FORTEO^®
teriparatide (rDNA origin) injection
750 mcg/3 mL

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, teriparatide should be prescribed only to patients for whom the potential benefits are considered to outweigh the potential risk. Teriparatide 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, open epiphyses, or prior external beam or implant radiation therapy involving the skeleton) (seeWARNINGSandPRECAUTIONS, Carcinogenesis).

FORTEO^® [teriparatide (rDNA origin) injection] contains recombinant human parathyroid hormone (1-34), [rhPTH(1-34)], which has an 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:

Teriparatide (rDNA origin) is manufactured by Eli Lilly and Company 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 pen device for subcutaneous injection. Each prefilled delivery device is filled with 3.3 mL to deliver 3 mL. Each mL contains 250 mcg teriparatide (corrected for acetate, chloride, and water span), 0.41 mg glacial acetic acid, 0.10 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3.0 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 pen device delivers 20 mcg of teriparatide per dose each day for up to 28 days.

See accompanying User Manual: Instructions for Use.

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. 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 are 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.

Teriparatide is extensively 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 rapid. 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.

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.

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.

Teriparatide affects calcium and phosphorus metabolism in a pattern consistent with the known actions of endogenous PTH (eg, increases serum calcium and decreases serum phosphorus).

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, placebo-controlled clinical study of 1637 postmenopausal women with osteoporosis (FORTEO 20 mcg, n=541).

This multicenter study was performed in the US and 16 other countries. All women received 1000 mg of calcium per day and at least 400 IU of vitamin D per day. Baseline and endpoint spinal radiographs were evaluated using the semiquantitative scoring method of Genant et al [J Bone Miner Res 1993;8(9):1137-48]. 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 group to 5.0% in the FORTEO group. This difference was statistically significant (p<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.

New nonvertebral osteoporotic fractures—Table 2 shows the effect of FORTEO on the risk of nonvertebral 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<0.05). The absolute reduction in risk was 2.9% and the relative reduction was 53%.

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 (seeFigure 1).

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, as shown in Figure 2.

Postmenopausal women with osteoporosis who were treated with FORTEO also had statistically significant increases in BMD at the femoral neck, total hip, and total body (seeTable 3).

Figure 3 shows the cumulative distribution of the percentage change from baseline of lumbar spine BMD for the FORTEO and placebo groups. FORTEO treatment increased lumbar spine BMD from baseline in 96% of postmenopausal women treated (seeFigure 3). 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).

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, placebo-controlled clinical study of 437 men with either primary (idiopathic) or hypogonadal osteoporosis (FORTEO 20 mcg, n=151). This multicenter efficacy study was performed in the US and 10 other countries. All men received 1000 mg of calcium per day 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 turnover, and baseline BMD. The effects of FORTEO at additional skeletal sites are shown in Table 4.

Figure 4 shows the cumulative distribution of the percentage change from baseline of lumbar spine BMD for the FORTEO and placebo groups. 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.

FORTEO is indicated for the treatment of postmenopausal women with osteoporosis who are at high risk for fracture. These include women with a history of osteoporotic fracture, or who have multiple risk factors for fracture, or who have failed or are intolerant of previous osteoporosis therapy, based upon physician assessment (seeBLACK BOX WARNING). In postmenopausal women with osteoporosis, FORTEO increases BMD and reduces the risk of vertebral and nonvertebral fractures.

FORTEO is indicated to increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture. These include men with a history of osteoporotic fracture, or who have multiple risk factors for fracture, or who have failed or are intolerant to previous osteoporosis therapy, based upon physician assessment (seeBLACK BOX WARNING). In men with primary or hypogonadal osteoporosis, FORTEO increases BMD. The effects of FORTEO on risk for fracture in men have not been studied.

• FORTEO reduces the risk of vertebral fractures in postmenopausal women with osteoporosis.
• FORTEO reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis.
• FORTEO increases vertebral and femoral neck BMD in postmenopausal women with osteoporosis and in men with primary or hypogonadal osteoporosis.
• The effects of FORTEO on fracture risk have not been studied in men.

For safe and effective use of FORTEO, the physician should inform patients about the following:

The safety of teriparatide has been evaluated in 24 clinical trials that enrolled over 2800 women and men. Four long-term Phase 3 clinical trials included 1 large placebo-controlled, double-blind, multinational trial with 1637 postmenopausal women; 1 placebo-controlled, double-blind, multinational trial with 437 men; and 2 active-controlled trials including 393 postmenopausal women. Teriparatide doses ranged from 5 to 100 mcg/day in short-term trials and 20 to 40 mcg/day in the other trials. A total of 1943 of the patients studied received teriparatide, including 815 patients at 20 mcg/day and 1107 patients at 40 mcg/day. In the clinical trials, a total of 1432 patients were treated with teriparatide for 3 months to 2 years, of whom 1137 were treated for greater than 1 year (500 at 20 mcg/day and 637 at 40 mcg/day). The maximum duration of treatment was 2 years. Adverse events associated with FORTEO usually were mild and generally did not require discontinuation of therapy.

