ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
FOSAVANCE 70 mg/2800 IU tablets
2.
Each tablet contains 70 mg alendronic acid as alendronate sodium trihydrate, and 70 micrograms
(2800 IU) colecalciferol (vitamin D
3
).
Excipients:
Each tablet contains 62 mg lactose anhydrous and 8 mg sucrose.
For a full list of excipients, see section 6.1.
3.
Tablet
Capsule-shaped, white to off-white tablets, marked with an outline of a bone image on one side, and
'710' on the other.
4.
FOSAVANCE is indicated for the treatment of postmenopausal osteoporosis in patients at risk of
vitamin D insufficiency. FOSAVANCE reduces the risk of vertebral and hip fractures.
Posology
The recommended dose is one FOSAVANCE tablet once weekly.
Patients should be instructed that if they miss a dose of FOSAVANCE they should take one tablet on
the morning after they remember. They should not take two tablets on the same day but should return
to taking one tablet once a week, as originally scheduled on their chosen day.
Due to the nature of the disease process in osteoporosis, FOSAVANCE is intended for long-term use.
Patients should receive supplemental calcium if intake from diet is inadequate (see section 4.4).
Additional supplementation with vitamin D should be considered on an individual basis taking into
account any vitamin D intake from vitamins and dietary supplements. The equivalence of intake of
2800 IU of vitamin D
3
weekly in FOSAVANCE to daily dosing of vitamin D 400 IU has not been
studied.
Elderly population:
In clinical studies there was no age-related difference in the efficacy or safety profiles of alendronate.
Therefore no dose adjustment is necessary for the elderly.
Renal impairment:
FOSAVANCE is not recommended for patients with renal impairment where GFR is less than
35 ml/min, due to lack of experience. No dose adjustment is necessary for patients with a glomerular
filtration rate (GFR) greater than 35 ml/min.
2
Paediatric population:
The safety and efficacy of FOSAVANCE in children less than 18 years of age has not been
established. FOSAVANCE should not be used in children less than 18 years of age because no data
are available.
Method of administration
Oral use.
To permit adequate absorption of alendronate:
FOSAVANCE must be taken with water only (not mineral water) at least 30 minutes before the first
food, beverage, or medicinal product (including antacids, calcium supplements and vitamins) of the
day. Other beverages (including mineral water), food and some medicinal products are likely to reduce
the absorption of alendronate (see section 4.5).
The following instructions should be followed exactly in order to minimize the risk of oesophageal
irritation and related adverse reactions (see section 4.4):
•
FOSAVANCE should only be swallowed after getting up for the day with a full glass of water
(not less than 200 ml or 7 fl.oz.).
•
Patients should only swallow FOSAVANCE whole. Patients should not crush or chew the tablet
or allow the tablet to dissolve in their mouths because of a potential for oropharyngeal
ulceration.
•
Patients should not lie down until after their first food of the day.
•
Patients should not lie down for at least 30 minutes after taking FOSAVANCE.
•
FOSAVANCE should not be taken at bedtime or before arising for the day.
•
Hypersensitivity to the active substances or to any of the excipients.
•
Abnormalities of the oesophagus and other factors which delay oesophageal emptying such as
stricture or achalasia.
•
Inability to stand or sit upright for at least 30 minutes.
•
Hypocalcaemia.
Alendronate
Upper gastrointestinal adverse reactions
Alendronate can cause local irritation of the upper gastrointestinal mucosa. Because there is a potential
for worsening of the underlying disease, caution should be used when alendronate is given to patients
with active upper gastrointestinal problems, such as dysphagia, oesophageal disease, gastritis,
duodenitis, ulcers, or with a recent history (within the previous year) of major gastrointestinal disease
such as peptic ulcer, or active gastrointestinal bleeding, or surgery of the upper gastrointestinal tract
other than pyloroplasty (see section 4.3). In patients with known Barrett's oesophagus, prescribers
should consider the benefits and potential risks of alendronate on an individual patient basis.
3
Oesophageal reactions (sometimes severe and requiring hospitalisation), such as oesophagitis,
oesophageal ulcers and oesophageal erosions, rarely followed by oesophageal stricture, have been
reported in patients receiving alendronate. Physicians should therefore be alert to any signs or
symptoms signalling a possible oesophageal reaction and patients should be instructed to discontinue
alendronate and seek medical attention if they develop symptoms of oesophageal irritation such as
dysphagia, pain on swallowing or retrosternal pain or new or worsening heartburn (see section 4.8).
The risk of severe oesophageal adverse reactions appears to be greater in patients who fail to take
alendronate properly and/or who continue to take alendronate after developing symptoms suggestive
of oesophageal irritation. It is very important that the full dosing instructions are provided to, and are
understood by the patient (see section 4.2). Patients should be informed that failure to follow these
instructions may increase their risk of oesophageal problems.
While no increased risk was observed in extensive clinical trials with alendronate, there have been rare
(post-marketing) reports of gastric and duodenal ulcers, some of which were severe and with
complications (see section 4.8).
Osteonecrosis of the jaw
Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including
osteomyelitis), has been reported in patients with cancer who are receiving treatment regimens
including primarily intravenously administered bisphosphonates. Many of these patients were also
receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in
patients with osteoporosis receiving oral bisphosphonates.
A dental examination with appropriate preventive dentistry should be considered prior to treatment
with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy,
radiotherapy, corticosteroids, poor oral hygiene, periodontal disease).
While on treatment, these patients should avoid invasive dental procedures if possible. For patients
who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate
the condition. For patients requiring dental procedures, there are no data available to suggest whether
discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw.
Clinical judgement of the treating physician should guide the management plan of each patient based
on individual benefit/risk assessment.
Musculoskeletal pain
Bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. In
post-marketing experience, these symptoms have rarely been severe and/or incapacitating (see
section 4.8). The time to onset of symptoms varied from one day to several months after starting
treatment. Most patients had relief of symptoms after stopping treatment. A subset had recurrence of
symptoms when rechallenged with the same medicinal product or another bisphosphonate.
Stress fractures
Stress fractures (also known as insufficiency fractures) of the proximal femoral shaft have been
reported in patients treated long-term with alendronic acid (time to onset in the majority of cases
ranged from 18 months to 10 years). The fractures occurred after minimal or no trauma and some
patients experienced thigh pain, often associated with imaging features of stress fractures, weeks to
months before presenting with a completed femoral fracture. Fractures were often bilateral; therefore
the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a
femoral shaft fracture. Poor healing of these fractures was also reported. Discontinuation of
bisphosphonate therapy in patients with stress fracture is advisable pending evaluation of the patient,
based on an individual benefit risk assessment.
Renal insufficiency
FOSAVANCE is not recommended for patients with renal impairment where GFR is less than
35 ml/min (see section 4.2).
4
Bone and mineral metabolism
Causes of osteoporosis other than oestrogen deficiency and ageing should be considered.
Hypocalcaemia must be corrected before initiating therapy with FOSAVANCE (see section 4.3).
Other disorders affecting mineral metabolism (such as vitamin D deficiency
and hypoparathyroidism)
should also be effectively treated before starting FOSAVANCE. The content of vitamin D in
FOSAVANCE is not suitable for correction of vitamin D deficiency. In patients with these conditions,
serum calcium and symptoms of hypocalcaemia should be monitored during therapy with
FOSAVANCE.
Due to the positive effects of alendronate in increasing bone mineral, decreases in serum calcium and
phosphate may occur especially in patients taking glucocorticoids in whom calcium absorption may be
decreased. These are usually small and asymptomatic. However, there have been rare reports of
symptomatic hypocalcaemia, which have occasionally been severe and often occurred in patients with
predisposing conditions (e.g. hypoparathyroidism, vitamin D deficiency and calcium malabsorption)
(see section 4.8).
Colecalciferol
Vitamin D
3
may increase the magnitude of hypercalcaemia and/or hypercalciuria when administered to
patients with disease associated with unregulated overproduction of calcitriol (e.g. leukaemia,
lymphoma, sarcoidosis). Urine and serum calcium should be monitored in these patients.
Patients with malabsorption may not adequately absorb vitamin D
3.
Excipients
This medicinal product contains lactose and sucrose. Patients with rare hereditary problems of fructose
intolerance, galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption or
sucrase-isomaltase insufficiency should not take this medicinal product.
Alendronate
If taken at the same time, it is likely that food and beverages (including mineral water), calcium
supplements, antacids, and some oral medicinal products will interfere with absorption of alendronate.
Therefore, patients must wait at least 30 minutes after taking alendronate before taking any other oral
medicinal product (see sections 4.2 and 5.2).
Since Non Steroidal Anti-Inflammatory Drug (NSAID) use is associated with gastrointestinal
irritation, caution should be used during concomitant use with alendronate.
Colecalciferol
Olestra, mineral oils, orlistat, and bile acid sequestrants (e.g. cholestyramine, colestipol) may impair
the absorption of vitamin D. Anticonvulsants, cimetidine and thiazides may increase the catabolism of
vitamin D. Additional vitamin D supplements may be considered on an individual basis.
FOSAVANCE is only intended for use in postmenopausal women and therefore it should not be used
during pregnancy or in breast-feeding women.
Pregnancy
There are no adequate data from the use of FOSAVANCE in pregnant women. Animal studies with
alendronate do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal
development, or postnatal development. Alendronate given during pregnancy in rats caused dystocia
related to hypocalcaemia (see section 5.3). Studies in animals have shown hypercalcaemia and
reproductive toxicity with high doses of vitamin D (see section 5.3).
5
Breastfeeding
It is not known whether alendronate is excreted into human breast milk. Colecalciferol and some of its
active metabolites pass into breast milk.
Fertility
Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a
period of years. The amount of bisphosphonate incorporated into adult bone, and hence, the amount
available for release back into the systemic circulation, is directly related to the dose and duration of
bisphosphonate use (see section 5.2). There are no data on fetal risk in humans. However, there is a
theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a
course of bisphosphonate therapy. The impact of variables such as time between cessation of
bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of
administration (intravenous versus oral) on the risk has not been studied.
Certain adverse reactions that have been reported with FOSAVANCE may affect some patients' ability
to drive or operate machinery. Individual responses to FOSAVANCE may vary (see section 4.8).
The most commonly reported adverse reactions are upper gastrointestinal adverse reactions including
abdominal pain, dyspepsia, oesophageal ulcer, dysphagia, abdominal distension and acid regurgitation
(≥ 1/100 to < 1/10).
