PIFORPA097FSAM01_PA000FSAM00_MOBILE.indd
Contents
1. Figure 1 Cumulative Percentage of Postmenopausal Women with Osteoporosis Sustaining New Nonvertebral Osteoporotic Fractures FORTEO Placebo MY wo A oa O N OW Percent of Patients with Nonvertebral Osteoporotic Fractures O 0 2 4 6 8 10 12 14 16 18 20 Months since Randomization Effect on Bone Mineral Density BMD FORTEO increased lumbar spine BMD in postmenopausal women with osteoporosis Statistically significant increases were seen at 3 months and continued throughout the treatment period Postmenopausal women with osteoporosis who were treated with FORTEO had statistically significant increases in BMD from baseline to endpoint at the lumbar spine femoral neck total hip and total body see Table 3 Table 3 Mean Percent Change in BMD from Baseline to Endpoint in Postmenopausal Women with Osteoporosis Treated with FORTEO or Placebo for a Median of 19 Months FORTEO Placebo N 541 N 544 Lumbar spine BMD 9 7 1 1 Femoral neck BMD 2 0 0 7 Total hip BMD 2 6 1 0 Trochanter BMD 39 0 2 Intertrochanter BMD 2 6 1 3 Ward s triangle BMD 4 2 0 8 Total body BMD 0 6 0 5 Distal 1 3 radius BMD 2 1 1 3 Ultradistal radius BMD 0 1 1 6 a intent to treat analysis last observation carried forward gt p lt 0 001 compared with placebo p lt 0 05 compared with placebo FORTEO treatment increased lumbar spine BMD from baseline in 96 of p2. Gender Although systemic exposure to teriparatide was approximately 20 to 30 lower in men than women the recommended dose for both genders is 20 mcg day Race The populations included in the pharmacokinetic analyses were 98 5 Caucasian The influence of race has not been determined Renal Impairment No pharmacokinetic differences were identified in 11 patients with mild or moderate renal impairment creatinine clearance CrCl 30 to 72 mL min administered a single dose of teriparatide In 5 patients with severe renal impairment CrCl lt 30 mL min the AUC and T of teriparatide were increased by 73 and 77 respectively Maximum serum concentration of teriparatide was not increased No studies have been performed in patients undergoing dialysis for chronic renal failure see Use in Specific Populations 8 7 Hepatic Impairment No studies have been performed in patients with hepatic impairment Non specific proteolytic enzymes in the liver possibly Kupffer cells cleave PTH 1 34 and PTH 1 84 into fragments that are cleared from the circulation mainly by the kidney see Use in Specific Populations 8 6 Drug Interactions Digoxin In a study of 15 healthy people administered digoxin daily to Steady state a single FORTEO dose did not alter the effect of digoxin on the systolic time interval from electrocardiographic Q wave onset to aortic valve closure a measure of digoxin s calcium mediated cardiac effect
3. 3 11 5 had a serum calcium gt 2 76 mmol L 11 0 mg dL and of those pretreated with alendronate 3 9 1 had a serum calcium gt 2 76 mmol L 11 0 mg dL The highest serum calcium reported was 3 12 mmol L 12 5 mg dL None of the women had Symptoms of hypercalcemia There were no placebo controls in this study In the study of patients with glucocorticoid induced osteoporosis the effects of FORTEO on serum calcium were similar to those observed in postmenopausal women with osteoporosis not taking glucocorticoids Urinary Calcium Excretion in a clinical study of postmenopausal women with osteoporosis who received 1000 mg of supplemental calcium and at least 400 IU of vitamin D daily FORTEO increased urinary calcium excretion The median urinary excretion of calcium was 4 8 mmol day 190 mg day at 6 months and 4 2 mmol day 170 mg day at 12 months These levels were 0 76 mmol day 30 mg day and 0 3 mmol day 12 mg day higher respectively than in women treated with placebo The incidence of hypercalciuria gt 7 5 mmol Ca day or 300 mg day was similar in the women treated with FORTEO or placebo Inaclinical study of men with either primary or hypogonadal osteoporosis whoreceived 1000 mg of supplemental calcium and atleast 400 IU of vitamin D daily FORTEO had inconsistent effects on urinary calcium excretion The median urinary excretion of calcium was 5 6 mmol day 220 mg day at 1 month and 5 3 mmol day 210 mg day at 6 months
4. However Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity Because FORTEO may transiently increase serum calcium FORTEO should be used with caution in patients taking digoxin see Drug Interactions 7 1 Hydrochlorothiazide In a study of 20 healthy people the coadministration of hydrochlorothiazide 25 mg with teriparatide did not affect the serum calcium response to teriparatide 40 mcg The 24 hour urine excretion of calcium was reduced by a clinically unimportant amount 15 The effect of coadministration of a higher dose of hydrochlorothiazide with teriparatide on serum calcium levels has not been studied see Drug Interactions 7 2 Furosemide In a study of 9 healthy people and 17 patients with mild moderate or severe renal impairment CrCl 13 to 72 mL min coadministration of intravenous furosemide 20 to 100 mg with teriparatide 40 mcg resulted in small increases in the serum calcium 2 and 24 hour urine calcium 37 responses to teriparatide that did not appear to be clinically important see Drug Interactions 7 3 13 NONCLINICAL TOXICOLOGY 13 1 Carcinogenesis Mutagenesis Impairment of Fertility Carcinogenesis Two carcinogenicity bioassays were conducted in Fischer 344 rats In the first study male and female rats were given daily subcutaneous teriparatide injections of 5 30 or 75 mcg kg day for 24 months from 2 months of age These doses resulted in system
5. e Qrthostatic hypotension Transient orthostatic hypotension may occur with initial doses of FORTEO 5 7 ADVERSE REACTIONS Most common adverse reactions gt 10 include arthralgia pain and nausea 6 1 To report SUSPECTED ADVERSE REACTIONS contact Eli Lilly and Company at 1 800 545 5979 or FDA at 1 800 FDA 1088 or www fda gov medwatch DRUG INTERACTIONS Digoxin Use FORTEO with caution in patients receiving digoxin Transient hypercalcemia may predispose patients to digitalis toxicity 5 8 7 1 12 3 USE IN SPECIFIC POPULATIONS e Pregnancy Based on animal studies may cause fetal harm 8 1 e Nursing Mothers Discontinue nursing or FORTEO taking into account the importance of treatment to the mother 8 3 e Pediatric Use FORTEO should not be used in pediatric and young adult patients with open epiphyses due to increased baseline risk of osteosarcoma 5 1 8 4 See 17 for PATIENT COUNSELING INFORMATION and Medication Guide Revised 03 2012 FULL PRESCRIBING INFORMATION CONTENTS WARNING POTENTIAL RISK OF OSTEOSARCOMA 1 INDICATIONS AND USAGE 1 1 Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture 1 2 Increase of Bone Mass in Men with Primary or Hypogonadal Osteoporosis at High Risk for Fracture 1 3 Treatment of Men and Women with Glucocorticoid Induced Osteoporosis at High Risk for Fracture DOSAGE AND ADMINISTRATION 2 1 Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fr
6. feel lightheaded or have palpitations after the injection they should sit or lie down until the symptoms resolve If symptoms persist or worsen patients should be instructed to consult a physician before continuing treatment see Warnings and Precautions 5 7 17 3 Hypercalcemia Although symptomatic hypercalcemia was not observed in clinical trials physicians should instruct patients taking FORTEO to contact a health care provider if they develop persistent symptoms of hypercalcemia e g nausea vomiting constipation lethargy muscle weakness 17 4 Other Osteoporosis Treatment Modalities Patients should be informed regarding the roles of supplemental calcium and or vitamin D weight bearing exercise and modification of certain behavioral factors such as cigarette smoking and or alcohol consumption 17 5 Use of Delivery Device Pen Patients and caregivers who administer FORTEO should be instructed on how to properly use the delivery device refer to User Manual properly dispose of needles and be advised not to share their delivery device with other patients The contents of the delivery device should NOT be transferred to a syringe Each FORTEO delivery device can be used for up to 28 days including the first injection from the delivery device After the 28 day use period discard the FORTEO delivery device even if it still contains some unused solution 17 6 Availability of Medication Guide and User Manual Patients should read th
