TEVA-TERIPARATIDE INJECTION SOLUTION

Canada - English - Health Canada

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Active ingredient:
TERIPARATIDE (TERIPARATIDE ACETATE)
Available from:
TEVA CANADA LIMITED
ATC code:
H05AA02
INN (International Name):
TERIPARATIDE
Dosage:
250MCG
Pharmaceutical form:
SOLUTION
Composition:
TERIPARATIDE (TERIPARATIDE ACETATE) 250MCG
Administration route:
SUBCUTANEOUS
Units in package:
1ML/5ML
Prescription type:
Prescription
Therapeutic area:
PARATHYROID AGENTS
Product summary:
Active ingredient group (AIG) number: 0150152001; AHFS: 68:24.08
Authorization status:
APPROVED
Authorization number:
02486423
Authorization date:
2019-08-06

Documents in other languages

Teva-Teriparatide Injection

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PRODUCT MONOGRAPH

Pr

TEVA-TERIPARATIDE INJECTION

250 mcg/mL teriparatide (as teriparatide acetate)

Sterile Solution for Subcutaneous Injection

Teva Standard

Bone Formation Agent

Teva Canada Limited

30 Novopharm Court

Toronto, ON M1B 2K9

Date of Preparation:

March 6, 2019

Submission Control No: 195082

Teva-Teriparatide

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Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION ..........................................................3

SUMMARY PRODUCT INFORMATION ........................................................................3

DESCRIPTION....................................................................................................................3

INDICATIONS AND CLINICAL USE ..............................................................................3

CONTRAINDICATIONS ...................................................................................................4

WARNINGS AND PRECAUTIONS ..................................................................................5

ADVERSE REACTIONS ....................................................................................................8

DRUG INTERACTIONS ..................................................................................................12

DOSAGE AND ADMINISTRATION ..............................................................................13

OVERDOSAGE ................................................................................................................13

ACTION AND CLINICAL PHARMACOLOGY ............................................................14

STORAGE AND STABILITY ..........................................................................................18

INSTRUCTIONS FOR PEN USE .....................................................................................18

DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................19

PART II: SCIENTIFIC INFORMATION ...............................................................................20

PHARMACEUTICAL INFORMATION ..........................................................................20

CLINICAL TRIALS ..........................................................................................................21

DETAILED PHARMACOLOGY .....................................................................................32

TOXICOLOGY .................................................................................................................33

REFERENCES ..................................................................................................................47

PART III: CONSUMER INFORMATION..............................................................................51

User Manual .................................................................................................................................53

Teva-Teriparatide Injection

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Pr

TEVA-TERIPARATIDE INJECTION

Teriparatide Injection

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form /

Strength

Nonmedicinal Ingredients

Subcutaneous

Injection

Sterile solution for

subcutaneous injection

250 mcg/mL in 2.4

mL prefilled pen

Glacial acetic acid, hydrochloric acid,

mannitol, metacresol, sodium acetate

trihydrate, sodium hydroxide and water for

injection.

DESCRIPTION

TEVA-TERIPARATIDE INJECTION contains human parathyroid hormone (1-34), [PTH(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.

INDICATIONS AND CLINICAL USE

TEVA-TERIPARATIDE INJECTION is indicated:

For the treatment of postmenopausal women with severe osteoporosis who are at high

risk of fracture or who have failed or are intolerant to previous osteoporosis therapy.

To increase bone mass in men with primary or hypogonadal severe osteoporosis who

have failed or are intolerant to previous osteoporosis therapy. The effects of teriparatide

on risk for fracture in men have not been demonstrated.

For the treatment of osteoporosis associated with sustained systemic glucocorticoid

therapy in men and women who are at increased risk for fracture.

The diagnosis of severe osteoporosis may be confirmed by the finding of low bone mass or the

presence or history of osteoporotic fracture. While non-vertebral fractures are usually clinically

apparent, vertebral fractures also may be manifested by back pain, height loss, or kyphosis.

Geriatrics: Of the patients receiving teriparatide in the osteoporosis treatment trial of 1637

postmenopausal women, 75% were 65 and over and 23% were 75 and over. No significant

Teva-Teriparatide Injection

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differences in bone response and no new safety findings were seen in geriatric patients receiving

teriparatide as compared with younger patients.

Of the patients receiving teriparatide in the osteoporosis treatment trial of 437 men, 39% were 65

and over and 13% were 75 and over. Fracture efficacy endpoints have not been evaluated in

these patients. No significant differences in bone response and no new safety findings were seen

in geriatric patients receiving teriparatide as compared with younger patients.

Of the 214 patients that received teriparatide in an active comparator trial of glucocorticoid-

induced osteoporosis, 28% were 65 and over and 9% were 75 and over. No significant

differences in bone response and no new safety findings were seen in geriatric patients (≥ 65)

receiving teriparatide as compared with younger patients.

Pediatrics: The safety and efficacy of teriparatide have not been studied in pediatric populations.

TEVA-TERIPARATIDE INJECTION is not indicated for use in pediatric patients or young

adults with open epiphysis (see WARNINGS AND PRECAUTIONS, Special Populations,

Pediatrics).

CONTRAINDICATIONS

TEVA-TERIPARATIDE INJECTION is contraindicated for:

Hypersensitivity to teriparatide or any of its excipients.

Pre-existing hypercalcemia.

Severe renal impairment.

Metabolic bone diseases other than primary osteoporosis (including hyperparathyroidism

and Paget's disease of the bone).

Unexplained elevations of alkaline phosphatase.

Prior external beam or implant radiation therapy involving the skeleton.

Bone metastases or a history of skeletal malignancies.

Pregnancy and nursing mothers (see WARNINGS and PRECAUTIONS, Special

Populations).

Pediatric patients or young adults with open epiphysis (see WARNINGS and

PRECAUTIONS, Special Populations).

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WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Physicians should become familiar with the full content of the Product Monograph prior to

prescribing TEVA-TERIPARATIDE INJECTION. TEVA-TERIPARATIDE INJECTION

should be prescribed only to patients for whom the potential benefits outweigh the

potential risk. In rats, teriparatide caused an increase in the incidence of osteosarcoma that

was dose and treatment duration dependent at systemic exposures ranging from 3 to 60

times the exposure in humans given a 20-mcg dose.

TEVA-TERIPARATIDE INJECTION should not be prescribed to patients who are at

increased baseline risk for osteosarcoma (see CONTRAINDICATIONS and WARNINGS

AND PRECAUTIONS, Carcinogenicity).

Carcinogenicity

Two carcinogenicity bioassays were conducted in Fischer 344 rats. In these studies, rats were

given daily subcutaneous teriparatide injections at doses that resulted in systemic exposures

between 3 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

increases in the incidence of bone tumours, including osteosarcoma, that occurred in association

with dose-dependant exaggerated increases in bone mass. The studies showed that the

occurrence of bone tumours was dependent upon dose and duration of exposure. The clinical

significance of the observations in rats has not been established. Osteosarcoma has not been

observed in teriparatide clinical trials.

TEVA-TERIPARATIDE INJECTION should not be prescribed to patients who are at increased

baseline risk for osteosarcoma (e.g. Paget’s disease, pediatric and young adult with open

epiphyses, history of radiation therapy involving the skeleton, etc.).

General

The safety and efficacy of teriparatide have been evaluated up to 2 years in studies GHAC,

GHAJ, GHBJ and GHCA (median 19 months in women in study GHAC and 10 months in men

in study GHAJ) An additional clinical study (GHBZ) evaluated the safety and efficacy of

teriparatide for up to 3 years. The maximum lifetime exposure to TEVA-TERIPARATIDE

INJECTION for an individual patient is 24 months.

In clinical trials, the frequency of urolithiasis was similar in patients treated with teriparatide and

placebo. However, teriparatide 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. TEVA-TERIPARATIDE INJECTION should be used with

caution in patients with active or recent urolithiasis because of the potential to exacerbate this

condition.

Teva-Teriparatide Injection

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Hypotension

In short-term clinical studies with teriparatide, isolated episodes of transient orthostatic

hypotension were observed. 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, was relieved by placing subjects

in a reclining position, and did not preclude continued treatment. Patients experiencing

symptoms associated with hypotension should not drive or operate machinery until they become

asymptomatic.

Information for Patients

For safe and effective use of TEVA-TERIPARATIDE INJECTION, the physician should inform

patients about the following: General: Physicians should instruct their patients to read the

Consumer Information Leaflet and Pen User Manual before starting therapy with TEVA-

TERIPARATIDE INJECTION and re-read them each time the prescription is renewed.

Osteosarcomas in rats: Patients should be made aware that teriparatide caused osteosarcomas in

rats and that the clinical relevance of these findings is unknown.

Orthostatic hypotension: Patients should be instructed that if they feel lightheaded after

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. Patients

experiencing symptoms associated with hypotension should not drive or operate machinery until

they become asymptomatic (see WARNINGS AND PRECAUTIONS, Hypotension).

Hypercalcemia: Although symptomatic hypercalcemia was not observed in clinical trials,

physicians should instruct patients to contact a health care provider if they develop persistent

symptoms of hypercalcemia (i.e., nausea, vomiting, constipation, lethargy, muscle weakness).

Use of the pen: Patients should be instructed on how to properly use the prefilled delivery device

(refer to Pen User Manual) and properly dispose of needles, and be advised not to share their

pens with other patients.

Other Osteoporosis Treatment and Prevention Measures: 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/coffee consumption.

Special Populations

Pregnant Women and Women of Childbearing Potential: TEVA-TERIPARATIDE

INJECTION should not be administered to women who are pregnant. The effect of teriparatide

treatment on human fetal development has not been studied. Women of childbearing potential

should use effective methods of contraception during use of TEVA-TERIPARATIDE

INJECTION. Should pregnancy occur, TEVA-TERIPARATIDE INJECTION should be

discontinued (see CONTRAINDICATIONS).

Nursing Women: There have been no clinical studies to determine if teriparatide is secreted into

breast milk. TEVA-TERIPARATIDE INJECTION should not be administered to nursing

mothers (see CONTRAINDICATIONS).

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Pediatrics: Teriparatide has not been studied in pediatric populations. TEVA-TERIPARATIDE

INJECTION should not be used in children or young adults with open epiphyses (see

CONTRAINDICATIONS).

Premenopausal Women: Before initiating therapy with TEVA-TERIPARATIDE INJECTION

in premenopausal women with glucocorticoid-induced osteoporosis, risk factors such as low

BMD, length and dosage of glucocorticoid therapy, previous fractures, family history, high bone

turnover, level of underlying disease activity, low sex steroid level or low body mass index,

should be considered.

Geriatrics: Of the patients receiving teriparatide in the osteoporosis treatment trial of 1637

postmenopausal women, 75% were 65 and over and 23% were 75 and over. No significant

differences in bone response and no new safety findings were seen in geriatric patients receiving

teriparatide as compared with younger patients.

Of the patients receiving teriparatide in the osteoporosis treatment trial of 437 men, 39% were 65

and over and 13% were 75 and over. Fracture efficacy endpoints have not been evaluated in

these patients. No significant differences in bone response and no new safety findings were seen

in geriatric patients receiving teriparatide as compared with younger patients.

Of the 214 patients that received teriparatide in an active comparator trial of glucocorticoid-

induced osteoporosis, 28% were 65 and over and 9% were 75 and over. No significant

differences in bone response and no new safety findings were seen geriatric patients (≥65)

receiving teriparatide as compared with younger patients.

Monitoring and Laboratory Tests

Serum calcium – Teriparatide transiently increases serum calcium, with the maximal effect

observed at approximately 4 to 6 hours post-dose. By 16 hours post-dose, serum calcium

generally has returned to or near baseline. These effects should be kept in mind because serum

calcium concentrations observed within 16 hours after a dose may reflect the pharmacologic

effect of teriparatide. Persistent hypercalcemia was not observed in clinical trials with

teriparatide injection. If persistent hypercalcemia is detected, treatment with TEVA-

TERIPARATIDE INJECTION should be discontinued pending further evaluation of the cause of

hypercalcemia.

Patients known to have an underlying hypercalcemic disorder, such as primary

hyperparathyroidism, should not be treated with TEVA-TERIPARATIDE INJECTION (see

CONTRAINDICATIONS).

Urinary calcium – Teriparatide increases urinary calcium excretion, but the frequency of

hypercalciuria in clinical trials was similar for patients treated with teriparatide and placebo (see

ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics, Urinary calcium

excretion).

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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. Long-term evaluation of patients with severe renal insufficiency, patients undergoing

acute or chronic dialysis, or patients who have functioning renal transplants has not been

performed. Caution should be exercised in patients with moderate and severe renal impairment.

