FORTEO is indicated in adults.

Treatment of osteoporosis in postmenopausal women and in men at increased risk of fracture (see section 5.1). In postmenopausal women, a significant reduction in the incidence of vertebral and non-vertebral fractures but not hip fractures has been demonstrated.

Treatment of osteoporosis associated with sustained systemic glucocorticoid therapy in women and men at increased risk for fracture (see section 5.1).

Posology

The recommended dose of FORTEO is 20 micrograms administered once daily.

Use of FORTEO for more than 2 years during a patient’s lifetime should only be considered if a patient remains at or has returned to having a high risk for fracture (see section 4.4).

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

Following cessation of FORTEO therapy, patients may be continued on other osteoporosis therapies.

Special populations

Patients with renal impairment

FORTEO must not be used in patients with severe renal impairment (see section 4.3.). In patients with moderate renal impairment, FORTEO should be used with caution. No special caution is required for patients with mild renal impairment.

 Patients with hepatic impairment

No data are available in patients with impaired hepatic function (see section 5.3). Therefore, FORTEO should be used with caution.

Paediatric population and young adults with open epiphyses:

The safety and efficacy of FORTEO in children and adolescents less than 18 years has not been established.  FORTEO should not be used in paediatric patients (less than 18 years), or young adults with open epiphyses.

 Elderly patients:

Dosage adjustment based on age is not required (see section 5.2).

Method of administration

FORTEO should be administered once daily by subcutaneous injection in the thigh or abdomen.

Patients must be trained to use the proper injection techniques (see section 6.6). A user manual is also available to instruct patients on the correct use of the pen.

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. • Pregnancy and breast-feeding (see sections 4.4 and 4.6) • Pre-existing hypercalcaemia • Severe renal impairment • Metabolic bone diseases (including hyperparathyroidism and Paget’s disease of the bone) other than primary osteoporosis or glucorticoid-induced osteoporosis. • Unexplained elevations of alkaline phosphatase • Prior external beam or implant radiation therapy to the skeleton • Patients with skeletal malignancies or bone metastases should be excluded from treatment with teriparatide.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number

of the administered product should be clearly recorded.

Osteosarcoma

An increase in the incidence of osteosarcoma (a malignant bone tumor) was observed in male and female rats treated with teriparatide. Osteosarcoma has been reported in patients treated with FORTEO in the post marketing setting; however, an increased risk of osteosarcoma has not been observed in observational studies in humans. There are limited data assessing the risk of osteosarcoma beyond 2 years of FORTEO use.

Avoid FORTEO use in patients with (these patients are at increased baseline risk of osteosarcoma):

• Open epiphyses (pediatric and young adult patients) (FORTEO is not approved in pediatric patients).
• Metabolic bone diseases other than osteoporosis, including Paget’s disease of the bone.
• Bone metastases or a history of skeletal malignancies.
• Prior external beam or implant radiation therapy involving the skeleton.
• Hereditary disorders predisposing to osteosarcoma.

Serum and urine calcium

In normocalcaemic patients, slight and transient elevations of serum calcium concentrations have been observed following teriparatide injection. Serum calcium concentrations reach a maximum between 4 and 6 hours and return to baseline by 16 to 24 hours after each dose of teriparatide. Therefore, if blood samples for serum calcium measurements are taken, this should be done at least 16 hours after the most recent FORTEO injection. Routine calcium monitoring during therapy is not required.

FORTEO may cause small increases in urinary calcium excretion, but the incidence of hypercalciuria did not differ from that in the placebo-treated patients in clinical trials.

Hypercalcemia

FORTEO has not been studied in patients with pre-existing hypercalcemia. FORTEO may cause hypercalcemia and may exacerbate hypercalcemia in patients with pre-existing hypercalcemia [see Adverse Reactions (6.1, 6.3)]. Avoid FORTEO in patients known to have an underlying hypercalcemic disorder, such as primary hyperparathyroidism.

Risk of Cutaneous Calcification Including Calciphylaxis

Serious reports of calciphylaxis and worsening of previously stable cutaneous calcification have been reported in the post-marketing setting in patients taking FORTEO. Risk factors for development of calciphylaxis include underlying auto-immune disease, kidney failure, and concomitant warfarin or systemic corticosteroid use. Discontinue FORTEO in patients who develop calciphylaxis or worsening of previously stable cutaneous calcification.

Urolithiasis

FORTEO has not been studied in patients with active urolithiasis. Consider the risks and benefits if use in patients with active or recent urolithiasis because of the potential to exacerbate this condition.