7. mg day and the median duration of glucocorticoid use was 1 5 years The mean SD baseline lumbar spine BMD was 0 85 0 13 g cm and lumbar spine BMD T score was 2 5 1 number of standard deviations below the mean BMD value for healthy adults A total of 30 of patients had prevalent vertebral fracture s and 43 had prior non vertebral fracture s The patients had chronic rheumatologic respiratory or other diseases that required sustained glucocorticoid therapy All patients received 1000 mg of calcium plus 800 IU of vitamin D supplementation per day Because of differences in mechanism of action anabolic vs anti resorptive and lack of clarity regarding differences in BMD as an adequate predictor of fracture efficacy data on the active comparator are not presented Effect on Bone Mineral Density BMD In patients with glucocorticoid induced osteoporosis FORTEQ increased lumbar spine BMD compared with baseline at 3 months through 18 months of treatment In patients treated with FORTEO the mean percent change in BMD from baseline to endpoint was 7 2 at the lumbar spine 3 6 at the total hip and 3 7 at the femoral neck p lt 0 001 all sites The relative treatment effects of FORTEO were consistent in subgroups defined by gender age geographic region body mass index underlying disease prevalent vertebral fracture baseline glucocorticoid dose prior bisphosphonate use and glucocorticoid discontinuation during trial 16 HOW
8. recommended 5 3 Bone Metastases and Skeletal Malignancies Patients with bone metastases or a history of skeletal malignancies should not be treated with FORTEO 5 4 Metabolic Bone Diseases Patients with metabolic bone diseases other than osteoporosis should not be treated with FORTEO 5 5 Hypercalcemia and Hypercalcemic Disorders FORTEO has notbeen studied in patients with pre existing hypercalcemia These patients should not be treated with FORTEO because of the possibility of exacerbating hypercalcemia Patients known to have an underlying hypercalcemic disorder such as primary hyperparathyroidism should not be treated with FORTEO 5 6 Urolithiasis or Pre existing Hypercalciuria In clinical trials the frequency of urolithiasis was similar in patients treated with FORTEO and placebo However FORTEO has not been studied in patients with active urolithiasis If active urolithiasis or pre existing hypercalciuria are suspected measurement of urinary calcium excretion should be considered FORTEO should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition 5 7 Orthostatic Hypotension FORTEO should be administered initially under circumstances in which the patient can sit or lie down if symptoms of orthostatic hypotension occur In short term clinical pharmacology studies with teriparatide transient episodes of symptomatic orthostatic hypotension were observed in 5 of patie
9. turnover and baseline BMD The effects of FORTEO at additional skeletal sites are shown in Table 4 FORTEO treatment for a median of 10 months increased lumbar spine BMD from baseline in 94 of men treated Fifty three percent of patients treated with FORTEO achieved at least a 5 increase in spine BMD and 14 gained 10 or more Table 4 Mean Percent Change in BMD from Baseline to Endpoint in Men with Primary or Hypogonadal Osteoporosis Treated with FORTEO or Placebo for a Median of 10 Months FORTEO Placebo N 151 N 147 Lumbar spine BMD 5 9 0 5 Femoral neck BMD Pes 0 3 Total hip BMD 1 2 0 5 Trochanter BMD 1 3 1 1 Intertrochanter BMD 1 2 0 6 Ward s triangle BMD 2 8 1 1 Total body BMD 0 4 0 4 Distal 1 3 radius BMD 0 5 0 2 Ultradistal radius BMD 0 5 0 3 a intent to treat analysis last observation carried forward gt p lt 0 001 compared with placebo p lt 0 05 compared with placebo 14 3 Treatment of Men and Women with Glucocorticoid Induced Osteoporosis The efficacy of FORTEO for treating glucocorticoid induced osteoporosis was assessed in a randomized double blind active controlled trial of 428 patients 19 men 81 women aged 22 to 89 years mean 57 years treated with gt 5 mg day prednisone or equivalent for a minimum of 3 months The duration of the trial was 18 months with 214 patients exposed to FORTEO Inthe FORTEO group the baseline median glucocorticoid dose was 7 5
10. was 1 in the FORTEO group and 1 in the placebo group The incidence of serious adverse events was 16 in FORTEO patients and 19 in placebo patients Early discontinuation due to adverse events occurred in 7 of FORTEO patients and 6 of placebo patients Table 1 lists adverse events from the two principal osteoporosis trials in men and postmenopausal women that occurred in gt 2 of FORTEO treated and more frequently than placebo treated patients Table 1 Percentage of Patients with Adverse Events Reported by at Least 2 of FORTEO Treated Patients and in More FORTEO Treated Patients than Placebo Treated Patients from the Two Principal Osteoporosis Trials in Women and Men Adverse Events are Shown Without Attribution of Causality FORTEO Placebo Event Classification Body as a Whole Pain Headache Asthenia Neck pain Cardiovascular Hypertension Angina pectoris syncope Digestive System Nausea Constipation Diarrhea Dyspepsia Vomiting Gastrointestinal disorder Tooth disorder MNW MNN wo O O O N A 01 O OI WOW MUON aoo Noo _ VN SS So FORTEO Placebo N 691 N 691 Musculoskeletal Arthralgia Leg cramps Nervous System Dizziness Depression Insomnia Vertigo Respiratory System Rhinitis Cough increased Pharyngitis Dyspnea Pneumonia Skin and Appendages Rash Sweating Immunogenicity In the clinical trial antibodies that cross reacted with teriparatide we
11. whether teriparatide is excreted in human milk Because of the potential for tumorigenicity shown for teriparatide in animal studies a decision should be made whether to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother 8 4 Pediatric Use The safety and efficacy of FORTEO have not been established in any pediatric population FORTEO should not be prescribed in patients at an increased baseline risk of osteosarcoma which include pediatric and young adult patients with open epiphyses Therefore FORTEO is not indicated for use in pediatric or young adult patients with open epiphyses see Warnings and Precautions 5 1 8 5 Geriatric Use Of the patients receiving FORTEO in the osteoporosis trial of 1637 postmenopausal women 75 were 65 years of age and over and 23 were 75 years of age and over Of the patients receiving FORTEO in the osteoporosis trial of 437 men 39 were 65 years of age and over and 13 were 75 years of age and over 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 8 6 Hepatic Impairment No studies have been performed in patients with hepatic impairment see Clinical Pharmacology 12 3 8 7 Renal Impairment I
12. HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use FORTEO safely and effectively See full prescribing information for FORTEO FORTEO teriparatide rDNA origin injection for subcutaneous use Initial U S Approval 2002 WARNING POTENTIAL RISK OF OSTEOSARCOMA See full prescribing information for complete boxed warning e In rats teriparatide caused an increase in the incidence of osteosarcoma a malignant bone tumor 5 1 13 1 e Because of the uncertain relevance of the rat osteosarcoma finding to humans prescribe FORTEO only for patients for whom potential benefits outweigh potential risk 5 1 e FORTEO should not be prescribed for patients at increased baseline risk for osteosarcoma e g those with Paget s disease of bone or unexplained elevations of alkaline phosphatase pediatric and young adult patients with open epiphyses or prior external beam or implant radiation therapy involving 5 1 RECENT MAJOR CHANGES None INDICATIONS AND USAGE FORTEO is recombinant human parathyroid hormone analog 1 34 rhPTH 1 34 indicated for e Treatment of postmenopausal women with osteoporosis at high risk for fracture 1 1 e Increase of bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture 1 2 e Treatmentofmen and women with osteoporosis associated with sustained systemic glucocorticoid therapy at high risk for fracture 1 3 DOSAGE AND ADM
