Forteo 600mcg/2.4ml

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 µg 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.

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 µg. 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.

In a study of 15 healthy people administered digoxin daily to steady state, a single teriparatide 20 µg 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 FORTEO [teriparatide (rDNA origin) injection] transiently increases serum calcium, FORTEO should be used with caution in patients taking digoxin.

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 µg/day in short-term trials and 20 to 40 µg/day in the long-term trials. A total of 1943 of the patients studied received teriparatide, including 815 patients at 20 µg/day and 1107 patients at 40 µg/day. In the long-term clinical trials, 1137 patients were exposed to teriparatide for greater than 1 year (500 at 20 µg/day and 637 at 40 µg/day). The maximum exposure duration to teriparatide was 2 years. Adverse events associated with FORTEO [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, 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).

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.

  
  

• As of November 30, 2006, in the post-marketing data analysis of benign, malignant and unspecified neoplasms, there were a total of 64 cases of neoplasms in the 2283 male reports (accounting for 1.1% of all events reported for males, and 2.8% of all male reports) and 478 cases of neoplasms in the 36 632 female reports (accounting for 0.5% of all events reported for females and 1.3% of all female reports). Based upon the number of patients treated, the ratio of cases reported for both men and women is equivalent (0.2%).

  
  

• 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).

FORTEO transiently increases serum calcium, with the maximal effect observed at approximately 4 to 6 hours post-dose. Serum calcium measured at least 16 hours post-dose was not different from pretreatment levels. In clinical trials, the frequency of at least 1 episode of transient hypercalcemia in the 4 to 6 hours after FORTEO administration was increased from 1.5% of women and none of the men treated with placebo to 11.1% of women and 6.0% of men treated with FORTEO. The number of patients treated with FORTEO whose transient hypercalcemia was verified on consecutive measurements was 3.0% of women and 1.3% of men.

In a large clinical trial, antibodies that cross reacted with teriparatide were detected in 2.8% of female patients receiving FORTEO. 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.

Drug-Related^a Adverse Events Reported in ≥1% of Patients Treated with FORTEO 20 µg/day or Alendronate 10 mg/day in a Principle Clinical Trial in Men and Women with Glucocorticoid-induced Osteoporosis

Of the patients receiving FORTEO 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 FORTEO as compared with younger patients.

Of the patients receiving FORTEO 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 FORTEO as compared with younger patients.

Of the 214 patients that received FORTEO 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 FORTEO as compared with younger patients.

The safety and efficacy of FORTEO have not been studied in pediatric populations. FORTEO is not indicated for use in pediatric patients or young adults with open epiphysis (see Warnings and Precautions, Special Populations, Pediatrics).

There is no specific antidote for teriparatide. Treatment of suspected overdose should include discontinuation of FORTEO, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration.

FORTEO increases urinary calcium excretion, but the frequency of hypercalciuria in clinical trials was similar for patients treated with FORTEO and placebo (see Action and Clinical Pharmacology, Pharmacodynamics, Urinary Calcium Excretion).

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.

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).

Before initiating therapy with FORTEO 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.

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).

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.

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.

FORTEO 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 FORTEO. If persistent hypercalcemia is detected, treatment with FORTEO 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 FORTEO (see Contraindications).

FORTEO has not been studied in pediatric populations. FORTEO should not be used in children or young adults with open epiphyses (see Contraindications).

Patients should be made aware that FORTEO caused osteosarcomas in rats and that the clinical relevance of these findings is unknown.

Of the patients receiving FORTEO 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 FORTEO as compared with younger patients.

Of the patients receiving FORTEO 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 FORTEO as compared with younger patients.

Of the 214 patients that received FORTEO 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 FORTEO as compared with younger patients.

FORTEO increases serum uric acid concentrations. In clinical trials, 2.8% of FORTEO 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.

Physicians should instruct their patients to read the Information for the Patient Leaflet and Pen User Manual before starting therapy with FORTEO and re-read them each time the prescription is renewed.

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 µg (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.

FORTEO 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 FORTEO. Should pregnancy occur, FORTEO should be discontinued (see Contraindications).

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.

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

There have been no clinical studies to determine if teriparatide is secreted into breast milk. FORTEO should not be administered to nursing mothers (see Contraindications).

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

Teriparatide is extensively absorbed after subcutaneous injection; the absolute bioavailability is approximately 95% based on pooled data from 20-, 40-, and 80-µg 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-µg 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.

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).

In the study of patients with glucocorticoid-induced osteoporosis, the effects of FORTEO on serum calcium and phosphorus were similar to those observed in postmenopausal women with osteoporosis not taking glucocorticoids.

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.

The primary effect of glucocorticoids on bone is to inhibit osteoblastic bone-forming activity. Glucocorticoids also increase bone resorption.

Daily administration of FORTEO 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.

Although systemic exposure to teriparatide is approximately 20% to 30% lower in men than in women, the recommended dose for both genders is 20 µg/day.

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.

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 FORTEO.

In clinical studies of daily FORTEO, 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.

The pharmacokinetics of teriparatide have not been evaluated in pediatric populations (see Warnings and Precautions, Special Populations, Pediatrics).

Median Percent Changes^{a , b} from Baseline in Bone Biomarkers in Patients with Glucocorticoid-Induced Osteoporosis

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.

No differences in teriparatide pharmacokinetics were detected with regard to age (range 31 to 85 years).

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.

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, FORTEO 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.

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, FORTEO 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.

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.

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 T_1/2 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).

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

When teriparatide 20 µg 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 FORTEO [teriparatide (rDNA origin) injection] was 2.42 mmol/L at 12 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 FORTEO 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 FORTEO whose serum calcium was above the upper limit of normal on consecutive 4- to 6-hour post-dose measurements was 3.0% compared with 0.2% of women treated with placebo. In these women, calcium supplements and/or FORTEO doses were reduced. The timing of these dose reductions was at the discretion of the investigator. FORTEO dose adjustments were made at varying intervals after the first observation of 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 FORTEO 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 FORTEO 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 FORTEO whose serum calcium was above the upper limit of normal on consecutive measurements was 1.3% (2 men) compared with none of the men treated with placebo. Although calcium supplements and/or FORTEO doses could have been reduced in these men, only calcium supplementation was reduced (see Warnings and Precautions and Adverse Reactions).

FORTEO has not been studied in patients with pre-existing hypercalcemia. These patients should be excluded from treatment with FORTEO because of the possibility of exacerbating hypercalcemia (see Contraindications).