Serum uric acid – Teriparatide increases serum uric acid concentrations. In clinical trials, 2.8%

of teriparatide patients had serum uric acid concentrations above the upper limit of normal

compared with 0.7% of placebo patients. However, the hyperuricemia did not result in an

increase in gout, arthralgia, or urolithiasis.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

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 one large placebo-controlled, double-

blind multicentre trial with 1637 postmenopausal women, one placebo-controlled, double-blind

multicentre trial with 437 men, and two 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 long-term 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 long-term clinical

trials, 1137 patients were exposed to teriparatide for greater than 1 year (500 at 20 mcg/day and

637 at 40 mcg/day). The maximum exposure duration to teriparatide was 2 years. Adverse events

associated with teriparatide usually were mild and generally did not require discontinuation of

therapy.

The safety of teriparatide has also been evaluated in a Phase 3 randomized, double blind,

doubledummy, active controlled clinical trial that enrolled 428 men and women with

glucocorticoidinduced osteoporosis. Patients received either teriparatide 20 mcg/day plus oral

placebo (n=214) or alendronate 10 mg/day plus injectable placebo (n=214) for up to 3 years.

An additional Phase 3, randomized, multinational, multicenter, open-label study that enrolled

868 patients evaluated safety and efficacy of up to 24 months continuous treatment with 20

mcg/day of teriparatide.

Clinical Trial Adverse Drug Reactions

In the two Phase 3, placebo-controlled clinical trials in men and postmenopausal women, early

discontinuation due to an adverse event occurred in 5.6% of patients assigned to placebo and

7.1% of patients assigned to teriparatide.

Table 1 lists adverse events occurring in the Phase 3, placebo-controlled clinical trials in

postmenopausal women and in men at a frequency ≥2.0% in the teriparatide groups and in more

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teriparatide-treated patients than in placebo-treated patients. Adverse events are shown without

attribution of causality.

Table 1: Adverse Events in Placebo-Controlled Clinical Trials (Irrespective of Causality)

a

.

Body System

% Patients

Teriparatide

Placebo

(N=691)

(N=691)

BODY AS A WHOLE

Pain

21.3

20.5

Headache

Asthenia

Neck Pain

CARDIOVASCULAR

Hypertension

Angina Pectoris

Syncope

DIGESTIVE SYSTEM

Nausea

Constipation

Diarrhea

Dyspepsia

Vomiting

Gastrointestinal Disorder

Tooth Disorder

METABOLIC

Hyperuricemia

MUSCULOSKELETAL

Arthralgia

10.1

Leg Cramps

NERVOUS SYSTEM

Dizziness

Depression

Insomnia

Vertigo

RESPIRATORY SYSTEM

Rhinitis

Cough Increased

Pharyngitis

Dyspnea

Pneumonia

SKIN AND APPENDAGES

Rash

Sweating

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Treatment emergent adverse events that occurred at a frequency≥2% in patients treated with teriparatide

at 20 mcg/day irrespective of causality assessment by Clinical Study Investigators.

COSTART terminology.

Treatment emergent adverse events considered by Clinical Study Investigators to be causally

related to teriparatide, reported by at least 1% of teriparatide-treated patients and reported in

more teriparatide-treated patients than placebo-treated patients are: dizziness, nausea, arthralgia,

asthenia and headache. Leg cramps is an adverse event that may also be causally related to

teriparatide.

NOTE: The incidence of hypertension, syncope, dyspepsia, rhinitis, and pharyngitis in patients

treated with teriparatide 40 mcg/day (twice the recommended dose) was lower than the incidence

in placebo-treated patients.

During the 18-month primary phase of a double-blind, double-dummy, active comparator

controlled study in men and women with glucocorticoid-induced osteoporosis, early

discontinuation due to treatment-emergent adverse events (TEAEs) occurred in 31 (15%)

patients assigned to teriparatide (N=214) and in 25 (12%) patients assigned to alendronate

(N=214).

Over 24 months, the early discontinuation due to TEAEs occurred in 35 (16.4%) patients

assigned to teriparatide (N=214) and in 27 (12.6%) patients assigned to alendronate (N=214).

Table 2 lists drug-related adverse events reported in ≥ 1% of patients treated with teriparatide or

alendronate 10 mg/day in a clinical trial of men and women with Glucocorticoid-induced

Osteoporosis up to 24 months.

Table 2: Drug-Related* Adverse Events Reported in

1% of Patients Treated with

Teriparatide 20 mcg/day or Alendronate 10 mg/day in a Principle Clinical Trial

in Men and Women with Glucocorticoid-induced Osteoporosis. Study B3D-US-

GHBZ, 24 Month data

Teriparatide

(N=214)

(%)

Alendronate

(N=214)

(%)

Gastrointestinal disorders

Nausea

Abdominal pain upper

Vomiting

Abdominal pain

Dyspepsia

Gastric Ulcer

Nervous system disorders

Dizziness

Headache

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Teriparatide

(N=214)

(%)

Alendronate

(N=214)

(%)

Musculoskeletal and connective tissue

disorders

Muscle spasms

* Considered to be possibly related by Clinical Study Investigators.

MedDRA (version 10.0) terminology.

The 24-month study, B3D-EW-GHCA (EUROFORS), was a multinational, multicenter,

prospective, open-label Phase 3/4 trial in postmenopausal women with osteoporosis. Study

GHCA had 2 substudies in which all patients received teriparatide 20 mcg/day plus calcium and

vitamin D during the first 12 months. In substudy 1, patients were randomized to receive an

additional one year of therapy with either teriparatide 20 mcg/day or raloxifene 60 mg/day, or no

treatment. In substudy 2, all patients received 24 months of teriparatide 20 mcg/day. All patients

received supplemental calcium and Vitamin D.

Table 3 lists drug-related adverse events reported in ≥ 1% of patients. Most reports of possibly

drug related TEAEs occurred in the first 6-month interval of the study.

Table 3: Drug-Related

*

Adverse Events Reported in

1% of Patients Treated with

Teriparatide 20 mcg/day in a Clinical Trial in Women with Osteoporosis. Study B3D-

EW-GHCA (EUROFORS), 24 Month Data

Teriparatide

(N=866)

(%)

Gastrointestinal disorders

Nausea

Vomiting

Diarrhea

Nervous System disorders

Headache

Dizziness

Vertigo

Muscloskeletal and connective tissue disorders

Muscle Cramp

Pain in extremity

Arthralgia

Back pain

Other

Hypercalcemia

Injection site erythema

* Considered to be possibly related by Clinical Study Investigators.

MedDRA (version 7.0) terminology.

Serum calcium - Teriparatide transiently increases serum calcium, with the maximal effect

observed at approximately 4 to 6 hours post-dose. Serum calcium measured at least 16 hours

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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 teriparatide 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 teriparatide. The number of patients treated with teriparatide

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 female patients receiving teriparatide. Generally, antibodies were first

detected following 12 months of treatment and diminished after withdrawal of therapy. There

were no effects of the antibodies on serum calcium or bone mineral density (BMD) response.

Post-Market Adverse Drug Reactions

Since global 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). Since first marketing in 2002,

spontaneous reports of anaphylaxis (irrespective of causality assessment) have been

reported very rarely (<1 in 25,000 patients treated). In these very rare case reports,

patients typically had alternative diagnoses explaining the events or subsequent negative

rechallenge.

Cases of bone tumor and osteosarcoma have been reported rarely in the postmarketing

period.

The causality to teriparatide use is unclear. Long term osteosarcoma surveillance studies

are ongoing.

In the post-marketing data analysis of benign, malignant and unspecified neoplasms, the

ratio of cases reported for both men and women is equivalent.

Hypercalcemia greater than 2.76 mmol/L (less than 1 in 100 patients treated).

Hypercalcemia greater than 3.25 mmol/L (less than 1 in 1000 patients treated).

Muscle spasms, such as of the leg or back, are reported commonly (≥1 in 100 and <1 in

10 patients treated), sometimes shortly after the first dose.

Serious back spasms have been reported very rarely (less than 1 in 10,000 patients

treated).

DRUG INTERACTIONS

Drug-Drug Interactions

Hydrochlorothiazide - In a study of 20 healthy subjects, the co-administration of 25-mg

hydrochlorothiazide 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 insignificant amount

(15%). The effect of co-administration of a higher dose of hydrochlorothiazide with teriparatide

on serum calcium levels has not been studied.

Furosemide - In a study of 9 healthy subjects and 17 patients with mild, moderate, and severe

renal insufficiency (creatinine clearance 13 to 72 mL/min), co-administration of intravenous

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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.

Digoxin - In a study of 15 healthy people administered digoxin daily to steady state, a single

teriparatide 20 mcg 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, sporadic case reports have suggested that hypercalcemia may

predispose patients to digitalis toxicity. Because teriparatide transiently increases serum calcium,

TEVA-TERIPARATIDE INJECTION should be used with caution in patients taking digoxin.

DOSAGE AND ADMINISTRATION

TEVA-TERIPARATIDE INJECTION should be administered as a subcutaneous injection into

the thigh or abdominal wall. The recommended dosage is 20 mcg once a day.

The safety and efficacy of teriparatide have been evaluated up to 2 years in studies GHAC,

GHAJ, GHBJ and GHCA (median 19 months in women in study GHAC and 10 months in men

in study GHAJ). An additional clinical study (GHBZ) evaluated the safety and efficacy of

teriparatide for up to 3 years. The maximum lifetime exposure to TEVA-TERIPARATIDE

INJECTION for an individual patient is 24 months.

TEVA-TERIPARATIDE INJECTION 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, Information for Patients).

Patients should receive supplemental Calcium and vitamin D if dietary intake is inadequate.

TEVA-TERIPARATIDE INJECTION should not be used in patients with severe renal

impairment (see CONTRAINDICATIONS).

TEVA-TERIPARATIDE INJECTION is a clear and colourless solution. Do not use if solid

particles appear or if the solution is cloudy or coloured. The TEVA-TERIPARATIDE

INJECTION 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 TEVA-TERIPARATIDE

INJECTION.

OVERDOSAGE

No cases of overdose were reported during clinical trials with teriparatide injection. 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.

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In post-marketing spontaneous reports, there have been cases of medication error in which the

entire contents (up to 800 mcg) of the teriparatide 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 TEVA-TERIPARATIDE INJECTION, monitoring

of serum calcium and phosphorus, and implementation of appropriate supportive measures, such

as hydration.

ACTION AND CLINICAL PHARMACOLOGY

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. 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

Pharmacodynamics

Effects on mineral metabolism - Teriparatide affects calcium and phosphorus metabolism in a

pattern consistent with the known actions of endogenous PTH (e.g., increases serum calcium and

decreases serum phosphorus).

Serum calcium concentrations - When TEVA-TERIPARATIDE INJECTION 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, 0.1 mmol/L). 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 teriparatide was 2.42 mmol/L at 12

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months. The peak serum calcium remained below 2.76 mmol/L in >99% of women at each visit.

Sustained hypercalcemia was not observed.

In this study, 11.1% of women treated with teriparatide had at least 1 serum calcium value above

the upper limit of normal (2.64 mmol/L) at the 4- to 6-hour post-dose peak measurement

compared with 1.5% of women treated with placebo. The 24-hour post-dose trough serum

calcium measurement was unchanged from baseline in both groups. The percentage of women

treated with teriparatide 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 teriparatide doses were

reduced. The timing of these dose reductions was at the discretion of the investigator.

Teriparatide dose adjustments were made at varying intervals after the first observation of

increased 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 teriparatide was 2.35 mmol/L at

12 months. The peak serum calcium remained below 2.76 mmol/L in 98% of men at each visit.

Sustained hypercalcemia was not observed.

In this study, 6.0% of men treated with teriparatide daily had at least 1 serum calcium value

above the upper limit of normal (2.64 mmol/L) at the 4- to 6-hour post-dose peak measurement

compared with none of the men treated with placebo. The 24-hour post-dose trough serum

calcium measurement was unchanged from baseline in both groups. The percentage of men

treated with teriparatide 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 teriparatide doses could have been reduced in

these men, only calcium supplementation was reduced (see WARNINGS AND PRECAUTIONS

and ADVERSE REACTIONS).

Teriparatide has not been studied in patients with pre-existing hypercalcemia. These patients

should be excluded from treatment with TEVA-TERIPARATIDE INJECTION because of the

possibility of exacerbating hypercalcemia (see CONTRAINDICATIONS).