13. INISTRATION e Recommended dose is 20 mcg subcutaneously once a day 2 1 2 2 2 3 e Administer as a subcutaneous injection into the thigh or abdominal wall 2 4 e Administer initially under circumstances in which the patient can sit or lie down if symptoms of orthostatic hypotension occur 2 4 e Use of the drug for more than 2 years during a patient s lifetime is not recommended 2 5 DOSAGE FORMS AND STRENGTHS Multi dose prefilled delivery device pen containing 28 daily doses of 20 mcg 3 ONTRAINDICATIONS e Patients with hypersensitivity to teriparatide or to any of its excipients 4 _ WARNINGS AND PRECAUTIONS _ e Patients with Paget s disease of bone pediatric and young adult patients with open epiphyses and patients with prior external beam or implant radiation involving the skeleton Should not be treated with FORTEO 5 1 8 4 e Treatment duration Use of FORTEO for more than 2 years during a patient s lifetime is not recommended 5 2 e Patients with bone metastases history of skeletal malignancies metabolic bone diseases other than osteoporosis or hypercalcemic disorders should not be treated with FORTEO 5 3 5 4 5 5 e Laboratory alterations FORTEO may increase serum calcium urinary calcium and serum uric acid 5 5 5 6 e Urolithiasis Use with caution in patients with active or recent urolithiasis because of risk of exacerbation 5 6
14. NSELING INFORMATION 17 1 Potential Risk of Osteosarcoma and Voluntary FORTEO Patient Registry 17 2 Orthostatic Hypotension 17 3 Hypercalcemia 17 4 Other Osteoporosis Treatment Modalities 17 5 Use of Delivery Device 17 6 Availability of Medication Guide and User Manual Sections or subsections omitted from the full prescribing information are not listed FULL PRESCRIBING INFORMATION WARNING POTENTIAL RISK OF OSTEOSARCOMA In male and female rats teriparatide caused an increase in the incidence of osteosarcoma a malignant bone tumor that was dependent on dose and treatment duration The effect was observed at systemic exposures to teriparatide ranging from 3 to 60 times the exposure in humans given a 20 mcg dose Because of the uncertain relevance of the rat osteosarcoma finding to humans prescribe FORTEO only for patients for whom the potential benefits are considered to outweigh the potential risk FORTEO should not be prescribed for patients who are at increased baseline risk for osteosarcoma including those with Paget s disease of bone or unexplained elevations of alkaline phosphatase pediatric and young adult patients with open epiphyses or prior external beam or implant radiation therapy involving the skeleton see Warnings and Precautions 5 1 Adverse Reactions 6 2 and Nonclinical Toxicology 13 1 1 INDICATIONS AND USAGE 1 1 Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture FORTEO is ind
15. SUPPLIED STORAGE AND HANDLING 16 1 How Supplied The FORTEO delivery device pen is available in the following package size e 2 4 mL prefilled delivery device NDC 0002 8400 01 MS8400 16 2 Storage and Handling e The FORTEO delivery device should be stored under refrigeration at 2 to 8 C 36 to 46 F at all times e Recap the delivery device when not in use to protect the cartridge from physical damage and light e During the use period time out of the refrigerator should be minimized the dose may be delivered immediately following removal from the refrigerator e Do not freeze Do not use FORTEO if it has been frozen 17 PATIENT COUNSELING INFORMATION See Medication Guide 17 1 Potential Risk of Osteosarcoma and Voluntary FORTEO Patient Registry Patients should be made aware that in rats teriparatide caused an increase in the incidence of osteosarcoma a malignant bone tumor that was dependent on dose and treatment duration Patients should be encouraged to enroll in the voluntary FORTEO Patient Registry which is designed to collect information about any potential risk of osteosarcoma in patients who have taken FORTEO Enrollment information can be obtained by calling 1 866 382 6813 or by visiting www forteoregistry rti org 17 2 Orthostatic Hypotension FORTEO should be administered initially under circumstances where the patient can immediately sit or lie down if symptoms occur Patients should be instructed that if they
16. TEO e Inject FORTEO one time each day in your thigh or abdomen lower stomach area Talk to a healthcare provider about how to rotate injection Sites e Before you try to inject FORTEO yourself a healthcare provider should teach you how to use the FORTEO delivery device to give your injection the right way e Read the detailed User Manual at the end of this Medication Guide You can take FORTEO with or without food or drink The FORTEO delivery device has enough medicine for 28 days It is set to give a 20 microgram dose of medicine each day Do not inject all the medicine in the FORTEO delivery device at any one time Do not transfer the medicine from the FORTEO delivery device to a syringe This can result in taking the wrong dose of FORTEO If you do not have pen needles to use with your FORTEO delivery device talk with your healthcare provider FORTEO should look clear and colorless Do not use FORTEO if it has particles in it or if it is cloudy or colored Inject FORTEO right away after you take the delivery device out of the refrigerator After each use safely remove the needle recap the delivery device and put it back in the refrigerator right away You can take FORTEO at any time of the day To help you remember to take FORTEO take it at about the same time each day e f you forget or can not take FORTEO at your usual time take it as soon as you can on that day Do not take more than one injection in the same
17. The biological actions of PTH and teriparatide are mediated through binding to specific high affinity cell surface receptors Teriparatide and the 34 N terminal amino acids of PTH bind to these receptors with the same affinity and have the same physiological actions on bone and kidney Teriparatide is not expected to accumulate in bone or other tissues The skeletal effects of teriparatide depend upon the pattern of systemic exposure Once daily administration of teriparatide stimulates new bone formation on trabecular and cortical periosteal and or endosteal bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity In monkey studies teriparatide improved trabecular microarchitecture and increased bone mass and strength by stimulating new bone formation in both cancellous and cortical bone In humans the anabolic effects of teriparatide manifest as an increase in skeletal mass an increase in markers of bone formation and resorption and an increase in bone strength By contrast continuous excess of endogenous PTH as occurs in hyperparathyroidism may be detrimental to the skeleton because bone resorption may be stimulated more than bone formation 12 2 Pharmacodynamics Pharmacodynamics in Men and Postmenopausal Women with Osteoporosis Effects on Mineral Metabolism Teriparatide affects calcium and phosphorus metabolism in a pattern consistent with the known actions of endogenous PTH e g increases
