When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
Internal change, reference to Forsteo 3ml pen removed. It was replaced by the 2.4ml pen, 2 years ago, and the 3 ml pen has been gradually phased out.
In Section 2, Qualitative and quantitative composition, the following text is deleted – ‘One pre-filled pen of 2.4 ml contains 600 micrograms of teriparatide (corresponding to 250 micrograms per ml). Or’
In Section 6.5, Nature and contents of container, the following text is deleted – ‘3ml solution in cartridge (siliconised Type I glass) with a plunger (halobutyl rubber), disc seal (polyisoprene/bromobutyl rubber laminate) and crimp cap (aluminium) assembled into a disposable pen. Or’
In Section 4.8 Undesirable effects, Nervous system disorders – Syncope moved from ‘Not known’ to ‘Common’; Renal and Urinary disorders – Nephrolithiasis added to ‘Uncommon’; Renal failure/impairment moved from ‘Not known’ to ‘Rare’; Musculoskeletal and connective tissue disorders - Back cramp/pain moved from ‘Not known’ to ‘Uncommon’ In Section 10 Date of revision of the text, the date of revision is updated.
4.6 Pregnancy and lactation
Change to section 4.6 sub-section heading (QRD template change)
- to 4.6 Fertility, Ppregnancy and lactation.
5.1 Pharmacodynamic properties
Correction of table number & cross reference to table (table number) – from Table 4 to Table 1. 10. DATE OF REVISION OF THE TEXT New date (as previous date) 27 May 2011
10. DATE OF REVISION OF THE TEXT
New date (as previous date)
27 May 2011
This SPC has been revised to remove the black triangle symbol (affecting UK SPC version only) – there are no other content changes. Accordingly, the Lilly internal SPC code has been updated to FS11M only.
Changes
Added text: ‘in bold, over size’
4. CLINICAL PARTICULARS
4.8 Undesirable effects
Of patients in the teriparatide trials, 82.8% of the FORSTEO patients and 84.5% of the placebo patients reported at least 1 adverse event.
The most commonly reported adverse reactions in patients treated with FORSTEO are nausea, pain in limb, headache and dizziness.
The undesirable 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), not known (cannot be estimated from the available data).
Investigations
Uncommon: Weight increased, Cardiac murmur, Alkaline phosphatase increase
Cardiac disorders
Common: Palpitations
Uncommon: Tachycardia
Blood and lymphatic system disorders
Common: Anaemia
Nervous system disorders
Common: Dizziness, Headache, Sciatica
Not known: Syncope
Ear and labyrinth disorders
Common: Vertigo
Respiratory, thoracic and mediastinal disorders
Common: Dyspnoea
Uncommon: Emphysema
Gastrointestinal disorders
Common: Nausea, Vomiting, Hiatus hernia, Gastro-oesophageal reflux disease
Uncommon: Haemorrhoids
Renal and urinary disorders
Uncommon: Urinary incontinence, Polyuria, Micturition urgency
Not known: Renal failure/impairment
Skin and subcutaneous tissue disorders
Common: Sweating increased
Musculoskeletal and connective tissue disorders
Very common: Pain in limb
Common: Muscle cramps
Uncommon: Myalgia, Arthralgia
Not known: Back cramp/pain*
Metabolism and nutrition disorders
Common: Hypercholesterolaemia
Uncommon: Hypercalcaemia greater than 2.76 mmol/L, Hyperuricaemia
Rare: Hypercalcaemia greater than 3.25 mmol/L
Vascular disorders
Common: Hypotension
General disorders and administration site conditions
Common: Fatigue, Chest pain, Asthenia, Mild and transient injection site events, including pain, swelling, erythema, localised bruising, pruritus 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)
Psychiatric disorders
Common: Depression
* Serious cases of back cramp or pain have been reported within minutes of the injection.
In clinical trials the following reactions were reported at a ≥ 1% difference in frequency from placebo: vertigo, nausea, pain in limb, dizziness, depression, dyspnoea.
FORSTEO increases serum uric acid concentrations. In clinical trials, 2.8% of FORSTEO patients had serum uric acid concentrations above the upper limit of normal compared with 0.7% of placebo patients. However, the hyperuricaemia 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 FORSTEO. Generally, antibodies were first detected following 12 months of treatment and diminished after withdrawal of therapy. There was no evidence of hypersensitivity reactions, allergic reactions, effects on serum calcium, or effects on BMD response.
New date
18 March 2010
4.3 Contraindications
Added (bold) deleted (strikethrough):
· Metabolic bone diseases (including hyperparathyroidism and Paget’s disease of the bone) other than primary osteoporosis or glucorticoid-induced osteoporosis (including hyperparathyroidism and Paget’s disease of the bone).
Added (bold):
The undesirable reactions associated with the use of teriparatide in osteoporosis clinical trials and post-marketing exposure are summarised in the table below.