Urinary calcium excretion - In a long-term (median of 19 months) study of postmenopausal

women with osteoporosis, who received 1000 mg of supplemental calcium and at least 400 IU of

vitamin D, teriparatide slightly increased urinary calcium excretion. The median values at 6 and

12 months were 0.76 mmol/day (30 mg/day) and 0.30 mmol/day (12 mg/day) higher,

respectively, than those of placebo-treated patients. 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. The

incidence of hypercalciuria (>7.5 mmol calcium/day or 300 mg/day) was not different from that

in placebo-treated subjects.

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In a long-term (median of 10 months) study of men with osteoporosis, who received 1000 mg of

supplemental calcium and at least 400 IU of vitamin D, teriparatide had inconsistent effects on

urinary calcium excretion. The median values at 1 and 6 months were 0.50 mmol/day (20

mg/day) higher and 0.20 mmol/day (8.0 mg/day) lower, respectively, than those of placebo-

treated patients. 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. The incidence of hypercalciuria (>7.5 mmol

Ca/day or 300 mg/day) was not different from that in placebo-treated subjects.

Phosphorus and vitamin D - In single-dose studies, teriparatide produced transient phosphaturia

and mild transient reductions in serum phosphorus concentration. However, hypophosphatemia

(<0.74 mmol/L or 2.4 mg/dL) was not observed in long-term (median of 10 and 19 months)

clinical trials with teriparatide.

In clinical studies of daily teriparatide, the median serum concentration of 1,25-

dihydroxyvitamin D at 12 months was increased by 19% in women and 14% in men, compared

to 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 to baseline. In the placebo group, this

concentration was unchanged in women and increased by 1% in men.

Effects on markers of bone turnover - Daily administration of teriparatide to men and

postmenopausal women with osteoporosis stimulated bone formation, as shown by rapid

increases in the formation markers: serum bone-specific alkaline phosphatase (BSAP) and

procollagen I carboxy-terminal propeptide (PICP). Peak concentrations of PICP approximately

41% above baseline were observed at 1 month of treatment, followed by a decline to near-

baseline values by 12 months. BSAP concentrations had increased by 1 month of treatment and

continued to rise more slowly from 6 through 12 months. Maximum increases of BSAP achieved

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 remodelling. Changes in BSAP, NTX, and DPD were somewhat lower

in men than in women, possibly because of lower systemic exposure to teriparatide in men.

Pharmacodynamics in Men and Women with Glucocorticoid-Induced Osteoporosis

Glucocorticoid-Induced Osteoporosis — The primary effect of glucocorticoids on bone is to

inhibit osteoblastic bone-forming activity. Glucocorticoids also increase bone resorption.

Effects on markers of bone turnover — During 18 months (the primary phase) of therapy in a 36-

month double-blind, double-dummy, active comparator-controlled study of patients with

glucocorticoid-induced osteoporosis who received either teriparatide 20 mcg/day or alendronate

10 mg/day, daily administration of teriparatide stimulated new bone formation as shown by

increases from baseline in the serum concentration of biochemical markers of bone formation

including BSAP, PICP, and amino-terminal propeptide of type I collagen (PINP) (see Table 4).

teriparatide also stimulated bone resorption as shown by increases from baseline in serum

concentrations of C-terminal telopeptide of type I collagen (CTX). Alendronate 10 mg/day

Teva-Teriparatide Injection

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induced decreases from baseline in the serum concentration of BSAP, PICP, PINP and CTX (see

Table 4). The effects of teriparatide on bone turnover markers in patients with glucocorticoid-

induced osteoporosis were qualitatively similar to the effects in postmenopausal women with

osteoporosis not taking glucocorticoids.

Table 4: Median Percent Changes

a,b

from Baseline in Bone Biomarkers in Patients

with

Glucocorticoid-Induced

Osteoporosis

PINP mcg/L

BSAP mcg/L

PICP mcg/L

CTX pmol/L

Treatment

Duration

Teriparatide

ALN

Teriparatide

ALN

Teriparatide

ALN

Teriparatide

ALN

1 month

6 month

18 month

The median percent changes in teripratide-treated patients were significantly different (p<0.01) compared with

alendronate-

treated (ALN) patients for each biomarker at all time points.

Values represent median percent changes with n=54 to 99 among the 4 biomarkers at the different time points.

Calcium and phosphorus concentrations — In the study of patients with glucocorticoid-induced

osteoporosis, the effects of teriparatide on serum calcium and phosphorus were similar to those

observed in postmenopausal women with osteoporosis not taking glucocorticoids.

Pharmacokinetics

Absorption: Teriparatide is extensively absorbed after subcutaneous injection; the absolute

bioavailability is approximately 95% based on pooled data from 20-, 40-, and 80-mcg doses

administered into the abdominal wall. 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. Peak molar

concentrations of teriparatide briefly exceed the upper limit of normal for endogenous PTH by 4-

to 5-fold.

Metabolism: No metabolism or excretion studies have been performed with teriparatide.

However, the mechanisms of metabolism and elimination of PTH(1-34) and intact endogenous

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.

Distribution and Elimination: 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. Inter-subject 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.

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Special Populations and Conditions

Pediatrics: The pharmacokinetics of teriparatide have not been evaluated in pediatric

populations (see WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics).

Geriatrics: No differences in teriparatide pharmacokinetics were detected with regard to age

(range 31 to 85 years).

Gender: Although systemic exposure to teriparatide is approximately 20% to 30% lower in men

than in women, the recommended dose for both genders is 20 mcg/day.

Race: The populations included in the pharmacokinetic analyses were predominantly Caucasian

(98.5%) with less than 1.5% representing Hispanic, Asian, and other origins. The influence of

race on serum teriparatide concentrations has not been determined.

Hepatic Insufficiency: 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. No studies have been performed in patients with hepatic impairment.

Renal Insufficiency: No pharmacokinetic differences were identified in 11 patients with mild or

moderate renal insufficiency [creatinine clearance (CrCl) 30 to 72 mL/min] administered a single

dose of teriparatide. In 5 patients with severe renal insufficiency (CrCl<30 mL/min), the AUC

and T1/2 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 CONTRAINDICATIONS).

Heart failure: No clinically relevant pharmacokinetic, blood pressure, pulse rate, or other safety

differences were identified in 13 patients with stable heart failure (New York Heart Association

Class I to III and additional evidence of cardiac dysfunction) after administration of two 20 mcg

doses of teriparatide. There are no data from patients with severe heart failure.

STORAGE AND STABILITY

The TEVA-TERIPARATIDE INJECTION pen should be stored under refrigeration at 2-8°C at

all times. During the use period, time out of the refrigerator should be minimized; the dose may

be delivered immediately following removal from the refrigerator. When stored under

refrigerated conditions at 2-8°C, TEVA-TERIPARATIDE INJECTION is stable until date of

expiry. Do not freeze. Do not use TEVA-TERIPARATIDE INJECTION if it has been frozen.

INSTRUCTIONS FOR PEN USE

Patients and caregivers who administer TEVA-TERIPARATIDE INJECTION should receive

appropriate training and instruction on the proper use of the TEVA-TERIPARATIDE

INJECTION pen from a qualified health professional. It is important to read, understand, and

follow the instructions for using the pen in the TEVA-TERIPARATIDE INJECTION Pen User

Manual. Failure to do so may result in inaccurate dosing. The 2.4 mL prefilled pen is not primed

before each dose. Each TEVA-TERIPARATIDE INJECTION pen can be used for up to 28 days

Teva-Teriparatide Injection

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including the first injection, if stored properly. After the 28-day use period, discard the TEVA-

TERIPARATIDE INJECTION pen, even if it still contains some unused solution. Never share a

TEVA-TERIPARATIDE INJECTION pen.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Form:

TEVA-TERIPARATIDE INJECTION is supplied as a sterile, colourless, clear, solution for

injection in a 3 mL cartridge contained in a prefilled delivery device (pen).

Composition:

Each mL of solution contains 250 mcg teriparatide (as teriparatide acetate) and 3.0 mg

metacresol (preservative) in addition to glacial acetic acid, sodium acetate (trihydrate), mannitol,

and water for injection. Hydrochloric acid solution and/or sodium hydroxide solution may have

been added to adjust the product to pH 4. Each 2.4 mL prefilled multidose injection pen delivers

20 mcg of TEVA-TERIPARATIDE INJECTION per dose.

Packaging:

TEVA-TERIPARATIDE INJECTION is available in (1) pre-filled pen per carton.

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PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Common name:

teriparatide

Chemical name: Teriparatide is identical to the 34 N-terminal amino acid sequence of

natural human parathyroid hormone: [PTH(1-34)]

1) L-Phenylalanine, L-seryl-L-valyl-L-seryl-L- α -glutamyl-L-isoleucyl-L-glutaminyl-L-

leucyl-L-methionyl-L-histidyl-L-asparaginyl-L-leucyl-L-glycyl-L-lysyl-L-histidyl-L-

leucyl-L-asparaginyl-L-seryl-L-methionyl-L- α -glutamyl-L-arginyl-L-valyl-L- α -

glutamyl-L-tryptophyl-L-leucyl-L-arginyl-L-lysyl-L-lysyl-L-leucyl-L-glutaminyl-L- α -

aspartyl-L-valyl-L-histidyl-L-asparaginyl-

2) L-Seryl-L-valyl-L-seryl-L- α -glutamyl-L-isoleucyl-L-glutaminyl-L-leucyl-L-

methionyl-L-histidyl-L-asparaginyl-L-leucyl-L-glycyl-L-lysyl-L-histidyl-L-leucyl-L-

asparaginyl-L-seryl-L-methionyl-L- α -glutamyl-L-arginyl-L-valyl-L- α -glutamyl-L-

tryptophyl-L-leucyl-L-arginyl-L-lysyl-L-lysyl-L-leucyl-L-glutaminyl-L-α-aspartyl-L-

valyl-L-histidyl-L-asparaginyl-L-phenylalanine

Molecular formula and molecular mass: C

, 4117.8 Daltons

Structural formula:

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CLINICAL TRIALS

Treatment of Osteoporosis in Postmenopausal Women

Study demographics and trial design

Table 5: Summary of Patient Demographics for Clinical Trials in Postmenopausal

Women with Osteoporosis

.

Study #

Trial design

Dosage, route of

administration and

duration

Study subjects

(n=number)

Mean age

(Range)

Gender

B3D-

GHAC

Double-blind,

placebo-controlled

Placebo, teriparatide 20

mcg, or teriparatide 40

mcg, subcutaneous

injection, once daily. Up

to 24 months (median:

19 months)

Postmenopausal

osteoporosis

(1637)

69.5 years

(42 to 86 years)

Women

The safety and efficacy of teriparatide once-daily for up to 24 months (median: 19 months), were

examined in a double-blind, placebo-controlled clinical study of 1637 postmenopausal women

(mean age: 69.5 years) with severe osteoporosis (mean T- score: -2.6). Among these women,

541 received teriparatide 20 mcg. All women received 1000 mg of calcium per day and at least

400 IU of vitamin D per day. 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.

Effect on fracture incidence

New vertebral fractures – Teriparatide, when taken with calcium and vitamin D and compared

with calcium and vitamin D alone, significantly reduced the risk of 1 or more new vertebral

fractures from 14.3% of women in the placebo group to 5.0% in the teriparatide group

(p<0.001). The absolute reduction in risk was 9.3% and the relative reduction was 65%. Eleven

women would need to be treated with teriparatide for a median of 19 months to prevent one or

more new vertebral fractures. Teriparatide was effective in reducing the risk for vertebral

fractures regardless of age, baseline rate of bone turnover, or baseline bone mineral density

(BMD).

Table 6: Effect of Teriparatide on Vertebral Fracture Incidence in Postmenopausal

Women with Osteoporosis.

Placebo

(N=448)

(%)

Teriparatide

(N=444) (%)

Absolute

Risk

Reduction

(%)

95% CI (%)

P-Value

New fracture (≥ 1)

14.3

(5.3, 13.4)

<0.001

Multiple fractures (≥ 2)

(1.3, 6.2)

0.001

Moderate or severe fracture (≥

1)

(5.4, 11.5)

<0.001

Percentages compared between treatment groups using Fisher’s Exact Test.

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Confidence Interval (CI) based on Fleiss Method (1981, p.29).

Effect on height loss - Both treatment groups lost height during the trial. The mean decreases

were 3.61 and 2.81 mm in the placebo and teriparatide groups, respectively. For the 86

postmenopausal women who experienced vertebral fractures, those treated with teriparatide had

significantly less height loss when compared to placebo (p = 0.001).

Effect on back pain - Teriparatide significantly reduced the incidence and severity of back pain.

In women with postmenopausal osteoporosis, there was a 26% reduction (p = 0.017) in the

spontaneous reports of new or worsened back pain compared to placebo.