The following adverse reactions have been reported during clinical studies and/or post-marketing use
with alendronate.
No additional adverse reactions have been identified for FOSAVANCE.
Frequencies are defined as:
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)
Rare:
symptomatic hypocalcaemia, often in association with
predisposing conditions. (see section 4.4)
Nervous system disorders:
Common:
headache
Eye disorders:
Rare:
uveitis, scleritis, episcleritis
Gastrointestinal
disorders:
Common:
abdominal pain, dyspepsia, constipation, diarrhoea, flatulence,
oesophageal ulcer*, dysphagia*, abdominal distension, acid regurgitation
Uncommon:
nausea, vomiting, gastritis, oesophagitis*,oesophageal
erosions*, melena
Rare:
oesophageal stricture*, oropharyngeal ulceration*, upper
gastrointestinal PUBs (perforation, ulcers, bleeding)(see section 4.4).
*See sections 4.2 and 4.4
Skin and subcutaneous
tissue disorders:
Uncommon:
rash, pruritus, erythema
Rare:
rash with photosensitivity
Very rare:
severe skin reactions including Stevens-Johnson syndrome
and toxic epidermal necrolysis
Musculoskeletal and
connective tissue
disorders:
Common:
musculoskeletal (bone, muscle or joint) pain
Rare:
severe musculoskeletal (bone, muscle or joint) pain (see
section 4.4)
General disorders and
administration site
conditions:
Rare:
transient symptoms as in an acute-phase response (myalgia,
malaise and rarely, fever), typically in association with initiation of
treatment.
6
Immune system disorders:
Rare:
hypersensitivity reactions including urticaria and angioedema
Metabolism and nutrition
disorders:
During post-marketing experience the following reactions have been reported (frequency not known):
Nervous system disorders:
dizziness, dysgeusia
Ear and labyrinth
disorders:
Vertigo
Skin and subcutaneous
tissue disorders:
Alopecia
Musculoskeletal,
connective tissue and
bone disorders:
Osteonecrosis of the jaw has been reported in patients treated by
bisphosphonates. The majority of the reports refer to cancer patients, but
such cases have also been reported in patients treated for osteoporosis.
Osteonecrosis of the jaw is generally associated with tooth extraction and
/ or local infection (including osteomyelitis). Diagnosis of cancer,
chemotherapy, radiotherapy, corticosteroids and poor oral hygiene are
also deemed as risk factors (see section 4.4); joint swelling; stress
fractures of the proximal femoral shaft (see section 4.4)
General disorders and
administration site
conditions:
asthenia, peripheral oedema
Alendronate
Hypocalcaemia, hypophosphataemia and upper gastrointestinal adverse reactions, such as upset
stomach, heartburn, oesophagitis, gastritis, or ulcer, may result from oral overdose.
No specific information is available on the treatment of overdose with alendronate. In case of overdose
with FOSAVANCE, milk or antacids should be given to bind alendronate. Owing to the risk of
oesophageal irritation, vomiting should not be induced and the patient should remain fully upright.
Colecalciferol
Vitamin D toxicity has not been documented during chronic therapy in generally healthy adults at a
dose less than 10,000 IU/day. In a clinical study of healthy adults a 4,000 IU daily dose of vitamin D
3
for up to five months was not associated with hypercalciuria or hypercalcaemia.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group:
Drugs for treatment of bone diseases,
Bisphosphonates, combinations,
ATC code: M05BB03
FOSAVANCE is a combination tablet containing the two active substances alendronate sodium
trihydrate and colecalciferol (vitamin D
3
).
Alendronate
Alendronate sodium is a bisphosphonate that inhibits osteoclastic bone resorption with no direct effect
on bone formation. Preclinical studies have shown preferential localisation of alendronate to sites of
active resorption. Activity of osteoclasts is inhibited, but recruitment or attachment of osteoclasts is
not affected. The bone formed during treatment with alendronate is of normal quality.
Colecalciferol (vitamin D
3
)
Vitamin D
3
is produced in the skin by conversion of 7-dehydrocholesterol to vitamin D
3
by ultraviolet
light. In the absence of adequate sunlight exposure, vitamin D
3
is an essential dietary nutrient.
Vitamin D
3
is converted to 25-hydroxyvitamin D
3
in the liver, and stored until needed. Conversion to
the active calcium-mobilizing hormone 1,25-dihydroxyvitamin D
3
(calcitriol) in the kidney is tightly
regulated. The principal action of 1,25-dihydroxyvitamin D
3
is to increase intestinal absorption of both
7
calcium and phosphate as well as regulate serum calcium, renal calcium and phosphate excretion, bone
formation and bone resorption.
Vitamin D
3
is required for normal bone formation. Vitamin D insufficiency develops when both
sunlight exposure and dietary intake are inadequate. Insufficiency is associated with negative calcium
balance, bone loss, and increased risk of skeletal fracture. In severe cases, deficiency results in
secondary hyperparathyroidism, hypophosphataemia, proximal muscle weakness and osteomalacia,
further increasing the risk of falls and fractures in osteoporotic individuals. Supplemental vitamin D
reduces these risks and their consequences.
Osteoporosis is defined as bone mineral density (BMD) of the spine or hip 2.5 standard deviations
(SD) below the mean value of a normal young population or as a previous fragility fracture,
irrespective of BMD.
FOSAVANCE studies
The effect of FOSAVANCE (alendronate 70 mg/vitamin D
3
2800 IU) on vitamin D status was
demonstrated in a 15-week, multinational study that enrolled 682 osteoporotic post-menopausal
women (serum 25-hydroxyvitamin D at baseline: mean, 56 nmol/l [22.3 ng/ml]; range,
22.5-225 nmol/l [9-90 ng/ml]). Patients received the lower strength (70 mg/2800 IU) of
FOSAVANCE (n=350) or FOSAMAX (alendronate) 70 mg (n=332) once a week; additional
vitamin D supplements were prohibited. After 15 weeks of treatment, the mean serum
25-hydroxyvitamin D levels were significantly higher (26 %) in the FOSAVANCE (70 mg/2800 IU)
group (56 nmol/l [23 ng/ml]) than in the alendronate-only group (46 nmol/l [18.2 ng/ml]). The
percentage of patients with vitamin D insufficiency (serum 25-hydroxyvitamin D < 37.5 nmol/l
[< 15 ng/ml]) was significantly reduced by 62.5 % with FOSAVANCE (70 mg/2800 IU) vs.
alendronate-only (12 % vs. 32 %, respectively), through week 15. The percentage of patients with
vitamin D deficiency (serum 25-hydroxyvitamin D < 22.5 nmol/l [< 9 ng/ml]) was significantly
reduced by 92 % with FOSAVANCE (70 mg/2800 IU) vs. alendronate-only (1 % vs 13 %,
respectively). In this study, mean 25-hydroxyvitamin D levels in patients with vitamin D insufficiency
at baseline (25-hydroxyvitamin D, 22.5 to 37.5 nmol/l [9 to < 15 ng/ml]) increased from 30 nmol/l
(12.1 ng/ml) to 40 nmol/l (15.9 ng/ml) at week 15 in the FOSAVANCE (70 mg/2800 IU) group
(n=75) and decreased from 30 nmol/l (12.0 ng/ml) at baseline to 26 nmol/l (10.4 ng/ml) at week 15 in
the alendronate-only group (n=70). There were no differences in mean serum calcium, phosphate, or
24-hour urine calcium between treatment groups.
Alendronate studies
The therapeutic equivalence of alendronate once weekly 70 mg (n=519) and alendronate 10 mg daily
(n=370) was demonstrated in a one-year multicentre study of post-menopausal women with
osteoporosis. The mean increases from baseline in lumbar spine BMD at one year were 5.1 % (95 %
CI: 4.8, 5.4 %) in the 70 mg once-weekly group and 5.4 % (95 % CI: 5.0, 5.8 %) in the 10 mg daily
group. The mean BMD increases were 2.3 % and 2.9 % at the femoral neck and 2.9 % and 3.1 % at the
total hip in the 70 mg once weekly and 10 mg daily groups, respectively. The two treatment groups
were also similar with regard to BMD increases at other skeletal sites.
The effects of alendronate on bone mass and fracture incidence in post-menopausal women were
examined in two initial efficacy studies of identical design (n=994) as well as in the Fracture
Intervention Trial (FIT: n=6,459).
In the initial efficacy studies, the mean BMD increases with alendronate 10 mg/day relative to placebo
at three years were 8.8 %, 5.9 % and 7.8 % at the spine, femoral neck and trochanter, respectively.
Total body BMD also increased significantly. There was a 48 % reduction (alendronate 3.2 % vs
placebo 6.2 %) in the proportion of patients treated with alendronate experiencing one or more
vertebral fractures relative to those treated with placebo. In the two-year extension of these studies
BMD at the spine and trochanter continued to increase and BMD at the femoral neck and total body
were maintained.
8
FIT consisted of two placebo-controlled studies using alendronate daily (5 mg daily for two years and
10 mg daily for either one or two additional years):
•
FIT 1: A three-year study of 2,027 patients who had at least one baseline vertebral
(compression) fracture. In this study alendronate daily reduced the incidence of ≥ 1 new
vertebral fracture by 47 % (alendronate 7.9 % vs. placebo 15.0 %). In addition, a statistically
significant reduction was found in the incidence of hip fractures (1.1 % vs. 2.2 %, a reduction of
51 %).
•
FIT 2: A four-year study of 4,432 patients with low bone mass but without a baseline vertebral
fracture. In this study, a significant difference was observed in the analysis of the subgroup of
osteoporotic women (37 % of the global population who correspond with the above definition of
osteoporosis) in the incidence of hip fractures (alendronate 1.0 % vs. placebo 2.2 %, a reduction
of 56 %) and in the incidence of ≥ 1 vertebral fracture (2.9 % vs. 5.8 %, a reduction of 50 %).
Laboratory test findings
In clinical studies, asymptomatic, mild and transient decreases in serum calcium and phosphate were
observed in approximately 18 % and 10 %, respectively, of patients taking alendronate 10 mg/day
versus approximately 12 % and 3 % of those taking placebo. However, the incidences of decreases in
serum calcium to < 8.0 mg/dl (2.0 mmol/l) and serum phosphate to ≤ 2.0 mg/dl (0.65 mmol/l) were
similar in both treatment groups.