In the two Phase 3 placebo-controlled clinical trials in men and postmenopausal women, early discontinuation due to adverse events occurred in 5.6% of patients assigned to placebo and 7.1% of patients assigned to FORTEO. Reported adverse events that appeared to be increased by FORTEO treatment were dizziness and leg cramps.

Table 5 uls adverse events that occurred in the two Phase 3 placebo-controlled clinical trials in men and postmenopausal women at a frequency ≥2.0% in the FORTEO groups and in more FORTEO-treated patients than in placebo-treated patients, without attribution of causality.

Serum calcium— FORTEO transiently increases 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 transient hypercalcemia in the 4 to 6 hours after FORTEO administration was increased from 1.5% of women and none of the men treated with placebo to 11.1% of women and 6.0% of men treated with FORTEO. The number of patients treated with FORTEO whose transient hypercalcemia was verified on consecutive measurements was 3.0% of women and 1.3% of men.

Immunogenicity— In a large clinical trial, antibodies that cross-reacted with teriparatide were detected in 2.8% of women 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, allergic reactions, effects on serum calcium, or effects on BMD response.

Since market introduction, adverse events reported have included:

• Possible allergic events soon after injection: acute dyspnea, oro/facial edema, generalized urticaria, chest pain. (less than 1 in 1000 patients treated).
• Hypercalcemia greater than 2.76 mmol/L (11 mg/dL) (less than 1 in 100 patients treated); hypercalcemia greater than 3.25 mmol/L (13 mg/dL) (less than 1 in 1000 patients treated).
• Injection site and injection technique events including pain, swelling, erythema, localized bruising, pruritus and minor bleeding at the injection site (less than 1 in 30 patients treated). These usually have been mild and transient.

FORTEO should be administered as a subcutaneous injection into the thigh or abdominal wall. The recommended dosage is 20 mcg once a day.

FORTEO should be administered initially under circumstances in which the patient can sit or lie down if symptoms of orthostatic hypotension occur (seePRECAUTIONS, Information for the Patient).

FORTEO is a clear and colorless liquid. Do not use if solid particles appear or if the solution is cloudy or colored. The FORTEO pen should not be used past the stated expiration date.

No data are available on the safety or efficacy of intravenous or intramuscular injection of FORTEO.

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 is not recommended.

Patients and caregivers who administer FORTEO should receive appropriate training and instruction on the proper use of the FORTEO pen from a qualified health professional. It is important to read, understand, and follow the instructions in the FORTEO pen User Manual for priming the pen and dosing. Failure to do so may result in inaccurate dosing. Each FORTEO pen can be used for up to 28 days including the first injection from the pen. After the 28-day use period, discard the FORTEO pen, even if it still contains some unused solution. Never share a FORTEO pen.

The FORTEO pen should be stored under refrigeration at 2° to 8°C (36° to 46°F) at all times. Recap the pen when not in use to protect the cartridge from physical damage and light. During the use period, time out of the refrigerator should be minimized; the dose may be delivered immediately following removal from the refrigerator.

Do not freeze. Do not use FORTEO if it has been frozen.

The FORTEO pen is available in the following package size: One 3 mL prefilled pen delivery device NDC 0002-8971-01 (MS8971)

Literature revised September 3, 2004 www.forteo.com

Manufactured by Lilly France S.A.S., - F-67640 Fegersheim, France for Eli Lilly and Company - Indianapolis, IN 46285, USA

Copyright © 2002, 2004, Eli Lilly and Company. All rights reserved.

FORTEO^®

Generic name: teriparatide (rDNA origin) injection

Read this information carefully before you start taking FORTEO (for-TAY-o) to learn about the benefits and risks of FORTEO. Before beginning therapy, read the FORTEO pen User Manual for information on how to use the pen to inject your medicine. Read the information you get with FORTEO each time you get a refill, in case something has changed. Talk with your health care provider if there is something you do not understand or if you want to learn more about FORTEO.

What is the most important information I should know about FORTEO?

As part of drug testing, teriparatide, the active ingredient in FORTEO, was given to rats for a significant part of their lifetime. In these studies, teriparatide caused some rats to develop osteosarcoma, a bone cancer. Osteosarcoma in humans is a serious but very rare cancer. Osteosarcoma occurs in about 4 out of every million older adults each year. It is not known if humans treated with FORTEO also have a higher chance of getting osteosarcoma.

FORTEO is approved for use in both men and postmenopausal (after the “change of life”) women with osteoporosis who are at high risk for having broken bones (fractures) from osteoporosis.

Before starting treatment, talk with your doctor about the possible benefits and risks of FORTEO so you can decide if it is right for you.

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:

• 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.
• medicines that may cause bone loss, for example: seizure medicines (such as phenytoin), blood thinners (such as heparin), steroids (such as prednisone), high doses of vitamins A or D.

What is FORTEO?

FORTEO is a prescription medicine used to treat osteoporosis by forming new bone. FORTEO is the brand name for teriparatide, which is the same as the active part of a natural hormone called parathyroid hormone or “PTH.” FORTEO forms new bone, increases bone mineral density and bone strength, and as a result, reduces the chance of getting a fracture. In a study of postmenopausal (after the “change of life”) women with osteoporosis, FORTEO reduced the number of fractures of the spine and other bones. The effect on fractures has not been studied in men.