New nonvertebral osteoporotic fractures - Table 7 shows the effect of teriparatide on the risk of

nonvertebral fractures. Teriparatide significantly reduced the risk of any nonvertebral fracture

from 5.5% in the placebo group to 2.6% in the teriparatide group (p<0.05). The absolute

reduction in risk was 2.9% and the relative reduction was 53%.

Table 7: Effects of Teriparatide on Risk of New Nonvertebral Fractures in

Postmenopausal Women with Osteoporosis.

Teriparatide

N=541

Placebo

a

N=544

Absolute Risk

Reduction (%)

95% CI (%)

P-Value

Skeletal site

Wrist

2 (0.4%)

7 (1.3%)

(-0.3, 2.2)

0.178

Ribs

3 (0.6%)

5 (0.9%)

(-0.8, 1.6)

0.726

Hip

1 (0.2%)

4 (0.7%)

(-0.4, 1.5)

0.374

Ankle/Foot

1 (0.2%)

4 (0.7%)

(-0.4, 1.5)

0.374

Humerus

2 (0.4%)

2 (0.4%)

-0.0

(-0.9, 0.9)

1.000

Pelvis

3 (0.6%)

(-0.3, 1.4)

0.249

Other

6 (1.1%)

8 (1.5%)

(-1.2, 1.9)

0.789

Total

14 (2.6%)

30 (5.5%)

(0.4, 5.5)

0.020

Data shown as number (%) of women with fractures.

Percentages compared between treatment groups using Fisher's Exact

Test. Confidence Interval (CI) based on Fleiss Method (1981, P.29).

The cumulative percentage of postmenopausal women with osteoporosis who sustained new

nonvertebral fractures was lower in women treated with teriparatide than in women treated with

placebo (see Figure 1).

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Figure 1: Cumulative percentage of postmenopausal women with osteoporosis sustaining

new nonvertebral osteoporotic fractures.*

* This graph includes all fractures listed above in Table 7.

Post- treatment fracture efficacy - Following treatment with teriparatide, 1262 postmenopausal

women from the pivotal trial enrolled in a post-treatment follow-up study. After 18 months,

approximately 50% of the women in each former treatment group had begun an approved

osteoporosis therapy (not including teriparatide) at the discretion of their physician. All women

were offered 1000 mg of calcium per day and at least 400 IU of vitamin D per day.

During a median of 18 months following discontinuation of teriparatide treatment, there was a

significant 40% reduction in relative risk for new vertebral fractures in women previously treated

with teriparatide, compared to placebo. (The relative risk reduction was similar for women with

and without osteoporosis treatment, 41% and 37%, respectively). During the same observation

period, there was a 42% risk reduction for nonvertebral fragility fractures in women previously

treated with teriparatide, compared with placebo.

Data from this study demonstrate that regardless of the follow-up treatment options, fracture risk

was reduced for women previously treated with teriparatide.

Teriparatide

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Effect on bone mineral density (BMD)

Teriparatide 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.

Figure 2: Time course of change in lumbar spine BMD in postmenopausal women with

osteoporosis treated with teriparatide vs placebo (women with data available at all time

points).

(p<0.001 for teriparatide compared with placebo at each post-baseline time point)

Postmenopausal women with osteoporosis who were treated with teriparatide also had

statistically significant increases in BMD at the femoral neck, total hip, and total body (see Table

Table 8: Mean Percent Change in BMD from Baseline to Endpoint* in

Postmenopausal Women with Osteoporosis, Treated with Teriparatide or Placebo.

Teriparatide

N=541

Placebo

N=544

Treatment

Difference

95% CI (%)

Lumbar spine BMD

(7.8 , 9.4)

Femoral neck BMD

-0.7

(2.8 , 4.2)

Total hip BMD

-1.0

(2.8 , 4.4)

Trochanter BMD

-0.2

(2.9 , 4.5)

Intertrochanter BMD

-1.3

(3.0 , 4.8)

Ward’s

triangle BMD

-0.8

(3.5 , 6.5)

Total body BMD

-0.5

(0.4 , 1.7)

Distal 1/3 radius BMD

-2.1

-1.3

-0.8

(-1.7 , 0.0)

Ultradistal radius BMD

-0.1

-1.6

(-0.2 , 3.3)

* Intent-to-treat analysis, last observation carried forward.

p<0.001 compared with placebo.

Teriparatide (N=129)

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p<0.05 compared with placebo.

Percentages compared between treatment groups using T-test

Figure 3 shows the cumulative distribution of the percentage change from baseline of lumbar

spine BMD for the teriparatideand placebo groups. Teriparatide treatment increased lumbar spine

BMD from baseline in 96% of postmenopausal women treated (see Figure 3). Seventy-two

percent of patients treated with teriparatide achieved at least a 5% increase in spine BMD, and

44% gained 10% or more.

Figure 3: Percent of postmenopausal women with osteoporosis attaining a lumbar spine

BMD percent change from baseline at least as great as the value on the x-axis

(median duration of treatment 19 months).

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). Teriparatide significantly increased cancellous

bone volume and connectivity, improved trabecular morphology with a shift toward a more

plate-like structure, and increased cortical bone thickness.

Teriparatide

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Treatment to Increase Bone Mass in Men with Primary or Hypogonadal Osteoporosis

Study demographics and trial design

Table 9: Summary of Patient Demographics for Clinical Trials in Men with

Primary or Hypogonadal Osteoporosis

.

Study #

Trial design

Dosage, route of

administration and

duration

Study

subjects

(n=number)

Mean age

(Range)

Gender

B3D-MC-

GHAJ

Double-blind,

placebo-controlled

Placebo, teriparatide 20

mcg, or teriparatide 40

mcg, subcutaneous

injection, once daily.

Up to 14 months

(median: 10 months)

Primary

(idiopathic) or

hypogonadal

osteoporosis

(437)

58.7 years

(28 to 85 years)

The safety and efficacy of teriparatide once-daily for up to 14 months (median: 10 months) were

examined in a double-blind, placebo-controlled clinical study of 437 men (mean age: 58.7 years)

with either primary (idiopathic) or hypogonadal osteoporosis (teriparatide 20 mcg, n=151). 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 bone mineral density (BMD).

Effect on bone mineral density (BMD)

Teriparatide 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. After a median treatment period of 10 months, BMD in the spine increased on average by

5.4% and in the total hip by 0.7% compared to placebo. Teriparatide was effective in increasing

lumbar spine BMD regardless of age, baseline rate of bone turnover, and baseline BMD. The

effects of teriparatide at additional skeletal sites are shown in Table 10.

Table 10: Mean Percent Change in BMD from Baseline to Endpoint*

in

Men with

Primary or Hypogonadal Osteoporosis, Treated w

i

th Teriparatide or Placebo for a

Median of 10 Months

Teriparatide

N=151

Placebo

N=147

Treatment

Difference

95% CI (%)

Lumbar spine BMD

(4.4 , 6.3)

Femoral neck BMD

(0.3 , 2.2)

Total hip BMD

(-0.0 , 1.3)

Trochanter BMD

(-0.7 , 1.1)

Intertrochanter BMD

(-0.2 , 1.3)

Ward’s

triangle BMD

(-0.2 , 3.7)

Total body BMD

-0.4

(-0.1 , 1.6)

Distal 1/3 radius BMD

-0.5

-0.2

-0.3

(-0.9 , 0.3)

Ultradistal radius BMD

-0.5

-0.3

-0.2

(-1.1 , 0.7)

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* Intent-to-treat analysis, last observation carried forward.

p<0.001 compared with placebo.

p<0.05 compared with placebo.

Percentages compared between treatment groups using T-test

Figure 4 shows the cumulative distribution of the percentage change from baseline of lumbar

spine BMD for the FORTEO and placebo groups. TERIPARATIDE 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 TERIPARATIDE achieved at least a 5% increase in spine BMD,

and 14% gained 10% or more.

Figure 4: Percent of men with primary or hypogonadal osteoporosis attaining a lumbar

spine BMD percent change from baseline at least as great as the value on the x-axis

(median duration of treatment 10 months).

Teriparatide

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Treatment of Men and Women with Glucocorticoid-Induced Osteoporosis

Study demographics and trial design

Table 11: Summary of Patient Demographics for Clinical Trial

in

Men

and

Women with

Glucocorticoid-Induced

Osteoporosis

Study #

Trial design

Dosage, route of

administration and

duration

Study subjects

(n=number)

Mean age (range)

Gender

B3D-US-

GHBZ

Double-blind,

active

comparator-

controlled

Placebo (oral and

injection), Teriparatide

20 mcg/day by

subcutaneous injection,

once daily,

Alendronate 10 mg/day,

oral

Duration 36 months:

Primary phase - 18

months; continuation

phase - 18 months

Glucocorticoid-

induced

osteoporosis

(428)

57 years (range 22-

Women

Glucocorticoid-induced osteoporosis affects both men and women. Loss of BMD occurs early

after the initiation of glucocorticoid therapy and may continue during sustained glucocorticoid

therapy. The safety and efficacy of once-daily teriparatide were examined in a multicenter,

randomized, double-blind, double-dummy, active comparator-controlled study of 83 men and

345 women taking systemic glucocorticoid medications (prednisone equivalent ≥5 mg/day for ≥3

consecutive months prior to screening) and had a BMD T-score of ≤-2 at the total hip, femoral

neck, or lumbar spine, or had ≥1 fragility fracture and a BMD T-score of ≤-1 at the total hip,

femoral neck, or lumbar spine. Patients received either teriparatide 20 mcg/day plus oral placebo

(N=214) or alendronate 10 mg/day plus injectable placebo (N=214). Patients received

supplemental calcium 1000 mg/day and vitamin D 800 IU/day.

The mean age of patients with glucocorticoid-induced osteoporosis was 57 years (range 22-89).

The baseline median glucocorticoid dose (prednisone equivalent) was 7.5 mg and the median

duration of glucocorticoid use was 1.3 years. The mean (SD) baseline lumbar spine BMD was

0.85 ± 0.13 g/cm2 and T-score was -2.5 ± 1. A total of 27% of patients had prevalent vertebral

fracture(s) and 43% had prior non-vertebral fracture(s). The patients had chronic diseases that

required sustained glucocorticoid therapy including 73% with rheumatologic or other joint and

musculoskeletal disorders, and 14% with respiratory disorders. There was no significant

difference in these baseline characteristics between the teriparatide and alendronate groups.

Effect on bone mineral density (BMD)

In patients with glucocorticoid-induced osteoporosis, both teriparatide and alendronate

significantly increased lumbar spine BMD compared with baseline at 3 months through 24

months of treatment. Table 12 shows the mean change in lumbar spine, total hip, and femoral

neck BMD from baseline to the primary 18-month endpoint in patients with

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glucocorticoidinduced osteoporosis who were treated with teriparatide or alendronate. The

analysis in Table 12 included all patients with a baseline and at least one post baseline BMD

measurement (last observation carried forward analysis).

Table 12: Least Squares Mean Change in BMD (g/cm

2

) from Baseline to Endpoint in

Men and Women with

Glucocorticoid-Induced Osteoporosis who

had a Baseline and at

Least One Post-baseline BMD Measurement

a

,

18 Month Data

Teriparatide 20 mcg/day

(N=214)

Alendronate 10 mg/day

(N=214)

n

Change in BMD (%)

n

Change in BMD (%)

Treatment difference

(95% CI)

Lumbar Spine

0.059 (7.2%)

0.028 (3.4%)

0.031 (0.021,

0.041)

Total Hip

0.026 (3.6%)

0.017 (2.2%)

0.009 (0.003,

0.015)

Femoral Neck

0.024 (3.7%)

0.014 (2.1%)

0.010 (0.002,

0.018)

Within group actual changes (percent change) in BMD from baseline to endpoint (last observation

carried forward, 18 months) were significant (p<0.01) at the lumbar spine, total hip, and femoral neck for

both TERIPARATIDE and alendronate

p<0.001, teriparatide versus alendronate

p<0.01, teriparatide versus alendronate

p<0.05, teriparatide versus alendronate

Between treatment group p values were obtained using the following analysis of variance model: Actual change in

BMD = treatment + region + prior bisphosphonate use + gender.

Figure 5 shows the mean percent changes from baseline in lumbar spine BMD in patients treated

with teriparatide or alendronate who had BMD measurements at each time point. The increase in

lumbar spine BMD induced by teriparatide was significantly greater compared with alendronate

after 6, 12, 18 and 24 months of therapy (p<0.001 for teriparatide vs. alendronate). The relative

treatment effects of teriparatide and alendronate 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.