5.2. Pharmacokineticproperties
Alendronate
Absorption
Relative to an intravenous reference dose, the oral mean bioavailability of alendronate in women was
0.64 % for doses ranging from 5 to 70 mg when administered after an overnight fast and two hours
before a standardised breakfast. Bioavailability was decreased similarly to an estimated 0.46 % and
0.39 % when alendronate was administered one hour or half an hour before a standardised breakfast.
In osteoporosis studies, alendronate was effective when administered at least 30 minutes before the
first food or beverage of the day.
The alendronate component in the FOSAVANCE (70 mg/2800 IU) combination tablet is
bioequivalent to the alendronate 70 mg tablet.
Bioavailability was negligible whether alendronate was administered with, or up to two hours after, a
standardised breakfast. Concomitant administration of alendronate with coffee or orange juice reduced
bioavailability by approximately 60 %.
In healthy subjects, oral prednisone (20 mg three times daily for five days) did not produce a clinically
meaningful change in oral bioavailability of alendronate (a mean increase ranging from 20 % to 44 %).
Distribution
Studies in rats show that alendronate transiently distributes to soft tissues following 1 mg/kg
intravenous administration but is then rapidly redistributed to bone or excreted in the urine. The mean
steady-state volume of distribution, exclusive of bone, is at least 28 litres in humans. Concentrations of
alendronate in plasma following therapeutic oral doses are too low for analytical detection (< 5 ng/ml).
Protein binding in human plasma is approximately 78 %.
Biotransformation
There is no evidence that alendronate is metabolised in animals or humans.
9
Elimination
Following a single intravenous dose of [
14
C]alendronate, approximately 50 % of the radioactivity was
excreted in the urine within 72 hours and little or no radioactivity was recovered in the faeces.
Following a single 10 mg intravenous dose, the renal clearance of alendronate was 71 ml/min, and
systemic clearance did not exceed 200 ml/min. Plasma concentrations fell by more than 95 % within
six hours following intravenous administration. The terminal half-life in humans is estimated to
exceed ten years, reflecting release of alendronate from the skeleton. Alendronate is not excreted
through the acidic or basic transport systems of the kidney in rats, and thus it is not anticipated to
interfere with the excretion of other medicinal products by those systems in humans.
Colecalciferol
Absorption
In healthy adult subjects (males and females), following administration of FOSAVANCE after an
overnight fast and two hours before a meal, the mean area under the serum-concentration-time curve
(AUC
0-120 hrs
) for vitamin D
3
(unadjusted for endogenous vitamin D
3
levels) was 296.4 ng•hr/ml. The
mean maximal serum concentration (C
max
) of vitamin D
3
was 5.9 ng/ml, and the median time to
maximal serum concentration (T
max
) was 12 hours. The bioavailability of the 2800 IU vitamin D
3
in
FOSAVANCE is similar to 2800 IU vitamin D
3
administered alone.
Distribution
Following absorption, vitamin D
3
enters the blood as part of chylomicrons. Vitamin D
3
is rapidly
distributed mostly to the liver where it undergoes metabolism to 25-hydroxyvitamin D
3
, the major
storage form. Lesser amounts are distributed to adipose and muscle tissue and stored as vitamin D
3
at
these sites for later release into the circulation. Circulating vitamin D
3
is bound to vitamin D-binding
protein.
Biotransformation
Vitamin D
3
is rapidly metabolized by hydroxylation in the liver to 25-hydroxyvitamin D
3
, and
subsequently metabolized in the kidney to 1,25-dihydroxyvitamin D
3
, which represents the
biologically active form. Further hydroxylation occurs prior to elimination. A small percentage of
vitamin D
3
undergoes glucuronidation prior to elimination.
Elimination
When radioactive vitamin D
3
was administered to healthy subjects, the mean urinary excretion of
radioactivity after 48 hours was 2.4 %, and the mean faecal excretion of radioactivity after 4 days was
4.9 %. In both cases, the excreted radioactivity was almost exclusively as metabolites of the parent.
The mean half-life of vitamin D
3
in the serum following an oral dose of FOSAVANCE
(70 mg/2800 IU) is approximately 24 hours.
Characteristics in patients
Preclinical studies show that alendronate that is not deposited in bone is rapidly excreted in the urine.
No evidence of saturation of bone uptake was found after chronic dosing with cumulative intravenous
doses up to 35 mg/kg in animals. Although no clinical information is available, it is likely that, as in
animals, elimination of alendronate via the kidney will be reduced in patients with impaired renal
function. Therefore, somewhat greater accumulation of alendronate in bone might be expected in
patients with impaired renal function (see section 4.2).
5.3 Preclinical safety data
Non-clinical studies with the combination of alendronate and colecalciferol have not been conducted.
Alendronate
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Studies in rats have
shown that treatment with alendronate during pregnancy was associated with dystocia in dams during
10
parturition which was related to hypocalcaemia. In studies, rats given high doses showed an increased
incidence of incomplete foetal ossification. The relevance to humans is unknown.
Colecalciferol
At doses far higher than the human therapeutic range, reproductive toxicity has been observed in
animal studies.
6.
6.1 List of excipients
Microcrystalline cellulose (E460)
Lactose anhydrous
Medium chain triglycerides
Gelatin
Croscarmellose sodium
Sucrose
Silica, colloidal anhydrous
Magnesium stearate (E572)
Butyl hydroxytoluene (E321)
Modified starch (maize)
Sodium aluminium silicate (E554)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
18 months.
6.4 Special precautions for storage
Store in the original blister in order to protect from moisture and light.
6.5 Nature and contents of container
Wallet with sealed aluminium/aluminium blisters, in cartons containing 2 (1 wallet x 2 tablets), 4
(1 wallet x 4 tablets), 6 (3 wallets x 2 tablets), 12 (3 wallets x 4 tablets) or 40 (10 wallets x 4tablets)
tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
11
8.
EU/1/05/310/001 – 2 tablets
EU/1/05/310/002 – 4 tablets
EU/1/05/310/003 – 6 tablets
EU/1/05/310/004 – 12 tablets
EU/1/05/310/005 – 40 tablets
9.
24 August 2005
Detailed information on this medicine is available on the website of the European Medicines Agency
12
1.
FOSAVANCE 70 mg/5600 IU tablets
2.
Each tablet contains 70 mg alendronic acid as alendronate sodium trihydrate and 140 micrograms
(5600 IU) colecalciferol (vitamin D
3
).
Excipients:
Each tablet contains 63 mg lactose anhydrous and 16 mg sucrose.
For a full list of excipients, see section 6.1.
3.
Tablet
Modified rectangle-shaped, white to off-white tablets, marked with an outline of a bone image on one
side, and '270' on the other.
4.
FOSAVANCE is indicated for the treatment of postmenopausal osteoporosis in patients who are not
receiving vitamin D supplementation and are at risk of vitamin D insufficiency.
FOSAVANCE reduces the risk of vertebral and hip fractures.
Posology
The recommended dose is one FOSAVANCE tablet once weekly.
Patients should be instructed that if they miss a dose of FOSAVANCE they should take one tablet on
the morning after they remember. They should not take two tablets on the same day but should return
to taking one tablet once a week, as originally scheduled on their chosen day.
Due to the nature of the disease process in osteoporosis, FOSAVANCE is intended for long-term use.
Patients should receive supplemental calcium if intake from diet is inadequate (see section 4.4). The
equivalence of intake of 5600 IU of vitamin D
3
weekly in FOSAVANCE to daily dosing of vitamin D
800 IU has not been studied.
Elderly population:
In clinical studies there was no age-related difference in the efficacy or safety profiles of alendronate.
Therefore no dose adjustment is necessary for the elderly.
Renal impairment:
FOSAVANCE is not recommended for patients with renal impairment where GFR is less than
35 ml/min, due to lack of experience. No dose adjustment is necessary for patients with a glomerular
filtration rate (GFR) greater than 35 ml/min.
13
Paediatric population:
The safety and efficacy of FOSAVANCE in children less than 18 years of age has not been
established. FOSAVANCE should not be used in children less than 18 years of age because no data
are available.
Method of administration
Oral use.
To permit adequate absorption of alendronate:
FOSAVANCE must be taken with water only (not mineral water) at least 30 minutes before the first
food, beverage, or medicinal product (including antacids, calcium supplements and vitamins) of the
day. Other beverages (including mineral water), food and some medicinal products are likely to reduce
the absorption of alendronate (see section 4.5).
The following instructions should be followed exactly in order to minimize the risk of oesophageal
irritation and related adverse reactions (see section 4.4):
•
FOSAVANCE should only be swallowed after getting up for the day with a full glass of water
(not less than 200 ml or 7 fl.oz.).
•
Patients should only swallow FOSAVANCE whole. Patients should not crush or chew the tablet
or allow the tablet to dissolve in their mouths because of a potential for oropharyngeal
ulceration.
•
Patients should not lie down until after their first food of the day.
•
Patients should not lie down for at least 30 minutes after taking FOSAVANCE.
•
FOSAVANCE should not be taken at bedtime or before arising for the day.
•
Hypersensitivity to the active substances or to any of the excipients.
•
Abnormalities of the oesophagus and other factors which delay oesophageal emptying such as
stricture or achalasia.
•
Inability to stand or sit upright for at least 30 minutes.
•
Hypocalcaemia.
Alendronate
Upper gastrointestinal adverse reactions
Alendronate can cause local irritation of the upper gastrointestinal mucosa. Because there is a potential
for worsening of the underlying disease, caution should be used when alendronate is given to patients
with active upper gastrointestinal problems, such as dysphagia, oesophageal disease, gastritis,
duodenitis, ulcers, or with a recent history (within the previous year) of major gastrointestinal disease
such as peptic ulcer, or active gastrointestinal bleeding, or surgery of the upper gastrointestinal tract
other than pyloroplasty (see section 4.3). In patients with known Barrett's oesophagus, prescribers
should consider the benefits and potential risks of alendronate on an individual patient basis.
14
Oesophageal reactions (sometimes severe and requiring hospitalisation), such as oesophagitis,
oesophageal ulcers and oesophageal erosions, rarely followed by oesophageal stricture, have been
reported in patients receiving alendronate. Physicians should therefore be alert to any signs or
symptoms signalling a possible oesophageal reaction and patients should be instructed to discontinue
alendronate and seek medical attention if they develop symptoms of oesophageal irritation such as
dysphagia, pain on swallowing or retrosternal pain or new or worsening heartburn (see section 4.8).
The risk of severe oesophageal adverse reactions appears to be greater in patients who fail to take
alendronate properly and/or who continue to take alendronate after developing symptoms suggestive
of oesophageal irritation. It is very important that the full dosing instructions are provided to, and are
understood by the patient (see section 4.2). Patients should be informed that failure to follow these
instructions may increase their risk of oesophageal problems.