18. These levels were 0 5 mmol day 20 mg day higher and 0 2 mmol day 8 0 mg day lower respectively than in men treated with placebo The incidence of hypercalciuria gt 7 5 mmol Ca day or 300 mg day was similar in the men treated with FORTEO or placebo Phosphorus and Vitamin D In single dose studies teriparatide produced transient phosphaturia and mild transient reductions in serum phosphorus concentration However hypophosphatemia lt 0 74 mmol L or 2 4 mg dL was not observed in clinical trials with FORTEO In clinical trials of daily FORTEO the median serum concentration of 1 25 dihydroxyvitamin D was increased at 12 months by 19 in women and 14 in men compared with baseline In the placebo group this concentration decreased by 2 in women and increased by 5 in men The median serum 25 hydroxyvitamin D concentration at 12 months was decreased by 19 in women and 10 in men compared with baseline In the placebo group this concentration was unchanged in women and increased by 1 in men In the study of patients with glucocorticoid induced osteoporosis the effects of FORTEO on serum phosphorus were similar to those observed in postmenopausal women with osteoporosis not taking glucocorticoids Effects on Markers of Bone Turnover Daily administration of FORTEO to men and postmenopausal women with osteoporosis in Clinical studies stimulated bone formation as shown by increases in the formation markers serum bone specific alkali
19. a voluntary Patient Registry for people who take FORTEO The purpose of the registry is to collect information about the possible risk of osteosarcoma in people who take FORTEO For information about how to sign up for this patient registry call 1 866 382 6813 or go to www forteoregistry rti org What is FORTEO FORTEO is a prescription medicine that is like a hormone made by the body called parathyroid hormone or PTH FORTEO may help to form new bone increase bone mineral density and bone Strength FORTEO can lessen the number of fractures of the spine and other bones in postmenopausal women with osteoporosis The effect on fractures has not been studied in men FORTEO is used in both men and postmenopausal women with osteoporosis who are at high risk for having fractures FORTEO can be used by people who have had a fracture related to osteoporosis or who have several risk factors for fracture or who can not use other osteoporosis treatments FORTEO is used in both men and women with osteoporosis due to use of glucocorticoid medicines such as prednisone for several months who are at high risk for having broken bones fractures These include men and women with either a history of broken bones who have several risk factors for fracture or who can not use other osteoporosis treatments It is not known if FORTEO is safe and effective in children FORTEO should not be used in children and young adults whose bones are still grow
20. acture 2 2 Increase of Bone Mass in Men with Primary or Hypogonadal Osteoporosis at High Risk for Fracture 2 3 Treatment of Men and Women with Glucocorticoid Induced Osteoporosis at High Risk for Fracture 2 4 Administration 2 0 Treatment Duration DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS 5 1 Osteosarcoma 5 2 Treatment Duration 5 3 Bone Metastases and Skeletal Malignancies 5 4 Metabolic Bone Diseases 5 0 Hypercalcemia and Hypercalcemic Disorders 5 6 Urolithiasis or Pre existing Hypercalciuria 5 7 Orthostatic Hypotension 5 8 Drug Interactions ADVERSE REACTIONS 6 1 Clinical Trials Experience 6 2 Postmarketing Experience DRUG INTERACTIONS 7 1 Digoxin 7 2 Hydrochlorothiazide 7 3 Furosemide USE IN SPECIFIC POPULATIONS 8 1 Pregnancy 8 3 Nursing Mothers 8 4 Pediatric Use 8 5 Geriatric Use 8 6 Hepatic Impairment 8 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12 1 Mechanism of Action 12 2 Pharmacodynamics 12 3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13 1 Carcinogenesis Mutagenesis Impairment of Fertility 13 2 Animal Toxicology 14 CLINICAL STUDIES 14 1 Treatment of Osteoporosis in Postmenopausal Women 14 2 Treatment to Increase Bone Mass in Men with Primary or Hypogonadal Osteoporosis 14 3 Treatment of Men and Women with Glucocorticoid Induced Osteoporosis 16 HOW SUPPLIED STORAGE AND HANDLING 16 1 How Supplied 16 2 Storage and Handling 17 PATIENT COU
21. cg subcutaneously once a day 2 2 Increase of Bone Mass in Men with Primary or Hypogonadal Osteoporosis at High Risk for Fracture The recommended dose is 20 mcg subcutaneously once a day 2 3 Treatment of Men and Women with Glucocorticoid Induced Osteoporosis at High Risk for Fracture The recommended dose is 20 mcg subcutaneously once a day 2 4 Administration e FORTEO should be administered as a subcutaneous injection into the thigh or abdominal wall There are no data available on the safety or efficacy of intravenous or intramuscular injection of FORTEO e FORTEQ should be administered initially under circumstances in which the patient can sit or lie down if symptoms of orthostatic hypotension occur see Warnings and Precautions 5 7 e Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit FORTEO is a clear and colorless liquid Do not use if solid particles appear or if the solution is cloudy or colored e Patients and caregivers who administer FORTEO should receive appropriate training and instruction on the proper use of the FORTEO delivery device from a qualified health professional see Patient Counseling Information 17 5 2 5 Treatment Duration The safety and efficacy of FORTEO have not been evaluated beyond 2 years of treatment Consequently use of the drug for more than 2 years during a patient s lifetime is not recommende
22. d 3 DOSAGE FORMS AND STRENGTHS Multi dose prefilled delivery device pen for subcutaneous injection containing 28 daily doses of 20 mcg 4 _CONTRAINDICATIONS Do not use FORTEO in patients with e Hypersensitivity to teriparatide or to any of its excipients Reactions have included angioedema and anaphylaxis see Adverse Reactions 6 2 5 WARNINGS AND PRECAUTIONS 5 1 Osteosarcoma In male and female rats teriparatide caused an increase in the incidence of osteosarcoma a malignant bone tumor that was dependent on dose and treatment duration see Boxed Warning and Nonclinical Toxicology 13 1 FORTEO should not be prescribed for patients at increased baseline risk of osteosarcoma These include e Paget s disease of bone Unexplained elevations of alkaline phosphatase may indicate Paget s disease of bone e Pediatric and young adult patients with open epiphyses e Prior external beam or implant radiation therapy involving the skeleton Patients should be encouraged to enroll in the voluntary FORTEO Patient Registry which is designed to collect information about any potential risk of osteosarcoma in patients who have taken FORTEO Enrollment information can be obtained by calling 1 866 382 6813 or by visiting www forteoregistry rti org 5 2 Treatment Duration The safety and efficacy of FORTEO have not been evaluated beyond 2 years of treatment Consequently use of the drug for more than 2 years during a patients lifetime is not
23. d serum calcium median 21 weeks During these intervals there was no evidence of progressive increases in serum calcium In a clinical study of men with either primary or hypogonadal osteoporosis the effects on serum calcium were similar to those observed in postmenopausal women The median peak serum calcium concentration measured 4 to 6 hours after dosing with FORTEO was 2 35 mmol L 9 44 mg dL at 12 months The peak serum calcium remained below 2 76 mmol L 11 0 mg dL in 98 of men at each visit Sustained hypercalcemia was not observed In this study 6 0 of men treated with FORTEO daily had at least 1 serum calcium value above the upper limit of normal 2 64 mmol L 10 6 mg dL compared with none of the men treated with placebo The percentage of men treated with FORTEO whose serum calcium was above the upper limit of normal on consecutive measurements was 1 3 2 men compared with none of the men treated with placebo Although calcium supplements and or FORTEO doses could have been reduced in these men only calcium supplementation was reduced see Warnings and Precautions 5 5 and Adverse Reactions 6 1 In a clinical study of women previously treated for 18 to 39 months with raloxifene n 26 or alendronate n 33 mean serum calcium gt 12 hours after FORTEO injection was increased by 0 09 to 0 14 mmol L 0 36 to 0 56 mg dL after 1 to 6 months of FORTEO treatment compared with baseline Of the women pretreated with raloxifene