Added:
5. PHARMACOLOGICAL PROPERTIES
Pharmaco-therapeutic group: parathyroid hormones and analogues, ATC code: H05 AA023.
28 August 2009
*Forsteo ‘new’ pen launch 2009 - SPC revised to create combined SPC for ‘old’ Forsteo pen and ‘new’ Forsteo pen. No other changes have been made.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
or
One pre-filled pen of 2.4 ml contains 600 micrograms of teriparatide (corresponding to 250 micrograms per ml).
6. PHARMACEUTICAL PARTICULARS
6.5 Nature and contents of container
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.
25 February 2009
4.2 Posology and method of administration
Deleted (strikethrough) Added (bold):
The maximum total duration of treatment with FORSTEO should be 18 24 months (see section 4.4). The 18 24-month course of FORSTEO should not be repeated over a patients lifetime.
4.4 Special warnings and precautions for use
Studies in rats indicate an increased incidence of osteosarcoma with long-term administration of teriparatide (see section 5.3). Until further clinical data become available, the recommended treatment time of 18 24 months should not be exceeded.
Postmenopausal women Postmenopausal osteoporosis:
Postmenopausal osteoporosis:
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 FORSTEO 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.
Glucocorticoid-induced osteoporosis:
The efficacy of Forsteo 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).
Sixty-nine percent of patients completed the 18-month primary phase. At the 18-month endpoint, FORSTEO significantly increased lumbar spine BMD (7.2%) compared with alendronate (3.4%) (p<0.001). FORSTEO 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).
Deleted:
A preliminary analysis of 336 spinal X-rays showed that 10 patients in the alendronate group (6.1%) had experienced a new vertebral fracture compared with 1 patient in the FORSTEO group (0.6%). In addition, 9 patients in the alendronate group (4.2%) had experienced a nonvertebral fracture compared with 12 patients in the FORSTEO group (5.6%).
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 FORSTEO patients showed that 13 patients in the alendronate group (7.7%) had experienced a new vertebral fracture compared with 3 patients in the FORSTEO group (1.7%) (p=0.01). In addition, 15 of 214 patients in the alendronate group (7.0%) had experienced a nonvertebral fracture compared with 16 of 214 patients in the FORSTEO group (7.5%) (p=0.84).
In premenopausal women, the increase in BMD from baseline to 18 month endpoint was significantly greater in the FORSTEO 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).
5.3 Preclinical safety data
Rats treated with near-life time daily injections had dose-dependent exaggerated bone formation and increased incidence of osteosarcoma most probably due to an epigenitic 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 nor 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.
Each dose contains 20 micrograms of teriparatide.
Each dose contains 20 micrograms of teriparatide. The pre-filled pen is intended for 28 days of dosing.
Deleted (bold):
Teriparatide, rhPTH(1-34),
the 34 N-terminal amino acid sequence of endogenous human parathyroid hormone.
Changed whole paragraph:
Paediatric population and young adults with open epiphyses:
than 18 years). FORSTEO should not be used in paediatric patients (less than 18 years), or young adults with open
epiphyses.
The most commonly reported adverse
headache and dizziness. Tables 1, 2 and 3 give an overview of all treatment emergent adverse events reactions
that were observed in the trial populations, irrespective of causal relationship. The following events reactions were
observed in clinical trials in 1382 patients.
The undesirable reactions associated with the use of teriparatide in osteoporosis clinical trials are summarised in
the table below. The following convention has been used for the classification of the adverse reactions: very
common (
very rare (<1/10,000), not known (cannot be estimated from the available data).
TABLE
In clinical trials the following reactions were reported at a
nausea, pain in limb, dizziness, depression, dyspnoea.
The following table of adverse reactions is based on post-marketing spontaneous reports.
The following convention has been used for the classification of the adverse reactions: very common (
(<1/10,000), not known (cannot be estimated from the available data).
4.9 Overdose
Overdose experience based on post-marketing spontaneous reports:
Changed to:
(up to 800
Pharmaco-therapeutic group: calcium homeostasis, ATC code: H05AA02
analogues, ATC code: H05 AA03.
1000 ¦Ìg/kg and 100 ¦Ìg/kg
6.1 List of excipients
Deleted (strikethrough):
Metacresol (preservative)
6.6 Special precautions for disposal
Changed (deleted strikethrough) to:
FORSTEO is supplied in a pre-filled pen and is intended for single patient use only. Each pen should be used by
only one patient. A new, sterile needle must be used for every injection.
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of last renewal 10 June 2008
20 May 2008
4.1 Therapeutic indications
Treatment of osteoporosis associated with sustained systemic glucocorticoid therapy in women and men at increased risk for fracture (see section 5.1).