While no increased risk was observed in extensive clinical trials with alendronate, there have been rare
(post-marketing) reports of gastric and duodenal ulcers, some of which were severe and with
complications (see section 4.8).
Osteonecrosis of the jaw
Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including
osteomyelitis) has been reported in patients with cancer who are receiving treatment regimens
including primarily intravenously administered bisphosphonates. Many of these patients were also
receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in
patients with osteoporosis receiving oral bisphosphonates.
A dental examination with appropriate preventive dentistry should be considered prior to treatment
with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy,
radiotherapy, corticosteroids, poor oral hygiene, periodontal disease).
While on treatment, these patients should avoid invasive dental procedures if possible. For patients
who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate
the condition. For patients requiring dental procedures, there are no data available to suggest whether
discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw.
Clinical judgement of the treating physician should guide the management plan of each patient based
on individual benefit/risk assessment.
Musculoskeletal pain
Bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. In
post-marketing experience, these symptoms have rarely been severe and/or incapacitating (see
section 4.8). The time to onset of symptoms varied from one day to several months after starting
treatment. Most patients had relief of symptoms after stopping treatment. A subset had recurrence of
symptoms when rechallenged with the same medicinal product or another bisphosphonate.
Stress fractures
Stress fractures (also known as insufficiency fractures) of the proximal femoral shaft have been
reported in patients treated long-term with alendronic acid (time to onset in the majority of cases
ranged from 18 months to 10 years). The fractures occurred after minimal or no trauma and some
patients experienced thigh pain, often associated with imaging features of stress fractures, weeks to
months before presenting with a completed femoral fracture. Fractures were often bilateral; therefore
the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a
femoral shaft fracture. Poor healing of these fractures was also reported. Discontinuation of
bisphosphonate therapy in patients with stress fracture is advisable pending evaluation of the patient,
based on an individual benefit risk assessment.
Renal insufficiency
FOSAVANCE is not recommended for patients with renal impairment where GFR is less than
35 ml/min (see section 4.2).
15
Bone and mineral metabolism
Causes of osteoporosis other than oestrogen deficiency and ageing should be considered.
Hypocalcaemia must be corrected before initiating therapy with FOSAVANCE (see section 4.3).
Other disorders affecting mineral metabolism (such as vitamin D deficiency
and hypoparathyroidism)
should also be effectively treated before starting FOSAVANCE. The content of vitamin D in
FOSAVANCE is not suitable for correction of vitamin D deficiency. In patients with these conditions,
serum calcium and symptoms of hypocalcaemia should be monitored during therapy with
FOSAVANCE.
Due to the positive effects of alendronate in increasing bone mineral, decreases in serum calcium and
phosphate may occur especially in patients taking glucocorticoids in whom calcium absorption may be
decreased. These are usually small and asymptomatic. However, there have been rare reports of
symptomatic hypocalcaemia, which have occasionally been severe and often occurred in patients with
predisposing conditions (e.g. hypoparathyroidism, vitamin D deficiency and calcium malabsorption)
(see section 4.8).
Colecalciferol
Vitamin D
3
may increase the magnitude of hypercalcaemia and/or hypercalciuria when administered to
patients with disease associated with unregulated overproduction of calcitriol (e.g. leukaemia,
lymphoma, sarcoidosis). Urine and serum calcium should be monitored in these patients.
Patients with malabsorption may not adequately absorb vitamin D
3.
Excipients
This medicinal product contains lactose and sucrose. Patients with rare hereditary problems of fructose
intolerance, galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption or
sucrase-isomaltase insufficiency should not take this medicinal product.
Alendronate
If taken at the same time, it is likely that food and beverages (including mineral water), calcium
supplements, antacids, and some oral medicinal products will interfere with absorption of alendronate.
Therefore, patients must wait at least 30 minutes after taking alendronate before taking any other oral
medicinal product (see sections 4.2 and 5.2).
Since Non Steroidal Anti-Inflammatory Drug (NSAID) use is associated with gastrointestinal
irritation, caution should be used during concomitant use with alendronate.
Colecalciferol
Olestra, mineral oils, orlistat, and bile acid sequestrants (e.g. cholestyramine, colestipol) may impair
the absorption of vitamin D. Anticonvulsants, cimetidine and thiazides may increase the catabolism of
vitamin D. Additional vitamin D supplements may be considered on an individual basis.
FOSAVANCE is only intended for use in postmenopausal women and therefore it should not be used
during pregnancy or in breast-feeding women.
Pregnancy
There are no adequate data from the use of FOSAVANCE in pregnant women. Animal studies with
alendronate do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal
development, or postnatal development. Alendronate given during pregnancy in rats caused dystocia
related to hypocalcaemia (see section 5.3). Studies in animals have shown hypercalcaemia and
reproductive toxicity with high doses of vitamin D (see section 5.3).
16
Breastfeeding
It is not known whether alendronate is excreted into human breast milk. Colecalciferol and some of its
active metabolites pass into breast milk.
Fertility
Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a
period of years. The amount of bisphosphonate incorporated into adult bone, and hence, the amount
available for release back into the systemic circulation, is directly related to the dose and duration of
bisphosphonate use (see section 5.2). There are no data on fetal risk in humans. However, there is a
theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a
course of bisphosphonate therapy. The impact of variables such as time between cessation of
bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of
administration (intravenous versus oral) on the risk has not been studied.
Certain adverse reactions that have been reported with FOSAVANCE may affect some patients' ability
to drive or operate machinery. Individual responses to FOSAVANCE may vary (see section 4.8).
The most commonly reported adverse reactions are upper gastrointestinal adverse reactions including
abdominal pain, dyspepsia, oesophageal ulcer, dysphagia, abdominal distension and acid regurgitation
(≥ 1/100 to < 1/10).
The following adverse reactions have been reported during clinical studies and/or post-marketing use
with alendronate.
No additional adverse reactions have been identified for FOSAVANCE.
Frequencies are defined as:
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)
Immune system
disorders:
Rare:
hypersensitivity reactions including urticaria and angioedema
Metabolism and nutrition
disorders:
Rare:
symptomatic hypocalcaemia, often in association with
predisposing conditions. (see section 4.4)
Nervous system
disorders:
Common:
headache
Eye disorders:
Rare:
uveitis, scleritis, episcleritis
Gastrointestinal
disorders:
Common:
abdominal pain, dyspepsia, constipation, diarrhoea, flatulence,
oesophageal ulcer*, dysphagia*, abdominal distension, acid regurgitation
Uncommon:
nausea, vomiting, gastritis, oesophagitis*,oesophageal
erosions*, melena
Rare:
oesophageal stricture*, oropharyngeal ulceration*, upper
gastrointestinal PUBs (perforation, ulcers, bleeding)(see section 4.4).
*See sections 4.2 and 4.4
Skin and subcutaneous
tissue disorders:
Uncommon:
rash, pruritus, erythema
rare:
rash with photosensitivity
Very rare:
severe skin reactions including Stevens-Johnson syndrome
and toxic epidermal necrolysis
Musculoskeletal and
connective tissue
disorders:
Common:
musculoskeletal (bone, muscle or joint) pain
Rare:
severe musculoskeletal (bone, muscle or joint) pain (see
section 4.4)
17
General disorders and
administration site
conditions:
Rare:
transient symptoms as in an acute-phase response (myalgia,
malaise and rarely, fever), typically in association with initiation of
treatment.
During post-marketing experience the following reactions have been reported (frequency not known):
Nervous system
disorders:
dizziness, dysgeusia
Ear and labyrinth
disorders:
Vertigo
Skin and subcutaneous
tissue disorders:
Alopecia
Musculoskeletal,
connective tissue and
bone disorders:
Osteonecrosis of the jaw has been reported in patients treated by
bisphosphonates. The majority of the reports refer to cancer patients, but
such cases have also been reported in patients treated for osteoporosis.
Osteonecrosis of the jaw is generally associated with tooth extraction and /
or local infection (including osteomyelitis). Diagnosis of cancer,
chemotherapy, radiotherapy, corticosteroids and poor oral hygiene are also
deemed as risk factors (see section 4.4); joint swelling; stress fractures of
the proximal femoral shaft (see section 4.4)
General disorders and
administration site
conditions:
asthenia, peripheral oedema
Alendronate
Hypocalcaemia, hypophosphataemia and upper gastrointestinal adverse reactions, such as upset
stomach, heartburn, oesophagitis, gastritis, or ulcer, may result from oral overdose.
No specific information is available on the treatment of overdose with alendronate. In case of overdose
with FOSAVANCE, milk or antacids should be given to bind alendronate. Owing to the risk of
oesophageal irritation, vomiting should not be induced and the patient should remain fully upright.
Colecalciferol
Vitamin D toxicity has not been documented during chronic therapy in generally healthy adults at a
dose less than 10,000 IU/day. In a clinical study of healthy adults a 4,000 IU daily dose of vitamin D
3
for up to five months was not associated with hypercalciuria or hypercalcaemia.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group:
Drugs for treatment of bone diseases,
Bisphosphonates, combinations,
ATC code: M05BB03
FOSAVANCE is a combination tablet containing the two active substances alendronate sodium
trihydrate and colecalciferol (vitamin D
3
).
Alendronate
Alendronate sodium is a bisphosphonate that inhibits osteoclastic bone resorption with no direct effect
on bone formation. Preclinical studies have shown preferential localisation of alendronate to sites of
active resorption. Activity of osteoclasts is inhibited, but recruitment or attachment of osteoclasts is
not affected. The bone formed during treatment with alendronate is of normal quality.
18
Colecalciferol (vitamin D
3
)
Vitamin D
3
is produced in the skin by conversion of 7-dehydrocholesterol to vitamin D
3
by ultraviolet
light. In the absence of adequate sunlight exposure, vitamin D
3
is an essential dietary nutrient.
Vitamin D
3
is converted to 25-hydroxyvitamin D
3
in the liver, and stored until needed. Conversion to
the active calcium-mobilizing hormone 1,25-dihydroxyvitamin D
3
(calcitriol) in the kidney is tightly
regulated. The principal action of 1,25 dihydroxyvitamin D
3
is to increase intestinal absorption of both
calcium and phosphate as well as regulate serum calcium, renal calcium and phosphate excretion, bone
formation and bone resorption.