 Orthostatic hypotension

In short-term clinical studies with FORTEO, 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.

Renal impairment

Caution should be exercised in patients with moderate renal impairment.

Younger adult population

Experience in the younger adult population, including premenopausal women, is limited (see section 5.1).  Treatment should only be initiated if the benefit clearly outweighs risks in this population.

Women of childbearing potential should use effective methods of contraception during use of FORTEO. If pregnancy occurs, FORTEO should be discontinued.

Sodium content

 This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

In a study of 15 healthy subjects administered digoxin daily to steady state, a single FORTEO dose did not alter the cardiac effect of digoxin. However, sporadic case reports have suggested that hypercalcaemia may predispose patients to digitalis toxicity. Because FORTEO transiently increases serum calcium, FORTEO should be used with caution in patients taking digitalis.

FORTEO has been evaluated in pharmacodynamic interaction studies with hydrochlorothiazide. No clinically significant interactions were noted.

Co-administration of raloxifene or hormone replacement therapy with FORTEO did not alter the effects of FORTEO on serum or urine calcium or on clinical adverse events.

Women of childbearing potential / Contraception in females

Women of childbearing potential should use effective methods of contraception during use of FORTEO.  If pregnancy occurs, FORTEO should be discontinued. 

Pregnancy

FORTEO is contraindicated for use during pregnancy (see section 4.3).

Breast-feeding

FORTEO is contraindicated for use during breast-feeding. It is not known whether teriparatide is excreted in human milk.

Fertility

Studies in rabbits have shown reproductive toxicity (see section 5.3). The effect of teriparatide on human foetal development has not been studied. The potential risk for humans is unknown.

FORTEO has no or negligible influence on the ability to drive and use machines. Transient, orthostatic hypotension or dizziness was observed in some patients. These patients should refrain from driving or the use of machines until symptoms have subsided.

Summary of the safety profile

The most commonly reported adverse reactions in patients treated with FORTEO are nausea, pain in limb, headache and dizziness. 

Tabulated list of adverse reactions

Of patients in the teriparatide trials, 82.8 % of the FORTEO patients and 84.5 % of the placebo patients reported at least 1 adverse event.

The adverse reactions associated with the use of teriparatide in osteoporosis clinical trials and post-marketing exposure are summarised in the table below. The following convention has been used for the classification of the adverse reactions: very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1,000 to <1/100), rare (≥ 1/10,000 to <1/1,000) very rare (<1/10,000).

Blood and lymphatic system disorders Common: Anaemia

Immune System Disorder Rare: Anaphylaxis

Metabolism and nutrition disorders Common: Hypercholesterolaemia Uncommon: Hypercalcaemia greater than 2.76 mmol/L, hyperuricemia Rare: Hypercalcaemia greater than 3.25 mmol/L

Psychiatric disorders Common: Anxiety, Depression

Nervous system disorders Common: Dizziness, headache, sciatica, syncope

Ear and labyrinth disorders Common: Vertigo

Cardiac disorders Common: Palpitations Uncommon: Tachycardia

Vascular disorders Common: Hypotension

Respiratory, thoracic and mediastinal disorders Common: Dyspnoea Uncommon: Emphysema

Gastrointestinal disorders Common: Nausea, vomiting, hiatus hernia, gastroesophageal reflux disease Uncommon: Haemorrhoids

Skin and subcutaneous tissue disorders Common: Sweating increased

Musculoskeletal and connective tissue disorders Very common: Pain in limb Common: Muscle cramps Uncommon: Myalgia, arthralgia, back cramp/pain*

Renal and urinary disorders Uncommon: Urinary incontinence, polyuria, micturition urgency, nephrolithiasis Rare:  Renal failure/impairment

General disorders and administration site conditions Common: Fatigue, chest pain, asthenia, mild and transient injection site events, including pain, swelling, erythema, localised bruising, pruritis and minor bleeding at injection site. Uncommon: Injection site erythema, injection site reaction Rare: Possible allergic events soon after injection: acute dyspnoea, oro/facial oedema, generalised urticaria, chest pain, oedema (mainly peripheral).

Investigations Uncommon: Weight increased, cardiac murmur, alkaline phosphatase increase

*Serious cases of back cramp or pain have been reported within minutes of the injection.

Description of selected adverse reactions

In clinical trials the following reactions were reported at a ≥ 1% difference in frequency from placebo: vertigo, nausea, pain in limb, dizziness, depression, dyspnoea.

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.