24. day o fyou take more FORTEO than prescribed call your healthcare provider If you take too much FORTEO you may have nausea vomiting weakness or dizziness Follow your healthcare provider s instructions about other ways you can help your osteoporosis such as exercise diet and reducing or stopping your use of tobacco and alcohol If your healthcare provider recommends calcium and vitamin D supplements you can take them at the same time you take FORTEO What are the possible side effects of FORTEO FORTEO can cause serious side effects including e See What is the most important information should Know about FORTEQO e Decrease in blood pressure when you change positions Some people feel dizzy get a fast heartbeat or feel faint right after the first few doses This usually happens within 4 hours of taking FORTEO and goes away within a few hours For the first few doses take your injections of FORTEO in a place where you can sit or lie down right away if you get these symptoms lf your symptoms get worse or do not go away Stop taking FORTEO and call your healthcare provider e Increased calcium in your blood Tell your healthcare provider if you have nausea vomiting constipation low energy or muscle weakness These may be signs there is too much calcium in your blood Common side effects of FORTEO include e nausea e joint aches e pain Your healthcare provider may take samples of blood and urine durin
25. e Medication Guide and delivery device pen User Manual before starting therapy with FORTEO and re read them each time the prescription is renewed Patients need to understand and follow the instructions in the FORTEO delivery device User Manual Failure to do so may result in inaccurate dosing Literature revised March 21 2012 Marketed by Lilly USA LLC Indianapolis IN 46285 USA www forteo com Copyright 2002 2012 Eli Lilly and Company All rights reserved PAO97FSAMO01 Medication Guide FORTEO for TAY o teriparatide rDNA origin injection Read this Medication Guide before you start taking FORTEO and each time you get a refill There may be new information Also read the User Manual that comes with the FORTEO delivery device pen for information on how to use the device to inject your medicine the right way This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment What is the most important information should know about FORTEO e During the drug testing process the medicine in FORTEO caused some rats to develop a bone cancer called osteosarcoma In_ people osteosarcoma is a serious but rare cancer Osteosarcoma has been reported rarely in people who took FORTEO It is not known if people who take FORTEO have a higher chance of getting osteosarcoma You should not take FORTEO for more than 2 years over your lifetime There is
26. e reactions including injection site pain swelling and bruising oro facial edema 7 DRUG INTERACTIONS 7 1 Digoxin A single FORTEO dose did not alter the effect of digoxin on the systolic time interval from electrocardiographic Q wave onset to aortic valve closure a measure of digoxin s calcium mediated cardiac effect However because FORTEO may transiently increase serum calcium FORTEO should be used with caution in patients taking digoxin see Warnings and Precaution 5 8 and Clinical Pharmacology 12 3 7 2 Hydrochlorothiazide The coadministration of hydrochlorothiazide 25 mg with teriparatide did not affect the serum calcium response to teriparatide 40 mcg The effect of coadministration of a higher dose of hydrochlorothiazide with teriparatide on serum calcium levels has not been studied see Clinical Pharmacology 12 3 7 3 Furosemide Coadministration of intravenous furosemide 20 to 100 mg with teriparatide 40 mcg in healthy people and patients with mild moderate or severe renal impairment CrCl 13 to 72 mL min resulted in small increases in the serum calcium 2 and 24 hour urine calcium 37 responses to teriparatide that did not appear to be clinically important see Clinical Pharmacology 12 3 8 USE IN SPECIFIC POPULATIONS 8 1 Pregnancy Pregnancy Category C There are no adequate and well controlled Studies of FORTEO in pregnantwomen In animal studies teriparatide increased skeletal deviations and variation
27. g treatment to check your response to FORTEO Also your healthcare provider may ask you to have follow up tests of bone mineral density Tell your healthcare provider if you have any side effect that bothers you or that does not go away These are not all the possible side effects of FORTEQO For more information ask your doctor or pharmacist Call your doctor for medical advice about side effects You may report side effects to FDA at 1 800 FDA 1088 How should I store FORTEO e Keep your FORTEO delivery device in the refrigerator between 36 to 46 F 2 to 8 C e Do not freeze the FORTEO delivery device Do not use FORTEO if it has been frozen e Do not use FORTEO after the expiration date printed on the delivery device and packaging e Throw away the FORTEO delivery device after 28 days even if ithas medicine in it See the User Manual Keep FORTEO and all medicines out of the reach of children General information about FORTEO Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide Do not use FORTEO for a condition for which it was not prescribed Do not give FORTEO to other people even if they have the same condition you have This Medication Guide summarizes the most important information about FORTEO If you would like more information talk with your healthcare provider You can ask your pharmacist or healthcare provider for information about FORTEO that is written for heal
28. h treatment period the monkeys were removed from teriparatide treatment and were observed for an additional 3 years The 5 mcg kg dose resulted in systemic exposures that were approximately 6 times higher than the systemic exposure observed in humans following a subcutaneous dose of 20 mcg based on AUC comparison Bone tumors were not detected by radiographic or histologic evaluation in any monkey in the study 14 CLINICAL STUDIES 14 1 Treatment of Osteoporosis in Postmenopausal Women The safety and efficacy of once daily FORTEO median exposure of 19 months were examined in a double blind multicenter placebo controlled Clinical study of 1637 postmenopausal women with osteoporosis FORTEO 20 mcg n 541 All women received 1000 mg of calcium and at least 400 IU of vitamin D per day Baseline and endpoint spinal radiographs were evaluated using the semiquantitative scoring Ninety percent of the women in the study had 1 or more radiographically diagnosed vertebral fractures at baseline The primary efficacy endpoint was the occurrence of new radiographically diagnosed vertebral fractures defined as changes in the height of previously undeformed vertebrae Such fractures are not necessarily symptomatic Effect on Fracture Incidence New Vertebral Fractures FORTEO when taken with calcium and vitamin D and compared with calcium and vitamin D alone reduced the risk of 1 or more new vertebral fractures from 14 3 of women in the placebo gro