Vitamin D
3
is required for normal bone formation. Vitamin D insufficiency develops when both
sunlight exposure and dietary intake are inadequate. Insufficiency is associated with negative calcium
balance, bone loss, and increased risk of skeletal fracture. In severe cases, deficiency results in
secondary hyperparathyroidism, hypophosphataemia, proximal muscle weakness and osteomalacia,
further increasing the risk of falls and fractures in osteoporotic individuals. Supplemental vitamin D
reduces these risks and their consequences.
Osteoporosis is defined as bone mineral density (BMD) of the spine or hip 2.5 standard deviations
(SD) below the mean value of a normal young population or as a previous fragility fracture,
irrespective of BMD.
FOSAVANCE studies
The effect of the lower dose of FOSAVANCE (alendronate 70 mg/vitamin D
3
2800 IU) on vitamin D
status was demonstrated in a 15-week, multinational study that enrolled 682 osteoporotic
post-menopausal women (serum 25-hydroxyvitamin D at baseline: mean, 56 nmol/l [22.3 ng/ml];
range, 22.5-225 nmol/l [9-90 ng/ml]). Patients received the lower strength (70 mg/2800 IU) of
FOSAVANCE (n=350) or FOSAMAX (alendronate) 70 mg (n=332) once a week; additional
vitamin D supplements were prohibited. After 15 weeks of treatment, the mean serum
25-hydroxyvitamin D levels were significantly higher (26 %) in the FOSAVANCE (70 mg/2800 IU)
group (56 nmol/l [23 ng/ml]) than in the alendronate-only group (46 nmol/l [18.2 ng/ml]). The
percentage of patients with vitamin D insufficiency (serum 25-hydroxyvitamin D < 37.5 nmol/l
[< 15 ng/ml]) was significantly reduced by 62.5 % with FOSAVANCE (70 mg/2800 IU) vs.
alendronate-only (12 % vs. 32 %, respectively), through week 15. The percentage of patients with
vitamin D deficiency (serum 25-hydroxyvitamin D < 22.5 nmol/l [< 9 ng/ml]) was significantly
reduced by 92 % with FOSAVANCE (70 mg/2800 IU) vs. alendronate-only (1 % vs 13 %,
respectively). In this study, mean 25-hydroxyvitamin D levels in patients with vitamin D insufficiency
at baseline (25-hydroxyvitamin D, 22.5 to 37.5 nmol/l [9 to < 15 ng/ml]) increased from 30 nmol/l
(12.1 ng/ml) to 40 nmol/l (15.9 ng/ml) at week 15 in the FOSAVANCE (70 mg/2800 IU) group
(n=75) and decreased from 30 nmol/l (12.0 ng/ml) at baseline to 26 nmol/l (10.4 ng/ml) at week 15 in
the alendronate-only group (n=70). There were no differences in mean serum calcium, phosphate, or
24-hour urine calcium between treatment groups.
The effect of the lower dose of FOSAVANCE (alendronate 70 mg/vitamin D
3
2800 IU) plus an
additional 2800 IU Vitamin D
3
for a total of 5600 IU (the amount of vitamin D
3
in the higher dose of
FOSAVANCE) once weekly was demonstrated in a 24-week, extension study that enrolled
619 osteoporotic post-menopausal women. Patients in the Vitamin D
3
2800 group received
FOSAVANCE (70 mg/2800 IU) (n=299) and patients in the Vitamin D
3
5600 group received
FOSAVANCE (70 mg/2800 IU) plus an additional 2800 IU vitamin D
3
(n=309) once a week;
additional vitamin D supplements were allowed. After 24-weeks of treatment, the mean serum
25-hydroxyvitamin D levels were significantly higher in the Vitamin D
3
5600 group (69 nmol/l
[27.6 ng/ml]) than in the Vitamin D
3
2800 group (64 nmol/l [25.5 ng/ml]). The percentage of patients
with vitamin D insufficiency was 5.4 % in the Vitamin D
3
2800 group vs. 3.2 % in the Vitamin D
3
5600 group through the 24-week extension. The percentage of patients with vitamin D deficiency was
0.3 % in the Vitamin D
3
2800 group vs. zero in the Vitamin D
3
5600 group. There were no differences
in mean serum calcium, phosphate, or 24-hour urine calcium between treatment groups. The
percentage of patients with hypercalciuria at the end of the 24-week extension was not statistically
different between treatment groups.
19
Alendronate studies
The therapeutic equivalence of alendronate once weekly 70 mg (n=519) and alendronate 10 mg daily
(n=370) was demonstrated in a one-year multicentre study of post-menopausal women with
osteoporosis. The mean increases from baseline in lumbar spine BMD at one year were 5.1 % (95 %
CI: 4.8, 5.4 %) in the 70 mg once-weekly group and 5.4 % (95 % CI: 5.0, 5.8 %) in the 10 mg daily
group. The mean BMD increases were 2.3 % and 2.9 % at the femoral neck and 2.9 % and 3.1 % at the
total hip in the 70 mg once weekly and 10 mg daily groups, respectively. The two treatment groups
were also similar with regard to BMD increases at other skeletal sites.
The effects of alendronate on bone mass and fracture incidence in post-menopausal women were
examined in two initial efficacy studies of identical design (n=994) as well as in the Fracture
Intervention Trial (FIT: n=6,459).
In the initial efficacy studies, the mean BMD increases with alendronate 10 mg/day relative to placebo
at three years were 8.8 %, 5.9 % and 7.8 % at the spine, femoral neck and trochanter, respectively.
Total body BMD also increased significantly. There was a 48 % reduction (alendronate 3.2 % vs
placebo 6.2 %) in the proportion of patients treated with alendronate experiencing one or more
vertebral fractures relative to those treated with placebo. In the two-year extension of these studies
BMD at the spine and trochanter continued to increase and BMD at the femoral neck and total body
were maintained.
FIT consisted of two placebo-controlled studies using alendronate daily (5 mg daily for two years and
10 mg daily for either one or two additional years):
•
FIT 1: A three-year study of 2,027 patients who had at least one baseline vertebral
(compression) fracture. In this study alendronate daily reduced the incidence of ≥ 1 new
vertebral fracture by 47 % (alendronate 7.9 % vs. placebo 15.0 %). In addition, a statistically
significant reduction was found in the incidence of hip fractures (1.1 % vs. 2.2 %, a reduction of
51 %).
•
FIT 2: A four year study of 4,432 patients with low bone mass but without a baseline vertebral
fracture. In this study, a significant difference was observed in the analysis of the subgroup of
osteoporotic women (37 % of the global population who correspond with the above definition of
osteoporosis) in the incidence of hip fractures (alendronate 1.0 % vs. placebo 2.2 %, a reduction
of 56 %) and in the incidence of ≥ 1 vertebral fracture (2.9 % vs. 5.8 %, a reduction of 50 %).
Laboratory test findings
In clinical studies, asymptomatic, mild and transient decreases in serum calcium and phosphate were
observed in approximately 18 % and 10 %, respectively, of patients taking alendronate 10 mg/day
versus approximately 12 % and 3 % of those taking placebo. However, the incidences of decreases in
serum calcium to < 8.0 mg/dl (2.0 mmol/l) and serum phosphate to ≤ 2.0 mg/dl (0.65 mmol/l) were
similar in both treatment groups.
5.2. Pharmacokineticproperties
Alendronate
Absorption
Relative to an intravenous reference dose, the oral mean bioavailability of alendronate in women was
0.64 % for doses ranging from 5 to 70 mg when administered after an overnight fast and two hours
before a standardised breakfast. Bioavailability was decreased similarly to an estimated 0.46 % and
0.39 % when alendronate was administered one hour or half an hour before a standardised breakfast.
In osteoporosis studies, alendronate was effective when administered at least 30 minutes before the
first food or beverage of the day.
The alendronate component in the FOSAVANCE (70 mg/5600 IU) combination tablet is
bioequivalent to the alendronate 70 mg tablet.
20
Bioavailability was negligible whether alendronate was administered with, or up to two hours after, a
standardised breakfast. Concomitant administration of alendronate with coffee or orange juice reduced
bioavailability by approximately 60 %.
In healthy subjects, oral prednisone (20 mg three times daily for five days) did not produce a clinically
meaningful change in oral bioavailability of alendronate (a mean increase ranging from 20 % to 44 %).
Distribution
Studies in rats show that alendronate transiently distributes to soft tissues following 1 mg/kg
intravenous administration but is then rapidly redistributed to bone or excreted in the urine. The mean
steady-state volume of distribution, exclusive of bone, is at least 28 litres in humans. Concentrations of
alendronate in plasma following therapeutic oral doses are too low for analytical detection (< 5 ng/ml).
Protein binding in human plasma is approximately 78 %.
Biotransformation
There is no evidence that alendronate is metabolised in animals or humans.
Elimination
Following a single intravenous dose of [
14
C]alendronate, approximately 50 % of the radioactivity was
excreted in the urine within 72 hours and little or no radioactivity was recovered in the faeces.
Following a single 10 mg intravenous dose, the renal clearance of alendronate was 71 ml/min, and
systemic clearance did not exceed 200 ml/min. Plasma concentrations fell by more than 95 % within
six hours following intravenous administration. The terminal half-life in humans is estimated to
exceed ten years, reflecting release of alendronate from the skeleton. Alendronate is not excreted
through the acidic or basic transport systems of the kidney in rats, and thus it is not anticipated to
interfere with the excretion of other medicinal products by those systems in humans.
Colecalciferol
Absorption
In healthy adult subjects (males and females), following administration of FOSAVANCE
70 mg/5600 IU after an overnight fast and two hours before a meal, the mean area under the serum-
concentration-time curve (AUC
0-80 hrs
) for vitamin D
3
(unadjusted for endogenous vitamin D
3
levels)
was 490.2 ng•hr/ml. The mean maximal serum concentration (C
max
) of vitamin D
3
was 12.2 ng/ml and
the median time to maximal serum concentration (T
max
) was 10.6 hours. The bioavailability of the
5600 IU vitamin D
3
in FOSAVANCE is similar to 5600 IU vitamin D
3
administered alone.
Distribution
Following absorption, vitamin D
3
enters the blood as part of chylomicrons. Vitamin D
3
is rapidly
distributed mostly to the liver where it undergoes metabolism to 25-hydroxyvitamin D
3
, the major
storage form. Lesser amounts are distributed to adipose and muscle tissue and stored as vitamin D
3
at
these sites for later release into the circulation. Circulating vitamin D
3
is bound to vitamin D-binding
protein.