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Figure 5: Percent change in lumbar spine BMD(g/cm

2

) in men and women with

glucocorticoid-induced osteoporosis (patients with BMD measurements at each visit

through 24 months)

**p<0.001: teriparatide vs. alendronate

Between 18 and 24 months in patients with glucocorticoid-induced osteoporosis treated with

teriparatide, the mean percent change in lumbar spine, total hip and femoral neck BMD increased

by an additional (0.014 g/cm

) 1.7%, (0.007 g/cm

) 0.9%, and (0.002 g/cm2) 0.4%, respectively.

Effect on vertebral and non-vertebral fractures

During the 18-month primary phase of Study B3D-US-GHBZ, 18 patients in the alendronate

group and 13 patients in the teriparatide group experienced vertebral and/or nonvertebral

fracture(s). One patient in the alendronate group experienced both a vertebral and a nonvertebral

fracture.

An analysis of 336 spinal X-rays, performed at 18 months, showed that 10 (6.1%) patients in the

alendronate group compared to 1(0.6%) in the TERIPARATIDE group had experienced a new

vertebral fracture. New nonvertebral fracture(s) were reported for 8 (3.7%) alendronate patients

and 12 (5.6%) teriparatide patients. At 36 months, analysis of spinal X-rays showed that 13 of

169 patients (7.7%) in the alendronate group had experienced a new vertebral fracture compared

with 3 of 173 patients in the teriparatide group (1.7%). Whereas, 15 of 214 patients in the

alendronate group (7.0%) had experienced a nonvertebral fracture compared with 16 of 214

patients in the teriparatide group (7.5%).

Teriparatide (N=122)

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2-Year Continuous Treatment of Osteoporosis in Postmenopausal Women with

Teriparatide Study demographics and trial design

Table 13: Summary of Patient Demographics for Clinical Trial of 24 month Continuous

Treatment with Teriparatide

Study #

Trial design

Dosage, route of

administration and

duration

Study subjects

(n=number)

Mean age

(range)

Gender

B3D-

GHCA

Multicenter,

prospective,

open-label phase

3/4 trial, 2

substudies.

Substudy 1:

randomized with

3 treatment arms.

Substudy 2: all

patients receiving

teriparatide for 24

months.

Teriparatide 20 mcg/day for

24 months in substudy 1

treatment arm 1 and

substudy 2, and for 12

months in substudy 1

treatment arms 2 and 3.

raloxifene HCL 60 mg/day

for the second 12 months

in substudy 1 treatment

arm 2. All patients

supplemented with 500

mg/day elemental calcium

and 400 to 800 IU/day

vitamin D;

Substudy 1: 632

Substudy 2: 234

(Total:866)

69.9 years

(range 55-

92.1)

Postmenopausal

women

The 24-month study, B3D-EW-GHCA (EUROFORS), was a multinational, multicenter,

outpatient, prospective, open-label, Phase 3/4 trial in postmenopausal women with severe

osteoporosis and ≥1 clinical fragility fracture (76% had received antiresorptive drugs). This

study had 2 substudies in which all patients received teriparatide 20 mcg/day during the first 12

months.

Substudy 1 (parallel, controlled, and randomized) enrolled postmenopausal women with a BMD

T-score 2.5 standard deviations (SDs) below the reference range for healthy premenopausal

n at the lumbar spine, total hip, or femoral neck, and ≥1 preexisting clinical vertebral or

nonvertebral fragility fracture within 3 years of screening. The 3 treatment arms of substudy 1

were:

treatment arm 1 – Teriparatide 20 mcg/day for 24 months

treatment arm 2 – Teriparatide 20 mcg/day for 12 months, followed by raloxifene

60mg/day for 12 months

treatment arm 3 - Teriparatide 20 mcg/day for 12 months, followed by no treatment

for 12 months

Substudy 2 (uncontrolled – all patients receive teriparatide 20 mcg/day for 24 months): patients

had to meet the criteria of patients in substudy 1 plus have 1 of the following: (a) a new,

documented clinical vertebral or nonvertebral fragility fracture despite prescription of

antiresorptive therapy in the year prior to this fracture; or (b) had a lumbar spine, femoral

neck,

total hip BMD T-score 3 SDs or more below the reference range for healthy premenopausal

women despite prescription of antiresorptive treatment for the past 2 years; or (c) a BMD

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decrease of ≥3.5% at any site, despite prescription of antiresorptive treatment for the past 2 years.

Thus, all patients in substudy 2 had an inadequate clinical response to prior osteoporosis therapy.

At baseline, the mean age in substudy 2 (N=234) was 70.2 years, 99.1% of patients had prior

antiresorptive therapy, and 99.6% had a history of fragility fracture. Study GHCA differs from

most clinical studies of teriparatide which enrolled treatment-naïve patients or patients with

limited previous use of antiresorptive drugs. In addition, this study enrolled high risk osteoporotic

patients who had failed to respond to other anti-osteoporosis drugs.

Effect on bone mineral density (BMD)

In study B3D-EW-GHCA, 503 postmenopausal women with severe osteoporosis and a

fragility fracture within the previous 3 years (83% had received previous osteoporosis therapy)

were treated with TERIPARATIDE for up to 24 months. At 24 months, the mean increase

from baseline in lumbar spine, total hip and femoral neck BMD was 0.076 g/cm2 (10.5%),

0.018 g/cm2 (2.6%) and 0.024 g/cm2 (3.9%) respectively. The mean increase in BMD from

18 to 24 months was 0.011 g/cm2 (1.4%), 0.008 g/cm2 (1.2%), and 0.010 g/cm2 (1.6%) at the

lumbar spine, total hip and femoral neck, respectively.

DETAILED PHARMACOLOGY

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.

Teriparatide increased bone mass, resistance to fracture (bone strength), and improved skeletal

architecture (e.g., cortical area and trabecular connectivity, number, thickness, and volume) in

rats, monkeys, and rabbits. These effects resulted from activation of osteoblasts, which

increased apposition of new bone at trabecular, endocortical, and periosteal surfaces, with

minimal effect on bone resorption. Increases in trabecular bone mass did not occur at the

expense of cortical bone. In short- and long-term studies in species that have cortical

remodelling (rabbits and monkeys), teriparatide increased cortical bone thickness and had

beneficial effects on cortical bone strength in parallel with an increase in Haversian

remodelling.

The BMD and strength of the vertebra, femoral neck, proximal tibia, and femoral diaphysis

were increased dose-dependently in male and female rats treated with teriparatide. Compared to

monkeys, rabbits, and humans, rats showed an exaggerated response to the skeletal effects of

teriparatide. Ovariectomized rats treated with teriparatide 40 mcg/kg/day for 1 year had an

approximate BMD increase of 72% in the femoral midshaft with significant loss of marrow

space and altered shape of femora and vertebrae. The greater response of the rat skeleton to

teriparatide is consistent with known differences in bone physiology, such as the nearly

continuous growth of the rat skeleton throughout life and the lack of Haversian remodelling in

cortical bone.

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In ovariectomized monkeys administered doses up to 5 mcg/kg/day for 18 months, teriparatide

increased BMD and resistance to fracture of the proximal femur (hip) and vertebra. Treatment

increased bone formation with normal mineralization, and improved bone architecture. Increased

connectivity was observed at all trabecular bone sites examined. Increased bone density and

bone strength achieved in monkeys after a 1-year treatment period were retained 6 months (2

remodelling

periods, equivalent to approximately 1 to 1.5 years in humans) after teriparatide

treatment was discontinued.

TOXICOLOGY

Acute Toxicity - Teriparatide is not acutely toxic (Table 14). No mortality occurred in rats given

doses of 1000 mcg/kg (540 times the human dose) or in mice given 10,000 mcg/kg (2700 times

the human dose).

Long-Term Toxicity - The primary effects produced by teriparatide in repeated-dose studies in

rats and monkeys up to 1 year in duration were either directly or indirectly related to the known

pharmacologic actions of PTH on bone metabolism and mineral ion regulation (Table 15).

Systemic

exposure of rats and monkeys to teriparatide at the NOAELs in the chronic studies

were estimated to be 2 to 5 times greater than for humans given a dose of teriparatide injection

20 mcg/day.

Carcinogenicity - Two carcinogenicity bioassays were conducted in Fischer 344 rats (Table 16).

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 systemic

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 tumour, 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

tumours 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 tumours. 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 tumours 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 tumours were also observed when mature 6-month old rats were

treated with 30 mcg/kg/day for 6 or 20 months. Tumours 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 tumour formation, associated with teriparatide

treatment, between mature and immature rats.

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The relevance of these findings to humans is not known. Osteosarcoma has not been observed in

teriparatide clinical studies.

Mutagenicity - 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 (Table 17).

Impairment of Fertility - Teriparatide had no effects on fertility of male or female rats at doses

up to 300 mcg/kg (160 times the human dose based on surface area, mcg /m

Teriparatide produced no teratogenic effects in rats, mice, or rabbits (Table 18). No

important effects on embryo/fetal development were seen in rats or mice given teriparatide at

doses up to 1000 mcg/kg (270 to 540 times the human dose based on surface area, mcg/m

Embryo/fetal mortality and reduced litter size was observed in pregnant rabbits administered

daily doses of 3 to 100 mcg/kg of teriparatide. The embryotoxicity observed in rabbits may

be related to the increased levels of blood ionized calcium.

Developmental effects in a perinatal/postnatal study in rats were limited to mild growth

retardation of the offspring at doses ≥ 225 mcg/kg (>120 times the human dose based on

surface area, mcg /m

) and decreased motor activity in offspring at 1000 mcg/kg.

Special Toxicology Studies - Subcutaneous administration of teriparatide at a dose of 40

mcg/kg/day to monkeys for approximately 4 months caused renal histologic changes which were

largely reversible and had a limited impact on kidney function (Table 19). However, no drug-

related histopathologic changes were observed in the kidneys of mature, ovariectomized monkeys

administered teriparatide doses up to 5 mcg/kg/day for 12 or 18 months.

Two limited repeated-dose studies were conducted in dogs: a 2-week study and an 8-week study.

Treatment groups included daily subcutaneous injections of teriparatide, and transmucosal

tablets of teriparatide, both at a dose of 2 mcg/kg in the 2-week study or 0.5 mcg/kg in the 8-

week study. Slight-to-moderate transient increases in blood ionized calcium occurred in all

teriparatide-treated groups of both studies. Minimal-to-moderate renal tubular lesions occurred

only in dogs given teriparatide transmucosally for 8 weeks, with one dog showing signs of renal

failure as evidenced by elevations in blood urea and creatinine that were accompanied by overt

hypercalcemia. These findings are consistent with the high sensitivity of dogs to the known

hypercalcemic effects of PTH.

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Table 14: Acute Toxicity Studies with Teriparatide

Species,

Strain

Number/Sex/

Group; Age

Dose

(mcg/kg)

Route of

Administration

Duration of

Observations

Parameters

Evaluated

Observations

Rat,

Fischer 344

9-10 weeks

0, 100, 300,

1000

Subcutaneous

2 weeks

Mortality

Clinical

observations

Body weight

Gross pathology

Redness of extremities 15 minutes postdose

(vasodilation).

No compound-related lesions.

Median Lethal Dose >1000 mcg /kg (M,F)

Rat,

Fischer 344

9-10 weeks

0, 300

Intravenous

2 weeks

Mortality

Clinical

observations

Body weight

Gross pathology

Redness of extremities 15 minutes

postdose (vasodilation).

No compound-related lesions.

Median Lethal Dose >300 mcg/kg (M,F)

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Table 15: Long-Term Toxicity Studies with Teriparatide (Page 1 of 4)

Species,

Strain

Number/Sex/

Group; Age

Dose

(mcg/kg)

Route of

Administration

Duration of

Observations

Parameters

Evaluated

Observations

Rat,

Fischer 344

8-9 weeks

0, 10, 30,

100, 300

Subcutaneous

6 weeks

Survival;

Clinical

observations;

Body weight;

Food

consumption;

Plasma

concentrations;

Hematology;

Clinical

chemistry; Organ

weights;

Pathology.

, 2 ng/mL at 10 mcg/kg, 195 ng/mL at 300 mcg/kg;

Redness of ears and paws (vasodilation) in all groups;

Body weight gain, EFU in high-dose females;

Trabecular bone formation in femurs in all treated

groups.

Erythrocytic parameters in all treated groups;

Neutrophil counts;

Spleen weight and extramedullary hematopoiesis in

treated groups;

ALP, serum calcium, cholesterol, triglycerides,

calcium excretion;

Testes and prostate weight in 1 to 3 males per

Treatment group with minimal degenerative testes

changes.