29. ic exposures that were respectively 3 20 and 60 times higher than the systemic exposure observed in humans following a subcutaneous dose of 20 mcg based on AUC comparison Teriparatide treatment resulted in a marked dose related increase in the incidence of osteosarcoma a rare malignant bone tumor in both male and female rats Osteosarcomas were observed at all doses and the incidence reached 40 to 50 in the high dose groups Teriparatide also caused a dose related increase in osteoblastoma and osteoma in both sexes No osteosarcomas osteoblastomas or osteomas were observed in untreated control rats The bone tumors in rats occurred in association with a large increase in bone mass and focal osteoblast hyperplasia The second 2 year study was carried out in order to determine the effect of treatment duration and animal age on the development of bone tumors Female rats were treated for different periods between 2 and 26 months of age with subcutaneous doses of 5 and 30 mcg kg equivalent to 3 and 20 times the human exposure at the 20 mcg dose based on AUC comparison The study showed that the occurrence of osteosarcoma osteoblastoma and osteoma was dependent upon dose and duration of exposure Bone tumors were observed when immature 2 month old rats were treated with 30 mcg kg day for 24 months or with 5 or 30 mcg kg day for 6 months Bone tumors were also observed when mature 6 month old rats were treated with 30 mcg kg day for 6 or 20 m
30. icated for the treatment of postmenopausal women with osteoporosis at high risk for fracture defined as a history of osteoporotic fracture multiple risk factors for fracture or patients who have failed or are intolerant to other available osteoporosis therapy In postmenopausal women with osteoporosis FORTEO reduces the risk of vertebral and nonvertebral fractures see Clinical Studies 14 1 1 2 Increase of Bone Mass in Men with Primary or Hypogonadal Osteoporosis at High Risk for Fracture FORTEO is indicated to increase bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture defined as a history of osteoporotic fracture multiple risk factors for fracture or patients who have failed or are intolerant to other available osteoporosis therapy see Clinical Studies 14 2 1 3 Treatment of Men and Women with Glucocorticoid Induced Osteoporosis at High Risk for Fracture FORTEO is indicated for the treatment of men and women with osteoporosis associated with sustained systemic glucocorticoid therapy daily dosage equivalent to 5 mg or greater of prednisone at high risk for fracture defined as a history of osteoporotic fracture multiple risk factors for fracture or patients who have failed or are intolerant to other available osteoporosis therapy see Clinical Studies 14 3 2 DOSAGE AND ADMINISTRATION 2 1 Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture The recommended dose is 20 m
31. id The peptide reaches peak serum concentrations about 30 minutes after Subcutaneous injection of a 20 mcg dose and declines to non quantifiable concentrations within 3 hours Distribution Systemic clearance of teriparatide approximately 62 L hr in women and 94 L hr in men exceeds the rate of normal liver plasma flow consistent with both hepatic and extra hepatic clearance Volume of distribution following intravenous injection is approximately 0 12 L kg Intersubject variability in systemic clearance and volume of distribution is 25 to 50 The half life of teriparatide in serum is 5 minutes when administered by intravenous injection and approximately 1 hour when administered by subcutaneous injection The longer half life following subcutaneous administration reflects the time required for absorption from the injection site Metabolism and Excretion No metabolism or excretion studies have been performed with teriparatide However the mechanisms of metabolism and elimination of PTH 1 34 and intact PTH have been extensively described in published literature Peripheral metabolism of PTH is believed to occur by non specific enzymatic mechanisms in the liver followed by excretion via the kidneys Pediatric Patients Pharmacokinetic data in pediatric patients are not available see Warnings and Precautions 5 1 Geriatric Patients No age related differences in teriparatide pharmacokinetics were detected range 31 to 85 years
32. ing Who should not use FORTEO Do not use FORTEO if you e are allergic to any of the ingredients in FORTEO see the end of this Medication Guide for a complete list of the ingredients in FORTEO What should I tell my healthcare provider before taking FORTEO Before you take FORTEO tell your healthcare provider if you have the condition listed in the section Who should not use FORTEO have Paget s disease or other bone disease have cancer in your bones have trouble injecting yourself and do not have Someone who can help you are a child or young adult whose bones are still growing have or have had kidney stones have had radiation therapy have or had too much calcium in your blood have any other medical conditions are pregnant or thinking about becoming pregnant It is not known if FORTEO will harm your unborn baby are breast feeding or plan to breast feed It is not known if FORTEO passes into your breast milk You and your doctor should decide if you will take FORTEO or breast feed You should not do both Tell your healthcare provider about all the medicines you take including prescription and non prescription medicines vitamins and herbal Supplements Your healthcare provider needs this information to help keep you from taking FORTEO with other medicines that may harm you e Especially tell your doctor if you take medicines that contain digoxin Digoxin Lanoxicaps Lanoxin How should use FOR
33. n blood thinners such as heparin and high doses of vitamin A This Medication Guide has been approved by the U S Food and Drug Administration The brands listed are trademarks of their respective owners and are not trademarks of Eli Lilly and Company Medication Guide revised March 13 2012 Marketed by Lilly USA LLC Indianapolis IN 46285 USA Copyright 2002 2012 Eli Lilly and Company All rights reserved PAOOOFSAMO00
34. n identical sequence to the 34 N terminal amino acids the biologically active region of the 84 amino acid human parathyroid hormone Teriparatide has a molecular weight of 4117 8 daltons and its amino acid sequence is shown below 1 5 10 H COCO Com 20 15 _OOMAC Rata EEEo 25 30 Teriparatide rDNA origin is manufactured using a strain of Escherichia coli modified by recombinant DNA technology FORTEO is supplied as a sterile colorless clear isotonic solution in a glass cartridge which is pre assembled into a disposable delivery device pen for subcutaneous injection Each prefilled delivery device is filled with 2 7 mL to deliver 2 4 mL Each mL contains 250 mcg teriparatide corrected for acetate chloride and water content 0 41 mg glacial acetic acid 0 1 mg sodium acetate anhydrous 45 4 mg mannitol 3 mg Metacresol and Water for Injection In addition hydrochloric acid solution 10 and or sodium hydroxide solution 10 may have been added to adjust the product to pH 4 Each cartridge pre assembled into a delivery device delivers 20 mcg of teriparatide per dose each day for up to 28 days 12 CLINICAL PHARMACOLOGY 12 1 Mechanism of Action Endogenous 84 amino acid parathyroid hormone PTH is the primary regulator of calcium and phosphate metabolism in bone and kidney Physiological actions of PTH include regulation of bone metabolism renal tubular reabsorption of calcium and phosphate and intestinal calcium absorption
35. n 5 patients with severe renal impairment CrCl lt 30 mL min the AUC and T of teriparatide were increased by 73 and 77 respectively Maximum serum concentration of teriparatide was not increased see Clinical Pharmacology 12 3 10 OVERDOSAGE Incidents of overdose in humans have not been reported in clinical trials Teriparatide has been administered in single doses of up to 100 mcg and in repeated doses of up to 60 mcg day for 6 weeks The effects of overdose that might be expected include a delayed hypercalcemic effect and risk of orthostatic hypotension Nausea vomiting dizziness and headache might also occur In postmarketing spontaneous reports there have been cases of medication errors in which the entire contents up to 800 mcg of the FORTEO delivery device pen have been administered as a single dose Transient events reported have included nausea weakness lethargy and hypotension In some cases no adverse events occurred as a result of the overdose No fatalities associated with overdose have been reported Overdose Management There is no specific antidote for teriparatide Treatment of suspected overdose should include discontinuation of FORTEO monitoring of serum calcium and phosphorus and implementation of appropriate supportive measures such as hydration 11 DESCRIPTION FORTEO teriparatide rDNA origin injection contains recombinant human parathyroid hormone 1 34 and is also called rhPTH 1 34 It has a