In a large clinical trial, antibodies that cross-reacted with teriparatide were detected in 2.8% of women receiving FORTEO.  Generally, antibodies were first detected following 12 months of treatment and diminished after withdrawal of therapy.  There was no evidence of hypersensitivity reactions, allergic reactions, effects on serum calcium, or effects on Bone Mineral Density BMD response.

Adverse Reactions from Postmarketing Spontaneous Reports

Adverse events reported since market introduction that were temporally related to FORTEO therapy include the following:

• Allergic Reactions: Anaphylactic reactions, drug hypersensitivity, angioedema, and urticaria.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed here.

To report any side effect(s):

The National Pharmacovigilance and Drug Safety Center (NPC)

·         Fax: +966-11-205-7662

·         SFDA Call Center: 19999

·         E-mail: npc.drug@sfda.gov.sa

·         Website: https://ade.sfda.gov.sa

Signs and symptoms

FORTEO has been administered in single doses of up to 100 micrograms and in repeated doses of up to 60 micrograms/day for 6 weeks.

The effects of overdose that might be expected include delayed hypercalcaemia and risk of orthostatic hypotension. Nausea, vomiting, dizziness, and headache can also occur.

 Overdose experience based on post-marketing spontaneous reports:

In post-marketing spontaneous reports, there have been cases of medication error where the entire contents (up to 800 mcg) (40 times the recommended dose) of the FORTEO prefilled pen have been administered as a single dose. Transient events reported have included nausea, weakness/lethargy and hypotension. No fatalities associated with overdose have been reported. Additional signs, symptoms, and complications of FORTEO overdosage may include a delayed hypercalcemic effect, vomiting, dizziness, and headache.

Overdose management:

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

 

Pharmaco-therapeutic group: Calcium homeostasis, parathyroid hormones and analogues, ATC code: H05 AA02.

 Mechanism of action:

Endogenous 84-amino-acid parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism in bone and kidney. FORTEO (rhPTH(1-34)) is the active fragment (1-34) of endogenous human parathyroid hormone. Physiological actions of PTH include stimulation of bone formation by direct effects on bone forming cells (osteoblasts) indirectly increasing the intestinal absorption of calcium and increasing the tubular re-absorption of calcium and excretion of phosphate by the kidney.

Pharmacodynamic effects

FORTEO is a bone formation agent to treat osteoporosis. The skeletal effects of FORTEO depend upon the pattern of systemic exposure. Once-daily administration of FORTEO increases apposition of new bone on trabecular and cortical bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity.

Clinical efficacy

Risk Factors

Independent risk factors, for example, low BMD, age, the existence of previous fracture, family history of hip fractures, high bone turnover and low body mass index should be considered in order to identify women and men at increased risk of osteoporotic fractures who could benefit from treatment.

Premenopausal women with glucocorticoid-induced osteoporosis should be considered at high risk for fracture if they have a prevalent fracture or a combination of risk factors that place them at high risk for fracture (e.g., low bone density [e.g., T score ≤−2], sustained high dose glucocorticoid therapy [e.g., ≥7.5 mg/day for at least 6 months], high underlying disease activity, low sex steroid levels).

Postmenopausal osteoporosis

The pivotal study included 1637 postmenopausal women (mean age 69.5 years). At baseline, ninety percent of the patients had one or more vertebral fractures, and on average, vertebral BMD was 0.82 g/cm² (equivalent to a T-score = - 2.6). All patients were offered 1000 mg calcium per day and at least 400 IU vitamin D per day. Results from up to 24 months (median: 19 months) treatment with FORTEO demonstrate statistically significant fracture reduction (Table 1). To prevent one or more new vertebral fractures, 11 women had to be treated for a median of 19 months.

Table 1

Fracture Incidence in Postmenopausal Women:
	Placebo (N = 544) (%)	FORTEO (N = 541) (%)	Relative risk (95% CI) vs. placebo
New vertebral fracture (≥1) a	14.3	5.0 b	0.35 (0.22, 0.55)
Multiple vertebral fractures (≥2) a	4.9	1.1 b	0.23 (0.09, 0.60)
Non-vertebral fragility fractures c	5.5%	2.6% d	0.47 (0.25, 0.87)
Major non-vertebral fragility fracturesc (hip, radius, humerus, ribs and pelvis)	3.9%	1.5% d	0.38 (0.17, 0.86)

Abbreviations:  N = number of patients randomly assigned to each treatment group; CI = Confidence Interval.

  ^a The incidence of vertebral fractures was assessed in 448 placebo and 444 FORTEO patients who had baseline and follow-up spine radiographs.

 ^b p£0.001 compared with placebo

^c A significant reduction in the incidence of hip fractures has not been demonstrated

^d p£0.025 compared with placebo.