FORTEO is approved for use 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 multiple risk factors for fracture (See “What is osteoporosis?”), or who cannot use other osteoporosis treatments.

Who should not use FORTEO?

Do not use FORTEO if you:

• have Paget's disease of the bone.
• have unexplained high levels of alkaline phosphatase in your blood, which means you might have Paget's disease. If you are not sure, ask your doctor.
• are a child or growing adult.
• have ever been diagnosed with bone cancer or other cancers that have spread (metastasized) to your bones.
• have had radiation therapy involving your bones.
• have certain bone diseases. If you have a bone disease, tell your doctor.
• have too much calcium in your blood (hypercalcemia).
• are pregnant or nursing.
• have had an allergic reaction to FORTEO or one of its ingredients (See the ingredients section at the end of this Medication Guide).
• have trouble injecting yourself and do not have someone who can help you.

FORTEO should not be used to prevent osteoporosis or to treat patients who are not considered to be at high risk for fracture.

Tell your health care provider and pharmacist about all the medicines you are taking when you start taking FORTEO, and if you start taking a new medicine after you start FORTEO treatment. Tell them about all medicines you get with prescriptions and without prescriptions, as well as herbal or natural remedies. Your doctor and pharmacist need this information to help keep you from taking a combination of products that may harm you.

How should I take FORTEO?

• Take FORTEO once a day for as long as your doctor prescribes it for you. Use of FORTEO for more than 2 years is not recommended. Your health care professional (doctor, nurse, or pharmacist) should teach you how to use the FORTEO pen (multidose prefilled delivery device). (See the User Manual for written instructions on how to use the FORTEO pen.)
• The FORTEO pen contains 28 daily doses. The daily dose is 20 micrograms (see the User Manual).
• Some patients get dizzy or get a fast heartbeat after the first few doses. For the first few doses, inject FORTEO where you can sit or lie down right away if you get dizzy.
• Inject FORTEO once each day in your thigh or abdomen (lower stomach area).
• You can take FORTEO with or without food or drink.
• 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.
• Do not use FORTEO if it has solid particles in it, or if it is cloudy or colored. It should be clear and colorless.
• Do not use FORTEO after the expiration date printed on the pen and pen packaging.
• Do not transfer the spans of the FORTEO pen to a syringe.
• Throw away any FORTEO pen that you started using more than 28 days earlier, even if it still has medicine in it (See the User Manual).
• Inject FORTEO shortly after you take the pen out of the refrigerator. Recap the pen and put it back into the refrigerator right after use (See the User Manual).
• If you forget or are unable to take FORTEO at your usual time, take it as soon as possible on that day. Do not take more than one injection in the same day.
• Talk with your health care provider about other ways you can help your osteoporosis, such as exercise, diet, supplements, and reducing or stopping your use of tobacco and alcohol. If your health care provider recommends calcium and vitamin D supplements, you can take them at the same time as FORTEO.

What are the possible side effects of FORTEO?

Most side effects are mild and include dizziness and leg cramps. If you become lightheaded or have fast heartbeats after your injection, sit or lie down until you feel better. If you do not feel better, call your health care provider before continuing treatment.

Contact your health care provider if you have continuing nausea, vomiting, constipation, low energy, or muscle weakness. These may be signs there is too much calcium in your blood.

Patients may experience 1 or more of the following at the site of the injection: redness, swelling, pain, itching, a few drops of blood, and bruising. These are usually mild and last for a short time.

These are not all the possible side effects of FORTEO. For more information, ask your health care provider or pharmacist.

Your health care provider may take samples of blood and urine during treatment to check your response to FORTEO. Also, your health care provider may ask you to have follow-up tests of bone mineral density.

How should I store FORTEO?

• Keep your FORTEO pen in the refrigerator at 36° to 46°F (2° to 8°C).
• Do not freeze the pen. Do not use FORTEO if it has been frozen.
• You can use your FORTEO pen for up to 28 days including the first injection from the pen.
• Throw away the pen properly (See the User Manual) after 28 days of use, even if it is not completely empty.
• Recap the pen after each use (See the User Manual) to protect from physical damage.

General information about using FORTEO safely and effectively

Medicines are sometimes prescribed for conditions that are not mentioned in Medication Guides. 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 doctor, nurse, or pharmacist. You can ask your pharmacist or health care provider for information about FORTEO that is written for health care professionals. You can also call Lilly toll free at 1-866-4FORTEO (1-866-436-7836).

Ingredients

In addition to the active ingredient teriparatide, inactive ingredients are 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 product pH.

This Medication Guide has been approved by the US Food and Drug Administration.

Literature revised September 3, 2004

Manufactured by Lilly France S.A.S.

F-67640 Fegersheim, France

for Eli Lilly and Company

Indianapolis, IN 46285, USA

www.forteo.com

Copyright © 2002, 2004, Eli Lilly and Company. All rights reserved.