Biotransformation
Vitamin D
3
is rapidly metabolized by hydroxylation in the liver to 25-hydroxyvitamin D
3
, and
subsequently metabolized in the kidney to 1,25-dihydroxyvitamin D
3
, which represents the
biologically active form. Further hydroxylation occurs prior to elimination. A small percentage of
vitamin D
3
undergoes glucuronidation prior to elimination.
Elimination
When radioactive vitamin D
3
was administered to healthy subjects, the mean urinary excretion of
radioactivity after 48 hours was 2.4 %, and the mean faecal excretion of radioactivity after 4 days was
4.9 %. In both cases, the excreted radioactivity was almost exclusively as metabolites of the parent.
The mean half-life of vitamin D
3
in the serum following an oral dose of FOSAVANCE
(70 mg/2800 IU) is approximately 24 hours.
21
Characteristics in patients
Preclinical studies show that alendronate that is not deposited in bone is rapidly excreted in the urine.
No evidence of saturation of bone uptake was found after chronic dosing with cumulative intravenous
doses up to 35 mg/kg in animals. Although no clinical information is available, it is likely that, as in
animals, elimination of alendronate via the kidney will be reduced in patients with impaired renal
function. Therefore, somewhat greater accumulation of alendronate in bone might be expected in
patients with impaired renal function (see section 4.2).
5.3 Preclinical safety data
Non-clinical studies with the combination of alendronate and colecalciferol have not been conducted.
Alendronate
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Studies in rats have
shown that treatment with alendronate during pregnancy was associated with dystocia in dams during
parturition which was related to hypocalcaemia. In studies, rats given high doses showed an increased
incidence of incomplete foetal ossification. The relevance to humans is unknown.
Colecalciferol
At doses far higher than the human therapeutic range, reproductive toxicity has been observed in
animal studies.
6.
6.1 List of excipients
Microcrystalline cellulose (E460)
Lactose anhydrous
Medium chain triglycerides
Gelatin
Croscarmellose sodium
Sucrose
Silica, colloidal anhydrous
Magnesium stearate (E572)
Butyl hydroxytoluene (E321)
Modified starch (maize)
Sodium aluminium silicate (E554)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
18 months.
6.4 Special precautions for storage
Store in the original blister in order to protect from moisture and light.
6.5 Nature and contents of container
Wallet with sealed aluminium/aluminium blisters, in cartons containing 2 (1 wallet x 2 tablets), 4
(1 wallet x 4 tablets), 12 (3 wallets x 4 tablets) or 40 (10 wallets x 4 tablets) tablets.
22
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
8.
EU/1/05/310/006 – 2 tablets
EU/1/05/310/007 – 4 tablets
EU/1/05/310/008 – 12 tablets
EU/1/05/310/009 – 40 tablets
9.
24 August 2005
Detailed information on this medicine is available on the website of the European Medicines Agency
23
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER(S)
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
24
A. MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer(s) responsible for batch release
Merck Sharp & Dohme BV
Waarderweg 39
2031 BN, Haarlem, Netherlands
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription.
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 6.0 (of
22 June 2009), presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and
functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 04 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the European Medicines Agency
25
ANNEX III
LABELLING AND PACKAGE LEAFLET
26
A. LABELLING
27
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER PACKAGING – CARTON FOR 1, 3 or 10 TRIFOLD PACK OF 2 or 4 TABLETS
1.
FOSAVANCE 70 mg/2800 IU tablets
Alendronic acid /colecalciferol
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains:
70 mg alendronic acid as alendronate sodium trihydrate and 70 micrograms (2800 IU) colecalciferol
(vitamin D
3.
).
3.
LIST OF EXCIPIENTS
Also contains: lactose anhydrous and sucrose. See package leaflet for further information.
4.
2 tablets
4 tablets
6 tablets
12 tablets
40 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
To be taken once weekly, on the same day each week. Read the package leaflet before use.
For oral use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Once weekly
8.
EXPIRY DATE
EXP
28
9.
SPECIAL STORAGE CONDITIONS
Store in the original blister in order to protect from moisture and light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
EU/1/05/310/001 (2 tablets)
EU/1/05/310/002 (4 tablets)
EU/1/05/310/003 (6 tablets)
EU/1/05/310/004 (12 tablets)
EU/1/05/310/005 (40 tablets)
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
FOSAVANCE
70 mg
2800 IU
29
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
IMMEDIATE PACKAGING –TRIFOLD PACK OF 2 or 4 TABLETS
1.
FOSAVANCE 70 mg/2800 IU tablets
Alendronic acid /colecalciferol
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains:
70 mg alendronic acid as alendronate sodium trihydrate and 70 micrograms (2800 IU) colecalciferol
(vitamin D
3.
).
3.
LIST OF EXCIPIENTS
Also contains: lactose anhydrous and sucrose. See package leaflet for further information.
4.
2 tablets
4 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
Important information
How to take FOSAVANCE tablets
1.
Take one tablet once a week.
2.
Choose the day of the week that best fits your schedule.
When you get out of bed on the day
you have chosen, and before taking your first food, drink or other medicines, swallow (do not
crush or chew the tablet or allow it to dissolve in your mouth) one
FOSAVANCE
tablet with a
full glass of water (not mineral water).
3.
Continue your morning activities.
You can sit, stand or walk – just stay fully upright. Don’t
lie down, eat, drink or take other medicines for at least 30 minutes. Do not lie down until after
your first food of the day.
4.
Remember
, take
FOSAVANCE once
each week on that same day for as long as your doctor
prescribes it.
If you miss a dose
, take only one
FOSAVANCE
tablet on the morning after you remember.
Do not
take two tablets on the same day.
Return to taking one tablet once a week, as originally scheduled on
your chosen day.
There is important additional information about how to take
FOSAVANCE
in the enclosed package
leaflet. Please read it carefully.
30
Take one tablet once a week
Mark the day of the week that best fits your schedule:
MON
SAT
WED
SUN
THU
WEEK 1. Date: ____
WEEK 2. Date: _____
WEEK 3. Date: ____
WEEK 4. Date: _____
TIME TO REFILL
For your convenience, place a sticker on your calendar each week as a reminder to take your
FOSAVANCE
.
FOSAVANCE
WEEK 1
FOSAVANCE
WEEK 2
FOSAVANCE
WEEK 3
FOSAVANCE
WEEK 4
TIME TO REFILL
To remove, push tablets through from
this
side.
To remove, push tablets through from other side.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Once weekly
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in the original blister in order to protect from moisture and light.
31
TUE
FRI
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
EU/1/05/310/001 (2 tablets)
EU/1/05/310/002 (4 tablets)
EU/1/05/310/003 (6 tablets)
EU/1/05/310/004 (12 tablets)
EU/1/05/310/005 (40 tablets)
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
32
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER PACKAGING – CARTON FOR 1, 3 or 10 TRIFOLD PACK OF 2 or 4 TABLETS
1.
FOSAVANCE 70 mg/5600 IU tablets
Alendronic acid /colecalciferol
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains:
70 mg alendronic acid as alendronate sodium trihydrate and 140 micrograms (5600 IU) colecalciferol
(vitamin D
3.
).
3.
LIST OF EXCIPIENTS
Also contains: lactose anhydrous and sucrose. See package leaflet for further information.
4.
2 tablets
4 tablets
12 tablets
40 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
To be taken once weekly, on the same day each week. Read the package leaflet before use.
For oral use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Once weekly
8.
EXPIRY DATE
EXP
33
9.
SPECIAL STORAGE CONDITIONS
Store in the original blister in order to protect from moisture and light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
EU/1/05/310/006 (2 tablets)
EU/1/05/310/007 (4 tablets)
EU/1/05/310/008 (12 tablets)
EU/1/05/310/009 (40 tablets)
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
FOSAVANCE
70 mg
5600 IU
34
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
IMMEDIATE PACKAGING –TRIFOLD PACK OF 2 or 4 TABLETS
1.
FOSAVANCE 70 mg/5600 IU tablets
Alendronic acid /colecalciferol
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains:
70 mg alendronic acid as alendronate sodium trihydrate and 140 micrograms (5600 IU) colecalciferol
(vitamin D
3.
).
3.
LIST OF EXCIPIENTS
Also contains: lactose anhydrous and sucrose. See package leaflet for further information.
4.
2 tablets
4 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
Important information
How to take FOSAVANCE tablets
1.
Take one tablet once a week.
2.
Choose the day of the week that best fits your schedule.
When you get out of bed on the day
you have chosen, and before taking your first food, drink or other medicines, swallow (do not
crush or chew the tablet or allow it to dissolve in your mouth) one
FOSAVANCE
tablet with a
full glass of water (not mineral water).
3.
Continue your morning activities.
You can sit, stand or walk – just stay fully upright. Don’t
lie down, eat, drink or take other medicines for at least 30 minutes. Do not lie down until after
your first food of the day.
4.
Remember
, take
FOSAVANCE once
each week on that same day for as long as your doctor
prescribes it.
If you miss a dose
, take only one
FOSAVANCE
tablet on the morning after you remember.
Do not
take two tablets on the same day.
Return to taking one tablet once a week, as originally scheduled on
your chosen day.
There is important additional information about how to take
FOSAVANCE
in the enclosed package
leaflet. Please read it carefully.
35
Take one tablet once a week
Mark the day of the week that best fits your schedule:
MON
SAT
WED
SUN
THU
WEEK 1. Date: ____
WEEK 2. Date: _____
WEEK 3. Date: ____
WEEK 4. Date: _____
TIME TO REFILL
For your convenience, place a sticker on your calendar each week as a reminder to take your
FOSAVANCE
.
FOSAVANCE
WEEK 1
FOSAVANCE
WEEK 2
FOSAVANCE
WEEK 3
FOSAVANCE
WEEK 4
TIME TO REFILL
To remove, push tablets through from
this
side.
To remove, push tablets through from other side.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Once weekly
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in the original blister in order to protect from moisture and light.
36
TUE
FRI
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
EU/1/05/310/006 (2 tablets)
EU/1/05/310/007 (4 tablets)
EU/1/05/310/008 (12 tablets)
EU/1/05/310/009 (40 tablets)
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
37
B. PACKAGE LEAFLET
38
PACKAGE LEAFLET: INFORMATION FOR THE USER
FOSAVANCE 70 mg/2800 IU tablets
Alendronic acid /colecalciferol
Read all of this leaflet carefully before you start taking this medicine, even if this is a repeat
prescription.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you
.
Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
-
It is particularly important to understand the information in section 3. HOW TO TAKE
FOSAVANCE, before taking this medicine.
In this leaflet
:
1.
What FOSAVANCE is and what it is used for
3.
How to take FOSAVANCE
4.
Possible side effects
5
How to store FOSAVANCE
6.
Further information
1.
WHAT FOSAVANCE IS AND WHAT IT IS USED FOR
What is FOSAVANCE?
FOSAVANCE is a tablet containing the two active substances, alendronic acid and colecalciferol
known as vitamin D
3
.
What is alendronate?
Alendronate belongs to a group of non-hormonal medicines called bisphosphonates. Alendronate
prevents the loss of bone that occurs in women after they have been through the menopause, and helps
to rebuild bone. It reduces the risk of spine and hip fractures.
What is vitamin D?
Vitamin D is an essential nutrient, required for calcium absorption and healthy bones. The body can
only absorb calcium properly from our food if it has enough vitamin D. Very few foods contain
vitamin D. The main source is through exposure to summer sunlight, which makes vitamin D in our
skin. As we get older our skin makes less vitamin D. Too little vitamin D may lead to bone loss and
osteoporosis. Severe vitamin D deficiency may cause muscle weakness which can lead to falls and a
greater risk of fractures.
What is FOSAVANCE used for?
Your doctor has prescribed FOSAVANCE to treat your osteoporosis and because you are at risk of
vitamin D insufficiency. FOSAVANCE reduces the risk of spine and hip fractures in women after
menopause.
FOSAVANCE
is a once weekly treatment.
What is osteoporosis?
Osteoporosis is a thinning and weakening of the bones. It is common in women after the menopause.
At the menopause, the ovaries stop producing the female hormone, oestrogen, which helps to keep a
woman’s skeleton healthy. As a result, bone loss occurs and bones become weaker. The earlier a
woman reaches the menopause, the greater the risk of osteoporosis.
39
2.
Before you take FOSAVANCE
Early on, osteoporosis usually has no symptoms. If left untreated, however, it can result in broken
bones. Although these usually hurt, breaks in the bones of the spine may go unnoticed until they cause
height loss. Broken bones can happen during normal, everyday activity, such as lifting, or from minor
injury that would not generally break normal bone. Broken bones usually occur at the hip, spine, or
wrist and can lead not only to pain but also to considerable problems like stooped posture (‘dowager’s
hump’) and loss of mobility.
How can osteoporosis be treated?
Osteoporosis can be treated and it is never too late to begin treatment. FOSAVANCE not only
prevents the loss of bone but actually helps to rebuild bone you may have lost and reduces the risk of
bones breaking in the spine and hip.
As well as your treatment with FOSAVANCE, your doctor may suggest you make changes to your
lifestyle to help your condition, such as:
Stopping smoking
Smoking appears to increase the rate at which you lose bone and, therefore,
may increase your risk of broken bones.
Exercise
Like muscles, bones need exercise to stay strong and healthy. Consult your
doctor before you begin any exercise programme.
Eating a balanced diet
Your doctor can advise you about your diet or whether you should take any
dietary supplements.
2.
BEFORE YOU TAKE FOSAVANCE
Do not take FOSAVANCE
•
if you are allergic (hypersensitive) to alendronate sodium trihydrate, colecalciferol or any of the
other ingredients,
•
if you have certain problems with your gullet (oesophagus - the tube that connects your mouth
with your stomach) such as narrowing or difficulty swallowing,
•
if you cannot stand or sit upright for at least 30 minutes,
•
if your doctor has told you that you have low blood calcium.
If you think any of these apply to you, do not take the tablets. Talk to your doctor first and follow the
advice given.
Take special care with FOSAVANCE
It is important to tell your doctor before taking FOSAVANCE
•
if you suffer from kidney problems,
•
if you have any swallowing or digestive problems,
•
if your doctor has told you that you have Barrett's oesophagus (a condition associated with
changes in the cells that line the lower oesophagus),
•
if you have been told you have low blood calcium,
•
if you have cancer,
•
if you are undergoing chemotherapy or radiotherapy,
•
if you are taking corticosteroids (such as prednisone or dexamethasone),
•
if you don’t receive routine dental care,
•
if you have gum disease,
•
if you have a planned dental extraction.
Irritation, inflammation or ulceration of the gullet (oesophagus – the tube that connects your mouth
with your stomach) often with symptoms of chest pain, heartburn, or difficulty or pain upon
swallowing may occur, especially if patients do not drink a full glass of water and/or if they lie down
40
less than 30 minutes after taking FOSAVANCE. These side effects may worsen if patients continue to
take FOSAVANCE after developing these symptoms.
Use in children
FOSAVANCE should not be given to children less than 18 years of age.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
It is likely that calcium supplements, antacids, and some oral medicines will interfere with the
absorption of FOSAVANCE if taken at the same time. Therefore, it is important that you follow the
advice given in section 3. HOW TO TAKE FOSAVANCE and wait at least 30 minutes before taking
any other oral medicines or supplements.
It is likely that certain medicines or food additives may prevent the vitamin D in FOSAVANCE from
getting into your body, including artificial fat substitutes, mineral oils, orlistat and the cholesterol-
lowering medicines, cholestyramine and colestipol. Medicines for fits (seizures) may decrease the
effectiveness of vitamin D. Additional vitamin D supplements may be considered on an individual
basis.
Taking FOSAVANCE with food and drink
It is likely that food and beverages (including mineral water) will make FOSAVANCE less effective if
taken at the same time. Therefore, it is important that you follow the advice given in section 3. HOW
TO TAKE FOSAVANCE.
Pregnancy and breast-feeding
FOSAVANCE is only intended for use in postmenopausal women. You should not take
FOSAVANCE if you are or think you may be pregnant, or if you are breast-feeding.
Driving and using machines
There have been side effects (for example blurred vision, dizziness and severe bone, muscle or joint
pain) reported with FOSAVANCE that may affect your ability to drive or operate machinery. (See
POSSIBLE SIDE EFFECTS.) If you experience any of these side effects you should not drive until
you feel better.
Important information about some of the ingredients of FOSAVANCE
FOSAVANCE contains lactose and sucrose. If you have been told by your doctor that you have an
intolerance to some sugars, contact your doctor before taking this medicine.
3.
HOW TO TAKE FOSAVANCE
Always take FOSAVANCE exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
Take one FOSAVANCE tablet once a week.
Follow these instructions carefully to make sure you will benefit from FOSAVANCE.
1) Choose the day of the week that best fits your schedule. Every week, take one FOSAVANCE
tablet on your chosen day.
It is very important to follow instructions 2), 3), 4) and 5) to help the FOSAVANCE tablet reach your
stomach quickly and help reduce the chance of irritating your gullet (oesophagus - the tube that
connects your mouth with your stomach).
41
2) After getting up for the day and before taking any food, drink, or other medicine, swallow your
FOSAVANCE tablet whole with a full glass of water only (not mineral water) (not less than
200 ml or 7 fl. oz.).
•
Do not take with mineral water (still or sparkling).
•
Do not take with coffee or tea.
•
Do not take with juice or milk.
Do not crush or chew the tablet or allow it to dissolve in your mouth.
3) Do not lie down — stay fully upright (sitting, standing or walking) — for at least 30 minutes
after swallowing the tablet. Do not lie down until after your first food of the day.
4) Do not take FOSAVANCE at bedtime or before getting up for the day.
5) If you develop difficulty or pain upon swallowing, chest pain, or new or worsening heartburn,
stop taking FOSAVANCE and contact your doctor.
6) After swallowing your FOSAVANCE tablet, wait at least 30 minutes before taking your first
food, drink, or other medicine of the day, including antacids, calcium supplements and vitamins.
FOSAVANCE is effective only if taken when your stomach is empty.
If you take more FOSAVANCE than you should
If you take too many tablets by mistake, drink a full glass of milk and contact your doctor
immediately. Do not make yourself vomit, and do not lie down.
If you forget to take FOSAVANCE
If you miss a dose, just take one tablet on the morning after you remember.
Do not take two tablets on
the same day.
Return to taking one tablet once a week, as originally scheduled on your chosen day.
If you stop taking FOSAVANCE
It is important that you continue taking FOSAVANCE for as long as your doctor prescribes the
medicine. FOSAVANCE can treat your osteoporosis only if you continue to take the tablets.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, FOSAVANCE can cause side effects, although not everybody gets them.
The frequency of possible side effects listed below is defined using the following convention:
very common (affects more than 1 user in 10)
common (affects 1 to 10 users in 100)
uncommon (affects 1 to 10 users in 1,000)
rare (affects 1 to 10 users in 10,000)
very rare (affects less than 1 user in 10,000)
not known (frequency cannot be estimated from the available data).
Common:
•
heartburn; difficulty swallowing; pain upon swallowing; ulceration of the gullet (oesophagus -
the tube that connects your mouth with your stomach) which can cause chest pain, heartburn or
difficulty or pain upon swallowing,
•
bone, muscle and/or joint pain,
•
abdominal pain; uncomfortable feeling in the stomach or belching after eating; constipation; full
or bloated feeling in the stomach; diarrhoea; flatulence,
•
headache.
42
Uncommon:
•
nausea; vomiting,
•
irritation or inflammation of the gullet (oesophagus – the tube that connects your mouth with
your stomach) or stomach,
•
black or tar-like stools,
•
rash; itching; redness of the skin.
Rare:
•
allergic reactions such as hives; swelling of the face, lips, tongue and/or throat, possibly causing
difficulty breathing or swallowing,
•
symptoms of low blood calcium levels including muscle cramps or spasms and/or tingling
sensation in the fingers or around the mouth,
•
stomach or peptic ulcers (sometimes severe or with bleeding),
•
narrowing of the gullet (oesophagus – the tube that connects your mouth with your stomach),
•
blurred vision, pain or redness in the eye,
•
rash made worse by sunlight,
•
severe bone, muscle and/or joint pain,
•
mouth ulcers when the tablets have been chewed or sucked,
•
transient flu-like symptoms, such as aching muscles, generally feeling unwell and sometimes
with fever usually at the start of treatment.
Very rare:
•
severe skin reactions.
During post-marketing experience the following side effects have been reported (frequency not
known):
•
dizziness,
•
changed sense of taste,
•
joint swelling,
•
tiredness,
•
hair loss,
•
jaw problems associated with delayed healing and infection, often following tooth extraction,
•
swelling in the hands or legs,
•
fracture of the thigh bone in patients on long-term treatment with FOSAVANCE. Thigh pain,
weakness or discomfort may be an early indication of a possible fracture of the thigh bone.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
It will help if you make a note of what you experienced, when it started and how long it lasted.