After 19 months (median) treatment, bone mineral density (BMD) had increased in the lumbar spine and total hip, respectively, by 9% and 4% compared with placebo (p<0.001).

Post-treatment management: Following treatment with FORTEO, 1262 postmenopausal women from the pivotal trial enrolled in a post-treatment follow-up study. The primary objective of the study was to collect safety data of FORTEO. During this observational period, other osteoporosis treatments were allowed and additional assessment of vertebral fractures was performed.

During a median of 18 months following discontinuation of FORTEO, there was a 41% reduction (p=0.004) compared with placebo in the number of patients with a minimum of one new vertebral fracture.

In an open-label study, 503 postmenopausal women with severe osteoporosis and a fragility fracture within the previous 3 years (83% had received previous osteoporosis therapy) were treated with FORTEO for up to 24 months. At 24 months, the mean increase from baseline in lumbar spine, total hip and femoral neck BMD was 10.5%, 2.6% and 3.9% respectively. The mean increase in BMD from 18 to 24 months was 1.4%, 1.2%, and 1.6% at the lumbar spine, total hip and femoral neck, respectively.

A 24-month, randomized, double-blind, comparator-controlled Phase 4 study included 1,360 postmenopausal women with established osteoporosis. 680 subjects were randomised to Forteo and 680 subjects were randomised to oral risedronate 35 mg/week. At baseline, the women had a mean age of 72.1 years and a median of 2 prevalent vertebral fractures; 57.9% of patients had received previous bisphosphonate therapy and 18.8% took concomitant glucocorticoids during the study. 1,013 (74.5%) patients completed the 24-month follow-up. The mean (median) cumulative dose of glucocorticoid was 474.3 (66.2) mg in the teriparatide arm and 898.0 (100.0) mg in the risedronate arm. The mean (median) vitamin D intake for the teriparatide arm was 1433 IU/day (1400 IU/day) and for the risedronate arm was 1191 IU/day (900 IU/day). For those subjects who had baseline and follow-up spine radiographs, the incidence of new vertebral fractures was 28/516 (5.4%) in Forteo- and 64/533 (12.0%) in risedronate-treated patients, relative risk (95% CI) = 0.44 (0.29-0.68), P<0.0001. The cumulative incidence of pooled clinical fractures (clinical vertebral and non vertebral fractures) was 4.8% in Forteo and 9.8% in risedronate-treated patients, hazard ratio (95% CI) = 0.48 (0.32-0.74), P=0.0009.

Male osteoporosis 

437 patients (mean age 58.7 years) were enrolled in a clinical trial for men with hypogonadal (defined as low morning free testosterone or an elevated FSH or LH) or idiopathic osteoporosis. Baseline spinal and femoral neck bone mineral density mean T-scores were -2.2 and -2.1, respectively.  At baseline, 35% of patients had a vertebral fracture and 59% had a non-vertebral fracture.

All patients were offered 1000 mg calcium per day and at least 400 IU vitamin D per day. Lumbar spine BMD significantly increased by 3 months. After 12 months, BMD had increased in the lumbar spine and total hip by 5% and 1%, respectively, compared with placebo. However, no significant effect on fracture rates was demonstrated.

Glucocorticoid-induced osteoporosis

The efficacy of FORTEO in men and women (N=428) receiving sustained systemic glucocorticoid therapy (equivalent to 5 mg or greater of prednisone for at least 3 months) was demonstrated in the 18-month primary phase of a 36 month, randomised, double-blind, comparator-controlled study (alendronate 10 mg/day). Twenty-eight percent of patients had one or more radiographic vertebral fractures at baseline. All patients were offered 1000 mg calcium per day and 800 IU vitamin D per day.

This study included postmenopausal women (N=277), premenopausal women (N=67), and men (N=83). At baseline, the postmenopausal women had a mean age of 61 years, mean lumbar spine BMD T score of −2.7, median prednisone equivalent dose of 7.5 mg/day, and 34% had one or more radiographic vertebral fractures; premenopausal women had a mean age of 37 years, mean lumbar spine BMD T score of −2.5, median prednisone equivalent dose of 10 mg/day, and 9% had one or more radiographic vertebral fractures; and men had a mean age of 57 years, mean lumbar spine BMD T score of −2.2, median prednisone equivalent dose of 10 mg/day, and 24% had one or more radiographic vertebral fractures.