36. ne phosphatase BSAP and procollagen carboxy terminal propeptide PICP Data on biochemical markers of bone turnover were available for the first 12 months of treatment Peak concentrations of PICP at 1 month of treatment were approximately 41 above baseline followed by a decline to near baseline values by 12 months BSAP concentrations increased by 1 month of treatment and continued to rise more slowly from 6 through 12 months The maximum increases of BSAP were 45 above baseline in women and 23 in men After discontinuation of therapy BSAP concentrations returned toward baseline The increases in formation markers were accompanied by secondary increases in the markers of bone resorption urinary N telopeptide NTX and urinary deoxypyridinoline DPD consistent with the physiological coupling of bone formation and resorption in skeletal remodeling Changes in BSAP NTX and DPD were lower in men than in women possibly because of lower systemic exposure to teriparatide in men In the study of patients with glucocorticoid induced osteoporosis the effects of FORTEO on serum markers of bone turnover were similar to those observed in postmenopausal women with osteoporosis not taking glucocorticoids 12 3 Pharmacokinetics Absorption Teriparatide is absorbed after subcutaneous injection the absolute bioavailability is approximately 95 based on pooled data from 20 40 and 80 mcg doses The rates of absorption and elimination are rap
37. nts Typically an event began within 4 hours of dosing and spontaneously resolved within a few minutes to a few hours When transient orthostatic hypotension occurred it happened within the first several doses it was relieved by placing the person in a reclining position and it did not preclude continued treatment 5 8 Drug Interactions Hypercalcemia may predispose patients to digitalis toxicity Because FORTEO transiently increases serum calcium patients receiving digoxin should use FORTEO with caution see Drug Interactions 7 1 and Clinical Pharmacology 12 3 6 ADVERSE REACTIONS 6 1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice Treatment of Osteoporosis in Men and Postmenopausal Women The safety of FORTEO in the treatment of osteoporosis in men and postmenopausal women was assessed in two randomized double blind placebo controlled trials of 1382 patients 21 men 79 women aged 28 to 86 years mean 67 years The median durations of the trials were 11 months for men and 19 months for women with 691 patients exposed to FORTEO and 691 patients to placebo All patients received 1000 mg of calcium plus at least 400 IU of vitamin D supplementation per day The incidence of all cause mortality
38. nts and 12 of active control patients and included dizziness 2 FORTEO 0 active control Adverse events reported at a higher incidence in the FORTEO group and with at least a 2 difference in FORTEO treated patients compared with active control treated patients were nausea 14 7 gastritis 7 3 pneumonia 6 3 dyspnea 6 3 insomnia 5 1 anxiety 4 1 and herpes zoster 3 1 respectively 6 2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of FORTEO 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 e Osteosarcoma Cases of bone tumor and osteosarcoma have been reported rarely in the postmarketing period The causality to FORTEO use is unclear Long term osteosarcoma surveillance studies are ongoing see Warnings and Precautions 5 1 e Hypercalcemia Hypercalcemia greater than 13 0 mg dL has been reported with FORTEO use Adverse events reported since market introduction that were temporally but not necessarily causally related to FORTEO therapy include the following e Allergic Reactions Anaphylactic reactions drug hypersensitivity angioedema urticaria Investigations Hyperuricemia Respiratory System Acute dyspnea chest pain Musculoskeletal Muscle spasms of the leg or back Other Injection sit
39. onths Tumors were not detected when mature 6 month old rats were treated with 5 mcg kg day for 6 or 20 months The results did not demonstrate a difference in susceptibility to bone tumor formation associated with teriparatide treatment between mature and immature rats The relevance of these animal findings to humans is uncertain Mutagenesis Teriparatide was not genotoxic in any of the following test systems the Ames test for bacterial mutagenesis the mouse lymphoma assay for mammalian cell mutation the chromosomal aberration assay in Chinese hamster ovary cells with and without metabolic activation and the in vivo micronucleus test in mice Impairment of Fertility No effects on fertility were observed in male and female rats given subcutaneous teriparatide doses of 30 100 or 300 mcg kg day prior to mating and in females continuing through gestation Day 6 16 to 160 times the human dose of 20 mcg based on surface area mcg m 13 2 Animal Toxicology In single dose rodent studies using subcutaneous injection of teriparatide no mortality was seen in rats given doses of 1000 mcg kg 540 times the human dose based on surface area mcg m or in mice given 10 000 mcg kg 2700 times the human dose based on surface area mcg m In a long term study skeletally mature ovariectomized female monkeys N 30 per treatment group were given either daily subcutaneous teriparatide injections of 5 mcg kg or vehicle Following the 18 mont
40. ostmenopausal women treated Seventy two percent of patients treated with FORTEO achieved at least a 5 increase in spine BMD and 44 gained 10 or more Both treatment groups lost height during the trial The mean decreases were 3 61 and 2 81 mm in the placebo and FORTEO groups respectively Bone Histology The effects of teriparatide on bone histology were evaluated in iliac crest biopsies of 35 postmenopausal women treated for 12 to 24 months with calcium and vitamin D and teriparatide 20 or 40 mcg day Normal mineralization was observed with no evidence of cellular toxicity The new bone formed with teriparatide was of normal quality as evidenced by the absence of woven bone and marrow fibrosis 14 2 Treatment to Increase Bone Mass in Men with Primary or Hypogonadal Osteoporosis The safety and efficacy of once daily FORTEO median exposure of 10 months were examined in a double blind multicenter placebo controlled clinical study of 437 men with either primary idiopathic or hypogonadal osteoporosis FORTEO 20 mcg n 151 All men received 1000 mg of calcium and at least 400 IU of vitamin D per day The primary efficacy endpoint was change in lumbar spine BMD FORTEO increased lumbar spine BMD in men with primary or hypogonadal osteoporosis Statistically significant increases were seen at 3 months and continued throughout the treatment period FORTEO was effective in increasing lumbar spine BMD regardless of age baseline rate of bone