NOAEL <10 mcg/kg (M); 10 mcg/kg (F)

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Table 15: Long-Term Toxicity Studies with Teriparatide (Page 2 of 4)

Species,

Strain

Number/Sex/

Group; Age

Dose

(mcg/kg)

Route of

Administration

Duration of

Observations

Parameters

Evaluated

Observations

Rat,

Fischer 344

27-28 weeks

0, 10, 30, 100

Subcutaneous

6 months

Survival;

Clinical

observations;

Body weight;

Food

consumption;

Plasma

concentrations;

Hematology;

Clinical

chemistry; Organ

weights;

Pathology.

(Day 140), 3.1 ng/mL at 10 mcg/kg,

75 ng/mL at 100 mcg/kg;

Body weight and EFU in high-dose males;

Body weight and EFU in treated females;

Trabecular and cortical bone formation in femur

and sternum in all treated groups;

Femur length in treated females;

Females with normal estrous cycles;

Serum inorganic phosphorus,

calcium in all treated groups;

Excretion of calcium and inorganic phosphorus

>

30 mcg/kg;

Serum globulin and

serum

albumin in all treated

groups;

Erythrocytic and leukocytic parameters in all treated

groups;

Extramedullary hematopoiesis in spleen in all treated

groups

and in liver of females at 100 mcg/kg;

Spleen weight in treated females;

Pituitary weight in females at

>

30 mcg/kg

NOAEL = 10 mcg/kg

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Table 15: Long-Term Toxicity Studies with Teriparatide (Page 3 of 4)

Species,

Strain

Number/Sex/

Group; Age

Dose

(mcg/kg)

Route of

Administration

Duration of

Observations

Parameters

Evaluated

Observations

Cynomolgus

Monkey

3 or 4;

Young adult,

2.5 years

0, 2, 10, 20, 40

Subcutaneous

3 months

Survival;

Clinical

observations;

Body weight;

Food

consumption;

Plasma

concentrations;

Hematology;

Clinical

chemistry; Hepatic

enzyme induction;

Organ weights;

Pathology.

0.51 to 0.70 ng/mL at 2 mcg/kg,

16.2 to 31.5 ng/mL at 40 mcg/kg;

Trabecular bone formation in femurs in

all treated groups;

Blood ionized calcium in all treated

groups; Minimal-to-moderate changes in renal

tubules and medullary interstitium at doses

mcg/kg;

Minimal expansion of medullary interstitium in

females given 2 mcg/kg;

Relative kidney weight in females given 20 or 40

mcg/kg

NOAEL = 2 mcg/kg

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Table 15: Long-Term Toxicity Studies with Teriparatide (Page 4 of 4)

Species,

Strain

Number/Sex/

Group; Age

Dose

(mcg/kg)

Route of

Administration

Duration of

Observations

Parameters

Evaluated

Observations

Cynomolgus

Monkey

Young adult

2 years

0, 0.5, 2, 10

Subcutaneous

1 year

Survival;

Clinical

observations;

Body weight;

Food

consumption;

Plasma

concentrations;

Hematology;

Clinical

chemistry;

Immunologic

response; Organ

weights;

Pathology..

, 0.15 ng/mL at 0.5 mcg/kg, 4.51 ng/mL at 10

mcg/kg;

Incidence of teriparatide-specific IgG levels

(0 of 8 in control to 6 of 8 at 10 mcg/kg);

Trabecular bone formation in femurs in

ll treated

groups;

Slight

erythron parameters in females at10 mcg/kg;

Blood ionized calcium in high-dose group;

Minimal-to-moderate changes in renal tubules and

medullary interstitium with slight

relative

kidney

weight in 6 of 8 animals at 10 mcg/kg and 1 female in

each of 0.5 and 2mcg/kg groups.

NOAEL = 2 mcg/kg

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Table 16: Carcinogenicity Studies with Teriparatide

Species,

Strain

Number/Sex/

Group; Age

Dose

(mcg/kg)

Route of

Administration

Duration of

Observations

Parameters

Evaluated

Observations

Rat,

Fischer 344

6-7 weeks

0, 5, 30, 75

Subcutaneous

2 years

Survival;

Clinical

observations;

Body weight;

Food

consumption;

Plasma

concentrations;

Hematology;

Clinical

chemistry;

Organ weights;

Pathology.

AUC, 0.9 ng-hr/mL at 5 mcg/kg, 17.1 ng-hr/mL at 75

mcg/kg.

Leg nodules, neurologic signs related to bone

neoplasms at all doses;

Exaggerated

in bone formation at all doses

including reduction of marrow space, periostial

expansion with altered bone architecture;

Incidence of hyperplastic and neoplastic bone

lesions, including osteosarcomas at all doses;

No increase in neoplasms of non-osseous tissues.

Rat,

Fischer 344

n = 30 or 60

Age = 6-7

weeks or 24-

26 weeks

0, 5, 30

Subcutaneous

6 months

20 months

24 months

Survival;

Clinical

observations;

Body weight;

Food

consumption;

Plasma

concentrations;

Quantitative bone

analyses;

Bone

histopathology

Plasma concentration at 5 mcg/kg = 1.12 to 1.36

ng/mL Plasma concentration at 30 mcg/kg = 7.39 to

11.40 ng/mL Exaggerated

in bone formation at all

doses.

No bone tumours detected when mature 6-month old

rats were treated with 5 mcg/kg/day for 6 or 20 months;

Bone tumours were detected when immature

month old rats were treated with 30 mcg/kg/day for 24

months or 5 or 30 mcg/kg/day for 6 months;

Bone tumours were detected when mature

6-month

old rats were treated with 30 mcg/kg/day for 6 or 20

months.

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Table 17: Mutagenicity Studies with Teriparatide

Type of Study

Species, Cells

Route of Administration

Dose/Concentrations

Results

Ames

Escherichia coli

Salmonella typhimurium

In vitro

312.5 to 5000 mcg/plate

with and without metabolic

activation

Negative

Forward mutation at

thymidine kinase locus

L5178Y TK+/- mouse

lymphoma

In vitro

39 to 5000 mcg/mL, with

and without metabolic

activation

Negative

Chromosome aberration

Chinese hamster ovary

In vitro

1250 to 5000 mcg/mL, with

and without metabolic

activation

Negative

Micronucleus, in vivo

ICR Mouse, bone marrow

Subcutaneous injection

1000 to 10,000 mcg/kg/day

Negative

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Table 18:

Reproduction and Teratology Studies with Teriparatide (Page 1 of 3)

Species,

Strain/Study

Type

Number/

Group; Age

Dose

(mcg/kg/day)

Route of

Administration

Duration of

Treatment

Parameters

Evaluated

Observations

Rat,

Segment I

20 Males;

13 weeks

20 Females;

9 weeks

Males:

0, 30, 100, 300

Females:

not treated

Subcutaneous

7 weeks: 4

weeks prior to

and during

cohabitation

until

termination

Survival; Clinical

observations;

Body weight;

Food

consumption;

Testicular weight

and morphology;

Sperm

concentration

and motility;

Mating; Fertility.

Prostate weight in males at 300 mcg/kg;

Redness of the extremities in all treated males;

No adverse effects on body weight, food consumption,

mating, fertility, testicular weight, testicular

morphology, sperm concentration, or sperm motility

NOAEL = 300 mcg/kg

Rat,

Segment I

20 Males

20 Females;

9 weeks

Males:

not treated

Females:

0, 30, 100, 300

Subcutaneous

2 weeks prior to

and during

cohabitation

until postmating

Day 6

Survival

Clinical

observations

Body weight

Food

consumption

Mating

Fertility

Gestation

survival

Fetal parameters

Body weight and food consumption in females at 100

and 300 mcg/kg;

Redness of the extremities in all treated females;

No effects on maternal reproductive or fetal parameters

NOAEL = 300 mcg/kg

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Table 18:

Reproduction and Teratology Studies with Teriparatide (Page 2 of 3)

Species,

Strain/Study

Type

Number/

Group; Age

Dose

(mcg/kg/day)

Route of

Administration

Duration of

Treatment

Parameters

Evaluated

Observations

Rat,

Segment II

25 Pregnant

females; 12

weeks

0, 30, 225, 1000

Subcutaneous

Gestation Days

6 through 17

Survival; Clinical

observations;

Body weight;

Food

consumption;

Reproductive and

Uterine

parameters; Fetal

viability, weight,

and morphology.

Redness of the extremities in all treated females;

No treatment-related effects

on maternal body weight; food consumption;

reproductive and uterine parameters; or on fetal

viability, weight, or morphology

NOAEL = 1000 mcg/kg

Mouse,

CD-1

Segment II

30 Pregnant

females;

12 weeks

0, 30, 225, 1000

Subcutaneous

Gestation Days

6 through 15

Survival; Clinical

observations;

Body weight;

Food

consumption;

Reproductive and

uterine

parameters; Fetal

viability, weight,

and morphology.

Food consumption at 225 and 1000 mcg/kg;

Redness of the extremities in all treated females;

No treatment-related effects on maternal body weight;

reproductive and uterine parameters; or on fetal

viability, weight, or morphology

NOAEL = 1000 mcg/kg

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Table 18:

Reproduction and Teratology Studies with Teriparatide (Page 3 of 3)

Species,

Strain/Study

Type

Number/

Group; Age

Dose

(mcg/kg/day)

Route of

Administration

Duration of

Treatment

Parameters

Evaluated

Observations

Rabbit,

New Zealand

White

Segment II

(pilot)

5 Pregnant

females; 7

months

0, 3, 10, 30, 100 Subcutaneous

Gestation Days 7

through 19

Survival;

Clinical

observations;

Body weight; Food

consumption;

Reproductive and

uterine parameters;

Fetal viability,

weight, and

external

morphology.

Survival at 100 mcg/kg;

Blood ionized calcium in all treated groups; Totally

resorbed fetuses in all surviving females at >10

mcg/kg and 1 female at 3 mcg/kg;

Live fetuses per litter at 3 mcg/kg

NOAEL = < 3 mcg/kg

Rat,

Segment II/III

25 Pregnant

females; adult

0, 30, 225, 1000 Subcutaneous

Gestation Day 6

through

Postpartum Day

Survival;

Clinical

observations;

Body weight;

Food consumption;

Gestation length;

Litter size;

Progeny survival,

growth,

development,

behaviour,

reproductive

performance,

external and gross

internal

examination.

Redness of the extremities in all treated females;

Pup body weight on PND 14 in F

Females at 1000

mcg/kg;

Motor activity on PND 23 and 60 for F

At 1000

mcg/kg;

Growth retardation in F

males at

1000 mcg/kg and F

females at >225 mcg/kg

Maternal/Reproductive NOAEL =1000 mcg/kg

Developmental NOAEL = 30 mcg/kg

Teva-Teriparatide Injection

Page 45 of 57

Table 19: Special Toxicology Studies with Teriparatide (1 of 2)

Species,

Strain/Study

Type

Number/

Group; Age

Dose

(mcg/kg/day)

Route of

Administration

Duration of

Treatment

Parameters

Evaluated

Observations

Special renal

function study

with reversibility

Cynomolgus

Monkey

4 or 8 females;

Young adult

0, 40

Subcutaneous

4 months with

3-month

reversibility

Serum concentrations were 18.55 and 4.68 ng/mL

after 1 and 3 months at 40 mcg/kg;

Blood ionized calcium in treated monkeys; Renal

histologic changes in 7 of 8 monkeys given 40

mcg/kg for 4 months with changes partially reversed

after 3-month reversibility; Renal function changes in

1 of 8 monkeys; Renal failure in 1 monkey on Day 78

(returned to baseline after cessation of treatment)

Histopathologic

evaluation of

kidneys

Cynomolgus

Monkey

21 or 22

Ovariectomized

females;

Skeletally

mature

1, 5

Subcutaneous

12 or 18

months

No teriparatide-related histopathologic changes

observed in kidneys

Safety study

Dog,

Beagle

4 females;

7 to 28 months

0, 600, 1800

mcg for

transmucosal

delivery;

2 mcg/kg for

s.c. route

Buccal

(transmucosal),

Subcutaneous

16 days

Blood ionized calcium

(24% to 33% at 2 mcg/kg s.c.);

2 mcg/kg s.c. exceeded the MTD in dogs.

Teva-Teriparatide Injection

Page 46 of 57

Table 19: Special Toxicology Studies with Teriparatide (2 of 2)

Study Type

Species,

Strain

Number/Sex/Group;

Age

Dose

(mcg/kg/day)

Route of

Administration

Duration of

Treatment

Observations

Safety study

Dog,

Beagle

4 females;

6 to 12 months

0, 600, 1800

mcg for

transmucosal

delivery; 0.5

mcg/kg for s.c.

route

Buccal

(transmucosal),

Subcutaneous

8 weeks

No accumulation with repeated dosing;

Blood ionized calcium;

Renal tubular lesions in dogs given 600 or 1800

mcg by buccal route; Azotemia accompanied by

overt Hypercalcemia in 1 dog given 1800 mcg by

buccal route.

