetine absorption [see Warnings and Precautions]. 

Drugs Metabolized by CYP1A2—In vitro drug interaction studies demonstrate that 

duloxetine does not induce CYP1A2 activity. Therefore, an increase in the metabolism of 

CYP1A2 substrates (e.g., theophylline, caffeine) resulting from induction is not anticipated, 

although clinical studies of induction have not been performed. Duloxetine is an inhibitor 

of the CYP1A2 isoform in in vitro studies, and in two clinical studies the average 

(90% confidence interval) increase in theophylline AUC was 7% (1%-15%) and 20% 

(13%-27%) when co-administered with duloxetine (60 mg BID). 


Drugs Metabolized by CYP2D6—Duloxetine is a moderate inhibitor of CYP2D6. When 

duloxetine was administered (at a dose of 60 mg BID) in conjunction with a single 50-mg 

dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold [see 


Drugs Metabolized by CYP2C9—Duloxetine does not inhibit the in vitro enzyme activity 

of CYP2C9. Inhibition of the metabolism of CYP2C9 substrates is therefore not anticipated, 

although clinical studies have not been performed. 

Drugs Metabolized by CYP3A—Results of in vitro studies demonstrate that duloxetine 

does not inhibit or induce CYP3A activity. Therefore, an increase or decrease in the 

metabolism of CYP3A substrates (e.g., oral contraceptives and other steroidal agents) 

resulting from induction or inhibition is not anticipated, although clinical studies have not 

been performed. 

Drugs Metabolized by CYP2C19—Results of in vitro studies demonstrate that 

duloxetine does not inhibit CYP2C19 activity at therapeutic concentrations. Inhibition of 

the metabolism of CYP2C19 substrates is therefore not anticipated, although clinical studies 

have not been performed. 

Monoamine Oxidase Inhibitors—Switching Patients to or from a Monoamine Oxidase 

Inhibitor—At least 14 days should elapse between discontinuation of an MAOI and initiation 

of therapy with Cymbalta. In addition, at least 5 days should be allowed after stopping 

Cymbalta before starting an MAOI [see Contraindications and Warnings and Precautions]. 

Serotonergic Drugs—Based on the mechanism of action of SNRIs and SSRIs, including 

Cymbalta, and the potential for serotonin syndrome, caution is advised when Cymbalta is 

co-administered with other drugs that may affect the serotonergic neurotransmitter 

systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective 

MAOI), lithium, tramadol, or St. John's Wort. The concomitant use of Cymbalta with other 

SSRIs, SNRIs or tryptophan is not recommended [see Warnings and Precautions]. 

Triptans—There have been rare postmarketing reports of serotonin syndrome with use 

of an SSRI and a triptan. If concomitant treatment of Cymbalta with a triptan is clinically 

warranted, careful observation of the patient is advised, particularly during treatment 

initiation and dose increases [see Warnings and Precautions]. 

Alcohol—When Cymbalta and ethanol were administered several hours apart so that 

peak concentrations of each would coincide, Cymbalta did not increase the impairment of 

mental and motor skills caused by alcohol. 

In the Cymbalta clinical trials database, three Cymbalta-treated patients had liver injury 

as manifested by ALT and total bilirubin elevations, with evidence of obstruction. Substantial 

intercurrent ethanol use was present in each of these cases, and this may have contributed 

to the abnormalities seen [see Warnings and Precautions]. 

CNS Drugs—[see Warnings and Precautions]. 

Drugs Highly Bound to Plasma Protein—Because duloxetine is highly bound to plasma 

protein, administration of Cymbalta to a patient taking another drug that is highly protein 

bound may cause increased free concentrations of the other drug, potentially resulting in 

adverse reactions. 

USE IN SPECIFIC POPULATIONS: Pregnancy—Teratogenic g Effects, , Pregnancy g y Category g y C— 

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 teratogenicity at doses up to 45 mg/kg/day 

(7 times the maximum recommended human dose [MRHD, 60 mg/day] and 4 times the 

human dose of 120 mg/day on a mg/m2 basis, in rat; 15 times the MRHD and 7 times 

the human dose of 120 mg/day on a mg/m2 basis in rabbit). However, fetal weights were 

decreased at this dose, with a no-effect dose of 10 mg/kg/day (2 times the MRHD and 

≈1 times the human dose of 120 mg/day on a mg/m2 basis in rat; 3 times the MRHD 

and 2 times the human dose of 120 mg/day on a mg/m2 basis 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 (5 times the 

MRHD and 2 times the human dose of 120 mg/day on a mg/m2 therapy for the mother outweighs any potential risk to the infant, no dosage adjustment is 

required as lactation did not influence duloxetine pharmacokinetics. 

Pediatric Use—Safety and effectiveness in the pediatric population have not been 

established [see Boxed Warning and Warnings and Precautions]. Anyone considering the 

use of Cymbalta in a child or adolescent must balance the potential risks with the clinical need. 

Geriatric Use—Of the 2418 patients in premarketing clinical studies of Cymbalta 

for MDD, 5.9% (143) were 65 years of age or over. Of the 1074 patients in the DPNP 

premarketing studies, 33% (357) were 65 years of age or over. Premarketing clinical studies 

of GAD did not include sufficient numbers of subjects age 65 or over to determine whether 

they respond differently from younger subjects. In the MDD and DPNP studies, no overall 

differences in safety or effectiveness were observed between these subjects and younger 

subjects, and other reported clinical experience has not identified differences in responses 

between the elderly and younger patients, but greater sensitivity of some older individuals 

cannot be ruled out. SSRIs and SNRIs, including Cymbalta have been associated with 

cases of clinically significant hyponatremia in elderly patients, who may be at greater risk 

for this adverse event [see Warnings and Precautions]. 