41. re detected in 3 of women 15 541 receiving FORTEO Generally antibodies were first detected following 12 months of treatment and diminished after withdrawal of therapy There was no evidence of hypersensitivity reactions or allergic reactions among these patients Antibody formation did not appear to have effects on serum calcium or on bone mineral density BMD response Laboratory Findings Serum Calcium FORTEO transiently increased serum calcium with the maximal effect observed at approximately 4 to 6 hours post dose serum calcium measured at least 16 hours post dose was not different from pretreatment levels In clinical trials the frequency of at least 1 episode of o OMMNAR D ow 0 OL 00 D Q GO O1 O O ao A A OO NO Ce eS Sie Vase NO WOROMO NON WA No transient hypercalcemia in the 4 to 6 hours after FORTEO administration was increased from 2 of women and none of the men treated with placebo to 11 of women and 6 of men treated with FORTEO The number of patients treated with FORTEO whose transient hypercalcemia was verified on consecutive measurements was 3 of women and 1 of men Urinary Calcium FORTEO increased urinary calcium excretion but the frequency of hypercalciuria in clinical trials was similar for patients treated with FORTEO and placebo see Clinical Pharmacology 12 2 Serum Uric Acid FORTEO increased serum uric acid concentrations In Clinical trial
42. s 3 of FORTEO patients had serum uric acid concentrations above the upper limit of normal compared with 1 of placebo patients However the hyperuricemia did not result in an increase in gout arthralgia or urolithiasis Renal Function No clinically important adverse renal effects were observed in clinical studies Assessments included creatinine clearance measurements of blood urea nitrogen BUN creatinine and electrolytes in serum urine specific gravity and pH and examination of urine sediment Studies in Men and Women with Glucocorticoid Induced Osteoporosis The safety of FORTEO in the treatment of men and women with glucocorticoid induced osteoporosis was assessed in a randomized double blind active controlled trial of 428 patients 19 men 81 women aged 22 to 89 years mean 57 years treated with gt 5mg per day prednisone or equivalent for a minimum of 3 months The duration of the trial was 18 months with 214 patients exposed to FORTEO and 214 patients exposed to oral daily bisphosphonate active control All patients received 1000 mg of calcium plus 800 IU of vitamin D supplementation per day The incidence of all cause mortality was 4 in the FORTEO group and 6 in the active control group The incidence of serious adverse events was 21 in FORTEO patients and 18 in active control patients and included pneumonia 3 FORTEO 1 active control Early discontinuation because of adverse events occurred in 15 of FORTEO patie
43. s in mouse offspring at doses more than 60 times the equivalent human dose and produced mild growth retardation and reduced motor activity in rat offspring at doses more than 120 times the equivalent human dose FORTEO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus In animal studies pregnant mice received teriparatide during organogenesis at subcutaneous doses 8 to 267 times the human dose At doses gt 60 times the human dose the fetuses showed an increased incidence of skeletal deviations or variations interrupted rib extra vertebra or rib When pregnant rats received subcutaneous teriparatide during organogenesis at doses 16 to 540 times the human dose the fetuses showed no abnormal findings In a perinatal postnatal study pregnant rats received subcutaneous teriparatide from organogenesis through lactation Mild growth retardation in female offspring at doses gt 120 times the human dose based on surface area mcg m Mild growth retardation in male offspring and reduced motor activity in both male and female offspring occurred at maternal doses 540 times the human dose There were no developmental or reproductive effects in mice or rats at doses 8 or 16 times the human dose respectively Exposure multiples were normalized based on body surface area mcg m Actual animal doses mice 30 to 1000 mcg kg day rats 30 to 1000 mcg kg day 8 3 Nursing Mothers It is not known
44. serum calcium and decreases serum phosphorus Serum Calcium Concentrations When teriparatide 20 mcg is administered once daily the serum calcium concentration increases transiently beginning approximately 2 hours after dosing and reaching a maximum concentration between 4 and 6 hours median increase 0 4 mg dL The serum calcium concentration begins to decline approximately 6 hours after dosing and returns to baseline by 16 to 24 hours after each dose In a clinical study of postmenopausal women with osteoporosis the median peak serum calcium concentration measured 4 to 6 hours after dosing with FORTEO teriparatide 20 mcg was 2 42 mmol L 9 68 mg dL at 12 months The peak serum calcium remained below 2 76 mmol L 11 0 mg dL in gt 99 of women at each visit Sustained hypercalcemia was not observed In this study 11 1 of women treated with FORTEO had at least 1 serum calcium value above the upper limit of normal 2 64 mmol L 10 6 mg dL compared with 1 5 of women treated with placebo The percentage of women treated with FORTEO whose serum calcium was above the upper limit of normal on consecutive 4 to 6 hour post dose measurements was 3 0 compared with 0 2 of women treated with placebo In these women calcium supplements and or FORTEO doses were reduced The timing of these dose reductions was at the discretion of the investigator FORTEO dose adjustments were made at varying intervals after the first observation of increase
45. thcare professionals For more information go to www FORTEO com or call Lilly at 1 866 436 7836 What are the ingredients in FORTEO Active ingredient teriparatide Inactive ingredients glacial acetic acid sodium acetate anhydrous mannitol metacresol and water for injection In addition hydrochloric acid solution 10 and or sodium hydroxide solution 10 may have been added to adjust the product to pH 4 What is Osteoporosis Osteoporosis is a disease in which the bones become thin and weak increasing the chance of having a broken bone Osteoporosis usually causes no symptoms until a fracture happens The most common fractures are in the spine backbone They can shorten height even without causing pain Over time the spine can become curved or deformed and the body bent over Fractures from osteoporosis can also happen in almost any bone in the body for example the wrist rib or hip Once you have had a fracture the chance for more fractures greatly increases The following risk factors increase your chance of getting fractures from osteoporosis e past broken bones from osteoporosis very low bone mineral density BMD frequent falls limited movement such as using a wheelchair medical conditions likely to cause bone loss such as some kinds of arthritis taking steroid medicines called glucocorticoids such as prednisone other medicines that may cause bone loss for example seizure medicines such as phenytoi
46. up to 5 0 in the FORTEO group This difference was statistically Significant 0 lt 0 001 the absolute reduction in risk was 9 3 and the relative reduction was 65 FORTEO was effective in reducing the risk for vertebral fractures regardless of age baseline rate of bone turnover or baseline BMD see Table 2 Table 2 Effect of FORTEO on Risk of Vertebral Fractures in Postmenopausal Women with Osteoporosis Percent of Women With Fracture Absolute Risk Relative Risk FORTEO Placebo Reduction Reduction N 444 N 448 95 Cl 95 Cl New 6 0 14 3 9 3 5 5 13 1 65 45 78 fracture gt 1 1 fracture 3 8 9 4 2 fractures 0 9 2 9 gt 3 fractures 0 2 2 0 a p lt 0 001 compared with placebo New Nonvertebral Osteoporotic Fractures FORTEO significantly reduced the risk of any nonvertebral fracture from 5 5 in the placebo group to 2 6 in the FORTEO group p lt 0 05 The absolute reduction in risk was 2 9 and the relative reduction was 53 The incidence of new nonvertebral fractures in the FORTEO group compared with the placebo group was ankle foot 0 2 0 7 hip 0 2 0 7 humerus 0 4 0 4 pelvis 0 0 6 ribs 0 6 0 9 wrist 0 4 1 3 and other sites 1 1 1 5 respectively The cumulative percentage of postmenopausal women with osteoporosis who sustained new nonvertebral fractures was lower in women treated with FORTEO than in women treated with placebo see Figure 1
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