Teva-Teriparatide Injection

Page 47 of 57

REFERENCES

Boonen S, Marin F, Obermayer-Pietsch B, Simões ME, Barker C, Glass EV, Lyritis G,

Oertel H, Nickelsen T, McCloskey EV for the EUROFORS Investigators. 2008. Effects

of prior antiresorptive therapy on the bone mineral density response to two years of

teriparatide treatment in postmenopausal women with osteoporosis. J Clin Endocrinol

Metab 93(3):852-860.

Brown J, Josse R. 2002. 2002 clinical practice guidelines for the diagnosis and

management of osteoporosis in Canada. CMAJ: 167 (10 suppl).

Christiansen C. 1994. Treatment of osteoporosis. In: Lobo R, editor. Treatment of the

postmenopausal woman: basic and chemical aspects. New York (NY): Raven Press Ltd.

p 183-195.

Cosman F, Nieves J, Woelfert L, et al, 1998. Parathyroid responsivity in postmenopausal

women with osteoporosis during treatment with parathyroid hormone. J Clin Endocrinol

Metab 83(3):788-790.

Cosman F, Nieves J, Woelfert L, et al, 1998b. Alendronate does not block the anabolic

effect of PTH in postmenopausal osteoporotic women. J Bone Mineral Res 13(6):1051-

1055.

Daugaard H. 1996. Peripheral metabolism of parathyroid hormone. Danish Medical

Bulletin 43(3):203-215.

Dempster D, Cosman F, Parisien M, et al, 1995. Anabolic actions of parathyroid hormone

on bone: update 1995. Endocr Rev 4(1):247-250.

Dempster DW, Cosman F, Kurland ES, Zhou H, Nieves J, Woelfert L, Shane E, Plavetic

K, Muller R, Bilezikian J, Lindsay R. 2001. Effects of daily treatment with parathyroid

hormone on bone microarchitecture and turnover in patients with osteoporosis: a paired

biopsy study. J Bone Miner Res 16(10):1846-1853.

Deraska D, Neer RM. 1995. Parathyroid hormone (PTH) effects on osteoblast &

osteoclast activity in postmenopausal osteoporosis. J Bone Miner Res 10 (1 Suppl):S456.

Ensrud K, Thompson D, Cauley J, et al, 2000. Prevalent vertebral deformities predict

mortality and hospitalization in older women with low bone mass. Fracture Intervention

Trial Research Group. J Am Geriatr Soc 48(3):241-249.

Genant HK, Wu CY, van Kuijk C, Nevitt MC. 1993. Vertebral fracture assessment using

a semiquantitative technique. J Bone Miner Res 8(9):1137-1148.

Teva-Teriparatide Injection

Page 48 of 57

Hodsman A, Fraher L. 1990. Biochemical responses to sequential human parathyroid

hormone (1-38) and calcitonin in osteoporotic patients. Bone Miner 9(2):137-152.

Hodsman A, Papaioannou A, Cranney A, 2006. Clinical practice guidelines for the use of

parathyroid hormone in the treatment of osteoporosis. CMAJ 175(1):48-51.

Hodsman A, Steer B, Fraher L, et al, 1991. Bone densitometric and histomorphometric

responses to sequential human parathyroid hormone (1-38) and salmon calcitonin in

osteoporotic patients. J Bone Miner Res 14(1):67-83.

Jiang Y, Zhao J, Mitlak B, et al, 2003. Recombinant Human Parathyroid Hormone (1-34)

[Teriparatide] Improves Both Cortical and Cancellous Bone Structure. J Bone Miner Res

18:1932B1941.

Kado D, Browner W, Palermo L, et al, 1999. Vertebral fractures and mortality in older

women: a prospective study. Study of Osteoporotic Fractures Research Group. Arch

Intern Med 159(11):1215-1220.

Kiel D. 1996. The approach to osteoporosis in the elderly patient. In: Rosen, CJ, editor.

Osteoporosis: diagnostic and therapeutic principles. Totowa (NJ): Humana Press p 225-

238.

Kronenberg H. 1993. Parathyroid hormone: mechanisms of action. In: Favus M, editor.

Primer on the metabolic bone diseases and disorders of mineral metabolism.2nd ed. New

York(NY): Raven Press. p 58-60.

Kurland E, Cosman F, McMahon D, et al, 2000. Parathyroid hormone as a therapy for

idiopathic osteoporosis in men: effects on bone mineral density and bone markers. J Clin

Endocrinol Metab 85:3069-3076.

Lindsay R, Nieves J, Formica C, et al, 1997. Randomised controlled study of effect of

parathyroid hormone on vertebral-bone mass and fracture incidence among

postmenopausal women on oestrogen with osteoporosis. Lancet 350:550-555.

McClung MR, San Martin J, Miller PD, et al, 2005. Opposite bone remodeling effects of

teriparatide and alendronate in increasing bone mass. Arch Intern Med 165:1762-1768.

Minne H, Audran M, Simoes ME et al, 2008. Bone density after teriparatide in patients

with or without prior antiresorptive treatment: one-year results from the EUROFORS

study. Curr Med Res Opin 24(11):3117-3128.

Neer RM, Arnaud CD, Zanchetta JR, et al, 2001. Effect of parathyroid hormone (1-34)

on fractures and bone mineral density in postmenopausal women with osteoporosis. N

Engl J Med. 344:1434-1441.

Teva-Teriparatide Injection

Page 49 of 57

NIH Consensus Conference. 2001. Osteoporosis prevention, diagnosis, and therapy.

JAMA 285(6):785-795.

Obermayer-Pietsch BM, Marin F, McCloskey EV et al. 2008. Effects of Two Years of

Daily Teriparatide Treatment on BMD in Postmenopausal Women With Severe

Osteoporosis With and Without Prior Antiresorptive Treatment. J Bone Miner Res

23(10):1591-1600.

Orwoll E, Klein R. 1995. Osteoporosis in men. Endocrine Reviews 16:87-115.

Orwoll E, Scheele W, Paul S, et al, 2003. The Effect of Teriparatide [Human Parathyroid

Hormone (1-34)] Therapy on Bone Density in Men With Osteoporosis. J Bone Miner

Res: 18:9-17.

Podbesek R, Eduoard C, Meunier PJ, Parsons JA, Reeve J, Stevenson RW, Zanelli JM.

1983. Effects of two treatment regimes with synthetic human parathyroid hormone

fragment on bone formation and the tissue balance of trabecular bone in greyhounds.

Endocrinology 112:1000-1006.

Podbesek RD, Mawer EB, Zanelli GD, Parsons JA, Reeve J. 1984. Intestinal absorption

of calcium in greyhounds: the response to intermittent and continuous administration of

human synthetic parathyroid hormone fragment 1-34 (hPTH 1-34). Clin Sci 67(6):591-

599.

Riggs B, Melton L. 1992. The prevention and treatment of osteoporosis. N Engl J Med

327(9):620-627.

Roe E, Sanchez S, del Puerto G, Pierini E, Bacchetti P, Cann CE, Arnaud CD. 1999.

Parathyroid hormone 1-34 (hPTH 1-34) and estrogen produce dramatic bone density

increases in postmenopausal osteoporosis- results from a placebo-controlled randomized

trial. J Bone Miner Res 14(1 Suppl):S137.

Saag K, Shane E, Boonen S et al, 2007. Teriparatide or Alendronate in Glucocorticoid-

Induced Osteoporosis. N Engl J Med 357(20):2028-2039.

Smith J, Huvos A, Chapman M, et al, 1997. Hyperparathyroidism associated with

sarcoma of bone. Skeletal Radiol 26(2):107-112.

Vahle J, Sato M, Long G et al, 2002. Skeletal Changes in Rats Given Daily Subcutaneous

Injections of Recombinant Human Parathyroid Hormone (1-34) for 2 Years and

Relevance to Human Safety. Toxicologic Pathology 30(3): 312-321.

Zanchetta J, Bogado C, Ferretti J et al, 2003. Effects of Teriparatide [Recombinant

Human Parathyroid Hormone (1-34)] on Cortical Bone in Postmenopausal Women With

Osteoporosis. J Bone Miner Res:18:539-543.

Teva-Teriparatide Injection

Page 50 of 57

[WHO] World Health Organization. 1994. Assessment of fracture risk and its application

to screening for postmenopausal osteoporosis. Report of a WHO Study Group. Geneva:

World Health Organization. WHO Technical Report Series 843.

FORTEO

Product Monograph, Eli Lilly Canada Inc., Revision date February 9, 2010,

Submission Control No. 128554.

IMPORTANT: PLEASE READ

Teva-Teriparatide Injection

Page 51 of 57

PART III: CONSUMER INFORMATION

Pr

TEVA-TERIPARATIDE INJECTION

Teriparatide Injection

This leaflet is part III of a three-part "Product Monograph"

published when TEVA-TERIPARATIDE INJECTION was

approved for sale in Canada and is designed specifically for

Consumers. This leaflet is a summary and will not tell you

everything about TEVA-TERIPARATIDE INJECTION.

Contact your doctor or pharmacist if you have any questions

about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

TEVA-TERIPARATIDE INJECTION is a prescription medicine

used to treat osteoporosis by forming new bone. TEVA-

TERIPARATIDE INJECTION is approved for use in both men

and postmenopausal women with severe osteoporosis. TEVA-

TERIPARATIDE INJECTION is also approved for use in both

men and women with severe osteoporosis related to use of

corticosteroid medicines, such as prednisone, who are at high risk

for having broken bones (fractures). These include men and

women with either a history of broken bones or those with a low

bone mineral density (BMD).

What it does:

TEVA-TERIPARATIDE INJECTION builds new bone faster than

the old bone is lost. Your bones become stronger as you continue

to use TEVA-TERIPARATIDE INJECTION, and your risk for

fracture will be reduced.

When it should not be used:

Only take TEVA-TERIPARATIDE INJECTION if your doctor

has prescribed it for you. Do not take TEVA-TERIPARATIDE

INJECTION if you:

have had an allergic reaction to teriparatide or one of its

ingredients.

suffer from high calcium level (pre-existing hypercalcemia).

suffer from kidney problems (severe renal impairment).

have other bone diseases.

have high levels of alkaline phosphatase.

have had radiation therapy involving your bones.

have ever been diagnosed with bone cancer or other cancers that

have spread (metastasized) to your bones.

are a child or growing adult.

are pregnant or breast-feeding.

have trouble injecting yourself and do not have someone who

can help you.

What the medicinal ingredient is:

TEVA-TERIPARATIDE INJECTION contains teriparatide, which

is the same as the active part of a natural hormone called

parathyroid hormone or "PTH".

What the important nonmedicinal ingredients are:

In addition to the active ingredient teriparatide, inactive ingredients

are glacial acetic acid, sodium acetate (trihydrate), mannitol,

metacresol (preservative), and water for injection. In addition,

hydrochloric acid solution and/or sodium hydroxide solution may

have been added to adjust product pH.

What dosage forms it comes in:

TEVA-TERIPARATIDE INJECTION is supplied as a sterile

solution for subcutaneous injection in a 3 mL glass cartridge pre-

assembled into a disposable pen delivery device. Each mL

contains 250 mcg teriparatide (as teriparatide acetate). Each

cartridge pre-assembled into a pen device delivers 20 mcg of

TEVA-TERIPARATIDE INJECTION

per dose each day for up

to 28 days.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

As part of drug testing, teriparatide, the active ingredient in

TEVA-TERIPARATIDE INJECTION, was given to rats for

a significant part of their lifetime. In these studies,

teriparatide caused some rats to develop osteosarcoma, a

bone cancer. The potential to cause osteosarcoma in rats was

increased with higher doses and longer periods of treatment.

Osteosarcoma in humans is a serious but very rare cancer.

Osteosarcoma occurs in about 4 out of every million people

each year. None of the patients in the clinical trials or post-

treatment follow up developed osteosarcomas. Osteosarcoma

has been reported rarely in people who took prescription

TEVA-TERIPARATIDE INJECTION. It is not known if

people who take teriparatide have a higher chance of getting

osteosarcoma. You should discuss any safety concerns you

have about the use of TEVA-TERIPARATIDE INJECTION

with your doctor.