Sixty-nine percent of patients completed the 18-month primary phase.  At the 18 month endpoint, FORTEO significantly increased lumbar spine BMD (7.2%) compared with alendronate (3.4%) (p<0.001). FORTEO increased BMD at the total hip (3.6%) compared with alendronate (2.2%) (p<0.01), as well as at the femoral neck (3.7%) compared with alendronate (2.1%) (p<0.05). In patients treated with teriparatide, lumbar spine, total hip and femoral neck BMD increased between 18 and 24 months by an additional 1.7%, 0.9%, and 0.4%, respectively.

At 36 months, analysis of spinal X-rays from 169 alendronate patients and 173 FORTEO patients showed that 13 patients in the alendronate group (7.7%) had experienced a new vertebral fracture compared with 3 patients in the FORTEO group (1.7%) (p=0.01). In addition, 15 of 214 patients in the alendronate group (7.0%) had experienced a non-vertebral fracture compared with 16 of 214 patients in the FORTEO group (7.5%) (p=0.84).

In premenopausal women, the increase in BMD from baseline to 18 month endpoint was significantly greater in the FORTEO group compared with the alendronate group at the lumbar spine (4.2% versus −1.9%; p<0.001) and total hip (3.8% versus 0.9%; p=0.005).  However, no significant effect on fracture rates was demonstrated.

Distribution

 The volume of distribution is approximately 1.7 L/kg. The half-life of FORTEO is approximately 1 hour when administered subcutaneously, which reflects the time required for absorption from the injection site.

Biostransformation

No metabolism or excretion studies have been performed with FORTEO but the peripheral metabolism of parathyroid hormone is believed to occur predominantly in liver and kidney.

Elimination

FORTEO is eliminated through hepatic and extra-hepatic clearance (approximately 62 L/hr in women and 94 L/hr in men).

 Elderly

No differences in FORTEO pharmacokinetics were detected with regard to age (range 31 to 85 years). Dosage adjustment based on age is not required.

Teriparatide was not genotoxic in a standard battery of tests. It produced no teratogenic effects in rats, mice or rabbits. There were no important effects observed in pregnant rats or mice administered teriparatide at daily doses of 30 to 1000 µg/kg. However, fetal resorption and reduced litter size occurred in pregnant rabbits administered daily doses of 3 to 100 µg/kg. The embryotoxicity observed in rabbits may be related to their much greater sensitivity to the effects of PTH on blood ionised calcium compared with rodents.

Rats treated with near-life time daily injections had dose-dependent exaggerated bone formation and increased incidence of osteosarcoma most probably due to an epigenetic mechanism. Teriparatide did not increase the incidence of any other type of neoplasia in rats. Due to the differences in bone physiology in rats and humans, the clinical relevance of these findings is probably minor. No bone tumours were observed in ovariectomised monkeys treated for 18 months or during a 3-year follow-up period after treatment cessation. In addition, no osteosarcomas have been observed in clinical trials or during the post treatment follow-up study.

Animal studies have shown that severely reduced hepatic blood flow decreases exposure of PTH to the principal cleavage system (Kupffer cells) and consequently clearance of PTH(1-84).

 

Glacial acetic acid………………………………………………………………………………0.41mg/ml

Sodium acetate (anhydrous)………………………………………………………………….....0.10mg/ml

Mannitol………………………………………………………………………………………...45.4mg/ml

Metacresol………………………………………………………………………………………….3mg/ml

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

2 years Chemical, physical and microbiological in-use stability has been demonstrated for 28 days at 2-8°C. Once opened, the product may be stored for a maximum of 28 days at 2°C to 8°C. Other in-use storage times and conditions are the responsibility of the user.

Store in a refrigerator (2°C – 8°C) at all times. The pen should be returned to the refrigerator immediately after use. Do not freeze.

Do not store the injection device with the needle attached.

2.4 mL solution in cartridge (siliconised Type I glass) with a plunger (halobutyl rubber), disc seal (polyisoprene/bromobutyl rubber laminate)/aluminium assembled into a disposable pen.

FORTEO is available in pack sizes of 1 or 3 pens. Each pen contains 28 doses of 20 micrograms (per 80 microliters).

Not all pack sizes may be marketed.

FORTEO is supplied in a pre-filled pen. Each pen should be used by only one patient. A new, sterile needle must be used for every injection. Each FORTEO pack is provided with a user manual that fully describes the use of the pen. No needles are supplied with the product. The device can be used with insulin pen injection needles. After each injection, the FORTEO pen should be returned to the refrigerator.

FORTEO should not be used if the solution is cloudy, coloured or contains particles.

Please also refer to the user manual for instructions on how to use the pen.

Any unused product or waste material should be disposed of in accordance with local requirements.