Prescribing Information

Indication and Clinical use

Teriparatide (rDNA origin) 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

Contraindications

Teriparatide (rDNA origin) 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 Population)
Pediatric patients or young adults with open epiphysis (see Warnings and Precautions, Special Population).

Warnings and Precautions

In male and female rats, Teriparatide caused an increase in the incidence of osteosarcoma (a malignant bone tumor) that was dependent on dose and treatment duration. The effect was observed at systemic exposures to Teriparatide ranging from 3 to 60 times the exposure in humans given a 20-mcg dose. Because of the uncertain relevance of the rat osteosarcoma finding to humans, prescribe Teriparatide only for patients for whom the potential benefits are considered to outweigh the potential risk. Teriparatide should not be prescribed for patients who are at increased baseline risk for osteosarcoma (including those with Paget’s disease of bone or unexplained elevations of alkaline phosphatase, pediatric and young adult patients with open epiphyses, or prior external beam or implant radiation therapy involving the skeleton)

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 ofthe observations in rats has not been established. Osteosarcoma has not been observed in Teriparatide clinical trials.

General

The safety and efficacy of Teriparatide (rDNA origin) injection have not been evaluated beyond 2 years (median 19 months in women and 10 months in men). Consequently, the maximum lifetime exposure to Teriparatide for an individual patient is 18 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. Teriparatide should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition.

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.

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)

Other Osteoporosis treatment and prevention measures

Patients should be informed regarding the roles of supplemental Calcium and/or Vitamin D, weightbearing exercise, and modification of certain behavioral factors such as cigarette smoking and/or alcohol/coffee consumption.

Special Population

Pregnant women and women of childbearing potential: Teriparatide 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 Teriparatide. Should pregnancy occur, Teriparatide should be discontinued (see Contraindications).
Nursing women: There have been no clinical studies to determine ifTeriparatide is secreted into breast milk. Teriparatide should not be administered to nursing mothers (see Contraindications).
Pediatrics: Teriparatide has not been studied in pediatric populations. Teriparatide should not be used in children or young adults with open epiphyses (see Contraindications).
Pediatrics: Teriparatide has not been studied in pediatric populations. Teriparatide should not be used in children or young adults with open epiphyses (see Contraindications).
Premenopausal women: Before initiating therapy with Teriparatide 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 in geriatric patients (365) receiving Teriparatide as compared with younger patients.

Adverse Reactions

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 (rDNA origin) injection 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, double dummy, active controlled clinical trial that enrolled 428 men and women with glucocorticoid induced Osteoporosis. Patients received either Teriparatide 20 mcg/day plus oral placebo (n=214) or Alendronate 10 mg/day plus injectable placebo (n=214).
Adverse Events in Placebo-Controlled Clinical Trials (Irrespective of Causality)

Body System / Adverse Events	TERIFRAC (N=691)	Placebo (N=691)
Metabolic
Hyperuricemia	2.8%	0.7%
Musculoskeletal
Arthralgia	10.1%	8.4%
Leg Cramps	2.6%	1.3%
Nervous System
Dizziness	8.0%	5.4%
Depression	4.1%	2.7%
Insomnia	4.3%	3.6%
Vertigo	3.8%	2.7%
Respiratory System
Rhinitis	9.6%	8.8%
Cough Increased	6.4%	5.5%
Pharyngitis	5.5%	4.8%
Dyspnea	3.6%	2.6%
Pneumonia	3.9%	3.3%
Skin and Appendages
Rash	4.9%	4.5%
Sweating	2.2%	1.7%

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 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 (rDNA origin) injection transiently increases serum calcium, Teriparatide should be used with caution in patients taking Digoxin.

Dosage and administration

Teriparatide (rDNA origin) 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 not been evaluated beyond 2 years (median 19 months in women and 10 months in men). Consequently, the maximum lifetime exposure to Teriparatide for an individual patient is 18 months. Teriparatide 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). Teriparatide is a clear and colourless solution. Do not use if solid particles appear or if the solution is cloudy or coloured. The Teriparatide 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 Teriparatide.

Overdosage

No cases of overdose were reported during clinical trials with Teriparatide (rDNA origin) 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.
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 Teriparatide, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration.

Information For User

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