INTERACTIONS WITH THIS MEDICATION

Tell your health care provider and pharmacist about all the

medicines you are taking when you start taking TEVA-

TERIPARATIDE INJECTION, and if you start taking a new

medicine after you start TEVA-TERIPARATIDE INJECTION

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.

PROPER USE OF THIS MEDICATION

Take TEVA-TERIPARATIDE INJECTION once daily for as

long as your doctor prescribes it for you.

Refer to the Pen User Manual for instructions on how to use the

TEVA-TERIPARATIDE INJECTION pen. The TEVA-

TERIPARATIDE INJECTION prefilled pen injector will

deliver a preset dose of 20 mcg.

Take one subcutaneous injection of TEVA-TERIPARATIDE

INJECTION each day. The injection may be given into the

thigh or abdomen.

TEVA-TERIPARATIDE INJECTION can be taken at any time

of day. To help you remember to take TEVA-TERIPARATIDE

IMPORTANT: PLEASE READ

Teva-Teriparatide Injection

Page 52 of 57

INJECTION, take it at about the same time each day (for

example, at bedtime).

You should take your TEVA-TERIPARATIDE INJECTION

shortly after you take it out of the refrigerator as described in the

Pen User Manual. A warming period is not needed. Put the pen

back into the refrigerator immediately after use

If you forget or are unable to take TEVA-TERIPARATIDE

INJECTION at your usual time, take it at your next regularly

scheduled time. Do not take more than one injection in the same

day.

Calcium and/or vitamin D may be taken at the same time as

TEVA-TERIPARATIDE INJECTION. You should discuss with

your doctor how much calcium and vitamin D to take each day.

TEVA-TERIPARATIDE INJECTION can be taken with or

without food or drink.

Keep all medicines, including TEVA-TERIPARATIDE

INJECTION, away from children.

The TEVA-TERIPARATIDE INJECTION pen contains a

sterile, colorless, clear solution. Do not use if solid particles

appear or if the solution is cloudy or coloured. TEVA-

TERIPARATIDE INJECTION should never be used beyond the

date indicated on the carton.

Never share a TEVA-TERIPARATIDE INJECTION pen with

others, even if they have a similar disease. Their doctor should

decide if TEVA-TERIPARATIDE INJECTION is right for

them. TEVA-TERIPARATIDE INJECTION has been

prescribed just for you.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Most of the side effects of TEVA-TERIPARATIDE

INJECTION are mild. The most common side effects of TEVA-

TERIPARATIDE INJECTION are dizziness, nausea, pain in and

around joints, and leg cramps.

If you become dizzy do not drive or operate machinery; you

should sit or lie down until the symptoms go away. If symptoms

continue or get worse, you should call a doctor 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.

If you have any problems or questions while taking TEVA-

TERIPARATIDE INJECTION, ask your doctor, nurse, or

pharmacist for more information.

HOW TO STORE IT

Your TEVA-TERIPARATIDE INJECTION pen should be stored

in the refrigerator between 2°C to 8°C at all times.

Your TEVA-TERIPARATIDE INJECTION pen can be used for

up to 28 days including the first injection from the pen, if stored

properly.

The TEVA-TERIPARATIDE INJECTION pen should be properly

disposed of after 28 days of first use, even if it is not completely

empty.

Do not freeze. Do not use TEVA-TERIPARATIDE INJECTION if

it has been frozen.

Reporting Side Effects

You can report any suspected side effects associated with the

use of health products to Health Canada by:

Visiting the Web page on Adverse Reaction Reporting

(https://www.canada.ca/en/health-

canada/services/drugs-health-products/medeffect-

canada/adverse-reaction-reporting.html) for

information on how to report online, by mail or by

fax; or

Calling toll-free at 1-866-234-2345.

NOTE: Contact your health professional if you need

information about how to manage your side effects. The

Canada Vigilance Program does not provide medical advice.

MORE INFORMATION

This document plus the full product monograph, prepared for

health professionals can be found by contacting the sponsor, Teva

Canada Limited by:

Phone: 1-800-268-4127 ext. 3;

Email: druginfo@tevacanada.com; or

Fax: 1-416-335-4472

This leaflet was prepared by:

Teva Canada Limited

30 Novopharm Court

Toronto, Ontario

M1B 2K9

Canada

www.tevacanada.com

Last revised: March 6, 2019

IMPORTANT: PLEASE READ

Teva-Teriparatide Injection

Page 53 of 57

Pr

TEVA-TERIPARATIDE INJECTION PEN

teriparatide injection

User Manual

Before you use your new TEVA-TERIPARATIDE INJECTION PEN, please read the entire User Manual

completely. Follow the directions carefully when using the TEVA-TERIPARATIDE INJECTION PEN.

Do not share your delivery device or needles as this may risk transmission of infectious agents.

Your TEVA-TERIPARATIDE INJECTION PEN contains 28 days of medicine.

Write down your first injection date here: ______ / ______ / ______.

Throw away after: ______ / ______ / ______.

Refrigerate the TEVA-TERIPARATIDE INJECTION PEN immediately after every use.

TEVA-TERIPARATIDE INJECTION PEN Parts*

Wash your hands before every injection. Prepare the injection site as your healthcare provider instructed.

1

Pull off

blue cap

After pulling off the blue cap, clean the rubber seal on

the end of the TEVA-TERIPARATIDE INJECTION

PEN cartridge with an alcohol swab.

2

Attach

new

needle

Pull off paper tab.

Push needle

straight onto

medicine cartridge.

Screw on needle clockwise

until firmly attached.

Pull off large needle

cover and save it.

IMPORTANT: PLEASE READ

Teva-Teriparatide Injection

Page 54 of 57

3

Set

dose

Pull out black injection button

until it stops.

If you cannot pull out the black

injection button see

Troubleshooting, Problem E, on

back page.

Check to make sure red

stripe shows.

Pull off small needle protector

and throw away.

4

Inject

dose

Gently hold a fold of skin on your thigh or

abdomen and insert needle straight into

skin.

Push in black injection button until it stops. Hold it in

and count to 5 s-l-ow-l-y. You must wait until the

count of 5 to make sure you receive the correct

dose. Then pull the needle from skin.

5

Confirm

dose

IMPORTANT

After completing the

injection:

Once the needle is removed

from the skin, take your thumb

off the black injection button.

Check to make sure the black

injection button is all the way

in. If the yellow shaft does not

show, you have finished the

injection steps the right way.

You should NOT see any of

the yellow shaft. If you do and

have already injected the

medicine, do not inject

yourself a second time on the

same day. Instead, you

MUST reset the TEVA-

TERIPARATIDE

INJECTION PEN (see

Troubleshooting, Problem A,

on back page).

6

Remove

needle

Put large needle cover on

needle.

Unscrew the covered

needle all the way by

giving the large needle

cover 3 to 5 counter-

clockwise turns.

Pull off needle

and throw away

as directed by

your healthcare

professional.

Push blue cap back on.

Place TEVA-

TERIPARATIDE

INJECTION PEN in

the refrigerator

immediately after use.

IMPORTANT: PLEASE READ

Teva-Teriparatide Injection

Page 55 of 57

TEVA-TERIPARATIDE INJECTION PEN

Troubleshooting

Problem

Solution

A. The yellow shaft is

still showing after I

push in the black

injection button. How

do I reset my TEVA-

TERIPARATIDE

INJECTION PEN?

To reset the TEVA-TERIPARATIDE INJECTION PEN, follow

the steps below.

If you have already injected, DO NOT inject yourself a

second time on the same day.

Remove the needle.

Attach a new needle, pull off the large needle cover and

save it.

Pull out the black injection button until it stops. Check to

make sure the red stripe shows.

Pull off the small needle protector and throw away.

Point the needle down into an empty container. Push in the

black injection button until it stops. Hold it in and slowly

count to five. You may see a small stream or drop of fluid.

When you have finished, the black injection button should

be all the way in.

If you still see the yellow shaft showing, contact TEVA

(see Contact Information below) or your healthcare provider.

Put the large needle cover on needle. Unscrew the needle

all the way by giving the needle cover 3 to 5 counter-clockwise

turns. Pull off the covered needle and throw away as instructed

by your healthcare provider. Push the blue cap back on, and

put your TEVA-TERIPARATIDE INJECTION PEN in the

refrigerator.

You can prevent this problem by always using a NEW needle

for each injection, and by pushing the black injection

button all the way in and slowly counting to five.

B. How can I tell if TEVA-

TERIPARATIDE INJECTION

PEN works?

The TEVA-TERIPARATIDE INJECTION PEN is designed to

inject the full dose every time it is used according to the directions

in the User Manual. The black injection button should be all the

way in to show that the full dose of medicine has been injected

from the TEVA-TERIPARATIDE INJECTION PEN.

Remember to use a new needle every time you inject to be sure

your TEVA-TERIPARATIDE INJECTION PEN will work

properly.

C. I see an air bubble in my

TEVA-TERIPARATIDE

INJECTION PEN.

A small air bubble will not affect your dose and it will not harm

you. You can continue to take your dose as usual.

D. I cannot get the needle off.

Put the large needle cover on the needle.

Use the large needle cover to unscrew the needle.

Unscrew the needle all the way by giving the large needle

IMPORTANT: PLEASE READ

Teva-Teriparatide Injection

Page 56 of 57

cover 3 to 5 counter-clockwise turns.

If you still cannot get the needle off, ask someone to help

you.

E. What should I do if I have

difficulty pulling out the black

injection button?

Change to a new TEVA-TERIPARATIDE INJECTION PEN

to take your dose as instructed by your healthcare provider.

This indicates that you have now used all the medication that can

be injected accurately even though you may still see some

medication left in the medicine cartridge.

Cleaning and Storage

Cleaning Your TEVA-TERIPARATIDE INJECTION PEN

Wipe the outside of the TEVA-TERIPARATIDE INJECTION PEN with a damp cloth.

Do not place the TEVA-TERIPARATIDE FOR INJECTINO PEN in water, or wash or clean it with any

liquid.

Storing Your TEVA-TERIPARATIDE INJECTION PEN

Refrigerate the TEVA-TERIPARATIDE INJECTION PEN immediately after use. Read and follow the

instructions in the Consumer Information Insert on how to store the medication.

Do not store the TEVA-TERIPARATIDE INJECTION PEN with a needle attached as this may cause air

bubbles to form in the medicine cartridge.

Store the TEVA-TERIPARATIDE INJECTION PEN with the blue cap on.

Never store the TEVA-TERIPARATIDE INJECTION PEN in the freezer.

If the TEVA-TERIPARATIDE INJECTION PEN has been frozen, throw the device away and use a new

TEVA-TERIPARATIDE INJECTION PEN.

If the TEVA-TERIPARATIDE INJECTION PEN has been left out of the refrigerator, do not throw the pen

away. Place the pen back in the refrigerator and call Teva Canada Limited (see Contact Information).

Other Important Notes

The TEVA-TERIPARATIDE INJECTION PEN contains 28 days of medicine.

Do not transfer the medication to a syringe.

Read and follow the instructions in the Consumer Information insert for using the medicine.

Check the TEVA-TERIPARATIDE INJECTION PEN label to make sure you have the correct medicine and

that it has not expired.

Contact TEVA (see Contact Information) if you notice any of the following:

The TEVA-TERIPARATIDE INJECTION PEN appears damaged.

The medicine is not clear and colourless, or if it has particles, do not use it.

Use a new needle for each injection.

During injection, you may hear one or more clicks – this is normal device operation.

Do not share your medication.

The TEVA-TERIPARATIDE INJECTION PEN is not recommended for use by the blind or visually

impaired persons without the assistance of a person trained in the proper use of the device.

Keep your TEVA-TERIPARATIDE FOR INJECTION PEN out of the reach of children.

IMPORTANT: PLEASE READ

Teva-Teriparatide Injection

Page 57 of 57

Disposal of Pen Needles and Delivery Device

Disposal of Pen Needles and the TEVA-TERIPARATIDE INJECTION PEN Device

Before disposing of the TEVA-TERIPARATIDE INJECTION PEN device, be sure to remove the pen

needle.

Dispose of your TEVA-TERIPARATIDE INJECTION PEN and used needles as directed by your

healthcare professional and local institutional policies.

Dispose of the device 28 days after first use.

Contact Information

If you have questions or need help with your TEVA-TERIPARATIDE INJECTION PEN, contact your

healthcare professional or Teva Canada Limited by:

Phone: 1-800-268-4127 ext. 3;

Email: druginfo@tevacanada.com; or

Fax: 1-416-335-4472

This leaflet was prepared by:

Teva Canada Limited

30 Novopharm Court

Toronto, Ontario

M1B 2K9

Canada

www.tevacanada.com

Issue Date: March 6, 2019

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