Added (bold text):
The maximum total duration of treatment with FORSTEO should be 18 months (see section 4.4). The 18-month course of FORSTEO should not be repeated over a patient¡¯s lifetime.
Added (New Bullet):
¡¤ Pregnancy and lactation (see section 4.4 and 4.6)
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 FORSTEO. If pregnancy occurs, FORSTEO should be discontinued.
The potential risk for humans is unknown. Given the indication, FORSTEO should not be used during pregnancy or by breast-feeding women.
General recommendation
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.
It is not known whether teriparatide is excreted in human milk.
FORSTEO is contraindicated for use during pregnancy or breast-feeding.
Women of childbearing potential / Contraception in females
Adverse reactions
General Disorders and Administration Site Conditions
Rare: Possible allergic events soon after injection: acute dyspnoea, oro/facial oedema, generalized urticaria, chest pain, oedema (mainly peripheral).
Common: Mild and transient injection site events, including pain, swelling, erythema, localised bruising, pruritis and minor bleeding at injection site.
Metabolism and Nutrition Disorders
Uncommon: Hypercalcemia greater than 2.76 mmol/l (11mg/dl).
Rare: Hypercalcemia greater than 3.25 mmol/l (13mg/dl).
Musculoskeletal and Connective Tissue and Bone Disorders
Uncommon: myalgia, arthralgia,
Uncommon: alkaline phosphatase increase
Risk Factors
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 ¡Ü−2], sustained high dose glucocorticoid therapy [e.g., ¡Ý7.5 mg/day for at least 6 months], high underlying disease activity, low sex steroid levels).
Glucocorticoid-induced osteoporosis
The efficacy of Forsteo 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 an 18-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 study. At endpoint, FORSTEO significantly increased lumbar spine BMD (7.2%) compared with alendronate (3.4%) (p<0.001). FORSTEO 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 premenopausal women, the increase in BMD from baseline to endpoint was significantly greater in the FORSTEO 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.
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 mcg/kg. However, foetal resorption and reduced litter size occurred in pregnant rabbits administered daily doses of 3 to 100 mcg/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.
02 April 2008
Added ‘oedema (mainly peripheral)’ as a rare adverse reaction in the table listing post-marketing spontaneous reports.
21 August 2007
Added (new text in bold):
For a full list of excipients, see section 6.1.
Deletions in strikethrough text and added text in bold.
Treatment of established osteoporosis in postmenopausal women and in men at increased risk of fracture (see section 5.1). In post menopausal women a significant reduction in the incidence of vertebral and non-vertebral fractures, but not hip fractures has been demonstrated.
Children: Forsteo has not been studied in paediatric populations. Forsteo should not be used in paediatric patients or young adults with open epiphyses. There is no experience in children. Forsteo should not be used in paediatric patients or young adults with open epiphyses.
4.3 Contra-indications
Changed text shown in bold.
· Hypersensitivity to the active substance or to any of the excipients.
Changed the way the frequency classification is expressed in all tables.
Changes to following statement shown in bold text.
The following convention has been used for the classification of the adverse reactions: very common (³1/10), common (³1/100 to<1/10), uncommon (³1/1,000 to <1/100), rare (³1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).
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.
Deletion shown in strikethrough text and added texts shown in bold.
Postmenopausal women: with established osteoporosis (T-score below -2.5 in the presence of one or more fragility fracture):
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 1000mg calcium per day and at least 400IU vitamin D per day. Results from up to 24 months (median: 19 months) treatment with Forsteo demonstrate statistically significant fracture reduction (Table 4). To prevent one or more new vertebral fractures, 11 women had to be treated for a median of 19 months.
Changes to table shown in bold text:
Table 4
Fracture Incidence in Postmenopausal Women
Placebo
n = 544
(%)
Forsteo
n = 541
Relative Risk
(95% CI)
vs Placebo
New vertebral fracture (³1)a
14.3
5.0 b
0.35
(0.22, 0.55)
Multiple vertebral fractures (³2)a
4.9
1.1 b
0.23
(0.09, 0.60)
Non-vertebral fragility fractures c
5.5%
2.6% c
0.47(0.25, 0.87)
Major non-vertebral fragility fracturesc (hip, radius, humerus, ribs and pelvis)
3.9%
1.5% c
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 Forsteo patients who had baseline and follow-up spine radiographs.
b P£0.001 compared with placebo
c P£0.025 compared with placebo
Added text in bold
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.
6.4 Special precautions for storage
Changed storage instruction from ‘Store at 2ºC-8°C at all times.’ to ‘Store in a refrigerator (2ºC-8°C) at all times.’.
Changed the title of 6.6 from ’Instructions for use and handling’ to the above and deleted the reference to Becton Dickson needles in this section.
Any unused product or waste material should be disposed of in accordance with local requirements.
Date of first authorisation: 10 June 2003
22 June 2007