Gender—Duloxetine’s half-life is similar in men and women. Dosage adjustment based 

on gender is not necessary. 

Smoking Status—Duloxetine bioavailability (AUC) appears to be reduced by about 

one-third in smokers. Dosage modifications are not recommended for smokers. 

Race—No specific pharmacokinetic study was conducted to investigate the effects of race. 

Hepatic Insufficiency—[see Warnings and Precautions]. 

Severe Renal Impairment—[see Warnings and Precautions]. 

DRUG ABUSE AND DEPENDENCE: Abuse—In animal studies, duloxetine did not 

demonstrate barbiturate-like (depressant) abuse potential. 

While Cymbalta has not been systematically studied in humans for its potential for 

abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it 

is not possible to predict on the basis of premarketing experience the extent to which a 

CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, 

physicians should carefully evaluate patients for a history of drug abuse and follow such 

patients closely, observing them for signs of misuse or abuse of Cymbalta (e.g., development 

of tolerance, incrementation of dose, drug-seeking behavior). 

Dependence—In drug dependence studies, duloxetine did not demonstrate dependenceproducing 

potential in rats. 

OVERDOSAGE: Signs and Symptoms—In postmarketing experience, fatal outcomes 

have been reported for acute overdoses, primarily with mixed overdoses, but also with 

duloxetine only, at doses as low as 1000 mg. Signs and symptoms of overdose (duloxetine 

alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, 

syncope, tachycardia, hypotension, hypertension, and vomiting. 

Management of Overdose—There is no specific antidote to Cymbalta, but if serotonin 

syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature 

control) may be considered. In case of acute overdose, treatment should consist of those 

general measures employed in the management of overdose with any drug. 

NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, and Impairment of Fertility— 

Carcinogenesis g —Duloxetine was administered in the diet to mice and rats for 2 years. 

In female mice receiving duloxetine at 140 mg/kg/day (11 times the maximum 

recommended human dose [MRHD, 60 mg/day] and 6 times the human dose of 

120 mg/day on a mg/m 

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. 

There are no adequate and well-controlled studies in pregnant women; therefore, 

duloxetine should be used during pregnancy only if the potential benefit justifies the 

potential risk to the fetus. 

Nonteratogenic g Effects—Neonates 

exposed to SSRIs or serotonin and norepinephrine 

reuptake inhibitors (SNRIs), 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 features are consistent with either a direct toxic effect of 

SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, 

in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings 


When treating pregnant women with Cymbalta during the third trimester, the physician 

should carefully consider the potential risks and benefits of treatment. The physician may 

consider tapering Cymbalta in the third trimester. 

Labor and Delivery—The effect of duloxetine on labor and delivery in humans is 

unknown. Duloxetine should be used during labor and delivery only if the potential benefit 

justifies the potential risk to the fetus. 

Nursing Mothers—Duloxetine is excreted into the milk of lactating women. The 

estimated daily infant dose on a mg/kg basis is approximately 0.14% of the maternal 

dose. Because the safety of duloxetine in infants is not known, nursing while on Cymbalta 

is not recommended. However, if the physician determines that the benefit of duloxetine 

2 basis), there was an increased incidence of hepatocellular 

adenomas and carcinomas. The no-effect dose was 50 mg/kg/day (4 times the MRHD and 

2 times the human dose of 120 mg/day on a mg/m2 basis). Tumor incidence was not 

increased in male mice receiving duloxetine at doses up to 100 mg/kg/day (8 times the 

MRHD and 4 times the human dose of 120 mg/day on a mg/m2 basis). 

In rats, dietary doses of duloxetine up to 27 mg/kg/day in females (4 times the MRHD 

and 2 times the human dose of 120 mg/day on a mg/m2 basis) and up to 36 mg/kg/day 

in males (6 times the MRHD and 3 times the human dose of 120 mg/day on a mg/m2 basis) did not increase the incidence of tumors. 

Mutagenesis g —Duloxetine was not mutagenic in the in vitro bacterial reverse mutation 

assay (Ames test) and was not clastogenic in an in vivo chromosomal aberration test in 

mouse bone marrow cells. Additionally, duloxetine was not genotoxic in an in vitro 

mammalian forward gene mutation assay in mouse lymphoma cells or in an in vitro 

unscheduled DNA synthesis (UDS) assay in primary rat hepatocytes, and did not induce sister 

chromatid exchange in Chinese hamster bone marrow in vivo. 

Impairment p of Fertilityy—Duloxetine 

administered orally to either male or female rats 

prior to and throughout mating at doses up to 45 mg/kg/day (7 times the maximum 

recommended human dose of 60 mg/day and 4 times the human dose of 120 mg/day on 

a mg/m2 basis) did not alter mating or fertility. 

PATIENT COUNSELING INFORMATION: See FDA-approved Medication Guide and Patient 

Counseling Information section of full PI. 

Literature revised December 13, 2007 

PV 5907 AMP PRINTED IN USA 

Eli Lilly and Company 

Indianapolis, IN 46285, USA 

www.Cymbalta.com 

Copyright © 2007, Eli Lilly and Company. All rights reserved. 


32A 


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