5.
HOW TO STORE FOSAVANCE
Keep out of the reach and sight of children.
Do not use FOSAVANCE after the expiry date which is stated on the carton and the wallet after EXP.
The expiry date refers to the last day of that month.
Store in the original blister in order to protect from moisture and light.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
43
6.
FURTHER INFORMATION
What FOSAVANCE contains
The active substances are alendronic acid and colecalciferol (vitamin D
3
). Each tablet contains 70 mg
alendronic acid as alendronate sodium trihydrate and 70 micrograms (2800 IU) colecalciferol
(vitamin D
3
).
The other ingredients are microcrystalline cellulose (E460), lactose anhydrous, medium chain
triglycerides, gelatin, croscarmellose sodium, sucrose, colloidal silicon dioxide, magnesium stearate
(E572), butyl hydroxytoluene (E321), modified starch (maize), and sodium aluminium silicate (E554).
What FOSAVANCE looks like and contents of the pack
FOSAVANCE 70 mg/2800 IU tablets are available as capsule-shaped, white to off-white tablets
marked with an outline of a bone image on one side and ‘710’ on the other.
The tablets are supplied in wallets with sealed aluminium blisters in cartons in the following pack
sizes
•
2 tablets (1 wallet containing 2 tablets in aluminium blisters)
•
4 tablets (1 wallet containing 4 tablets in aluminium blisters)
•
6 tablets (3 wallets each containing 2 tablets in aluminium blisters).
•
12 tablets (3 wallets each containing 4 tablets in aluminium blisters).
•
40 tablets (10 wallets each containing 4 tablets in aluminium blisters).
Not all pack sizes may be marketed.
Marketing Authorisation Holder
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
Manufacturer
Merck Sharp & Dohme BV
Waarderweg 39
2031 BN, Haarlem, Netherlands
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
Belgique/België/Belgien
Merck Sharp & Dohme B.V.
Succursale belge/Belgisch bijhuis
Tél/Tel: +32 (0) 800 38693
MSDBelgium_info@merck.com
Luxembourg/Luxemburg
Merck Sharp & Dohme B.V.
Succursale belge
Tél: +32 (0) 800 38693
MSDBelgium_info@merck.com
България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3740
info-msdbg@merck.com
44
Česká republika
Merck Sharp & Dohme IDEA, Inc., org. sl.
Tel.: +420 233 010 111
msd_cr@merck.com
Malta
Merck Sharp & Dohme Cyprus Limited
Tel: +357 22866700
malta_info@merck.com
Danmark
Merck Sharp & Dohme
Tlf: +45 43 28 77 66
dkmail@merck.com
Nederland
Merck Sharp & Dohme BV
Tel: +31 (0) 23 5153153
msdbvnl@merck.com
Deutschland
MSD SHARP & DOHME GMBH
Tel: +49 (0) 89 4561 2612
Infocenter@msd.de
Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no
Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 613 9750
msdeesti@merck.com
Österreich
Merck Sharp & Dohme Ges.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com
Eλλάδα
BIANEΞ Α.Ε
Τηλ: +3 0210 80091 11
Mailbox@vianex.gr
Polska
MSD Polska Sp.z o.o.
Tel.: +48 22 549 51 00
msdpolska@merck.com
España
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
Fosavance@msd.es
Portugal
Merck Sharp & Dohme, Lda
Tel: + 351 214 465 700
informacao_doente@merck.com
France
Laboratoires Merck Sharp & Dohme – Chibret
Tél: +33 (0)1 47 54 87 00
Contact@msd-france.com
România
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com
Ireland
Merck Sharp and Dohme Ireland (Human Health)
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com
Slovenija
Merck Sharp & Dohme, inovativna zdravila
d.o.o.
Tel: + 386 1 5204201
msd_slovenia@merck.com
Ísland
Icepharma hf.
Sími: +354 540 8000
ISmail@merck.com
Slovenská republika
Merck Sharp & Dohme IDEA, Inc.
Tel.: +421 2 58282010
msd_sk@merck.com
Ιtalia
Merck Sharp & Dohme (Italia) S.p.A.
Tel: +39 06 361911
doccen@merck.com
Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0) 9 804650
info@msd.fi
Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ: +357 22866700
cyprus_info@merck.com
Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 (0) 8 626 14 00
medicinskinfo@merck.com
45
Latvija
SIA “Merck Sharp & Dohme Latvija”
Tel: +371 67364 224
msd_lv@merck.com
United Kingdom
Merck Sharp and Dohme Limited
Tel: +44 (0) 1992 467272
medinfo_uk@merck.com
Lietuva
UAB “Merck Sharp & Dohme”
Tel.: +370 5 278 02 47
msd_lietuva@merck.com
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency website:
http://www.ema.europa.eu
46
PACKAGE LEAFLET: INFORMATION FOR THE USER
FOSAVANCE 70 mg/5600 IU tablets
Alendronic acid /colecalciferol
Read all of this leaflet carefully before you start taking this medicine, even if this is a repeat
prescription.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you
.
Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
-
It is particularly important to understand the information in section 3. HOW TO TAKE
FOSAVANCE, before taking this medicine.
In this leaflet
:
1.
What FOSAVANCE is and what it is used for
3.
How to take FOSAVANCE
4.
Possible side effects
5.
How to store FOSAVANCE
6.
Further information
1.
WHAT FOSAVANCE IS AND WHAT IT IS USED FOR
What is FOSAVANCE?
FOSAVANCE is a tablet containing the two active substances, alendronic acid and colecalciferol
known as vitamin D
3
.
What is alendronate?
Alendronate belongs to a group of non-hormonal medicines called bisphosphonates. Alendronate
prevents the loss of bone that occurs in women after they have been through the menopause, and helps
to rebuild bone. It reduces the risk of spine and hip fractures.
What is vitamin D?
Vitamin D is an essential nutrient, required for calcium absorption and healthy bones. The body can
only absorb calcium properly from our food if it has enough vitamin D. Very few foods contain
vitamin D. The main source is through exposure to summer sunlight, which makes vitamin D in our
skin. As we get older our skin makes less vitamin D. Too little vitamin D may lead to bone loss and
osteoporosis. Severe vitamin D deficiency may cause muscle weakness which can lead to falls and a
greater risk of fractures.
What is FOSAVANCE used for?
Your doctor has prescribed FOSAVANCE to treat your osteoporosis and because you are at risk of
vitamin D insufficiency. FOSAVANCE reduces the risk of spine and hip fractures in women after
menopause.
FOSAVANCE
is a once weekly treatment.
What is osteoporosis?
Osteoporosis is a thinning and weakening of the bones. It is common in women after the menopause.
At the menopause, the ovaries stop producing the female hormone, oestrogen, which helps to keep a
woman’s skeleton healthy. As a result, bone loss occurs and bones become weaker. The earlier a
woman reaches the menopause, the greater the risk of osteoporosis.
47
2.
Before you take FOSAVANCE
Early on, osteoporosis usually has no symptoms. If left untreated, however, it can result in broken
bones. Although these usually hurt, breaks in the bones of the spine may go unnoticed until they cause
height loss. Broken bones can happen during normal, everyday activity, such as lifting, or from minor
injury that would not generally break normal bone. Broken bones usually occur at the hip, spine, or
wrist and can lead not only to pain but also to considerable problems like stooped posture (‘dowager’s
hump’) and loss of mobility.
How can osteoporosis be treated?
Osteoporosis can be treated and it is never too late to begin treatment. FOSAVANCE not only
prevents the loss of bone but actually helps to rebuild bone you may have lost and reduces the risk of
bones breaking in the spine and hip.
As well as your treatment with FOSAVANCE, your doctor may suggest you make changes to your
lifestyle to help your condition, such as:
Stopping smoking
Smoking appears to increase the rate at which you lose bone and, therefore,
may increase your risk of broken bones.
Exercise
Like muscles, bones need exercise to stay strong and healthy. Consult your
doctor before you begin any exercise programme.
Eating a balanced diet
Your doctor can advise you about your diet or whether you should take any
dietary supplements.
2.
BEFORE YOU TAKE FOSAVANCE
Do not take FOSAVANCE
•
if you are allergic (hypersensitive) to alendronate sodium trihydrate, colecalciferol or any of the
other ingredients,
•
if you have certain problems with your gullet (oesophagus - the tube that connects your mouth,
with your stomach) such as narrowing or difficulty swallowing,
•
if you cannot stand or sit upright for at least 30 minutes,
•
if your doctor has told you that you have low blood calcium.
If you think any of these apply to you, do not take the tablets. Talk to your doctor first and follow the
advice given.
Take special care with FOSAVANCE
It is important to tell your doctor before taking FOSAVANCE
•
if you suffer from kidney problems,
•
if you have any swallowing or digestive problems,
•
if your doctor has told you that you have Barrett's oesophagus (a condition associated with
changes in the cells that line the lower oesophagus),
•
if you have been told you have low blood calcium,
•
if you have cancer,
•
if you are undergoing chemotherapy or radiotherapy,
•
if you are taking corticosteroids (such as prednisone or dexamethasone),
•
if you don’t receive routine dental care,
•
if you have gum disease,
•
if you have a planned dental extraction.
Irritation, inflammation or ulceration of the gullet (oesophagus – the tube that connects your mouth
with your stomach) often with symptoms of chest pain, heartburn, or difficulty or pain upon
swallowing may occur, especially if patients do not drink a full glass of water and/or if they lie down
48
less than 30 minutes after taking FOSAVANCE. These side effects may worsen if patients continue to
take FOSAVANCE after developing these symptoms.
Use in children
FOSAVANCE should not be given to children less than 18 years of age.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
It is likely that calcium supplements, antacids, and some oral medicines will interfere with the
absorption of FOSAVANCE if taken at the same time. Therefore, it is important that you follow the
advice given in section 3. HOW TO TAKE FOSAVANCE and wait at least 30 minutes before taking
any other oral medicines or supplements.
It is likely that certain medicines or food additives may prevent the vitamin D in FOSAVANCE from
getting into your body, including artificial fat substitutes, mineral oils, orlistat and the cholesterol-
lowering medicines, cholestyramine and colestipol. Medicines for fits (seizures) may decrease the
effectiveness of vitamin D.
Taking FOSAVANCE with food and drink
It is likely that food and beverages (including mineral water) will make FOSAVANCE less effective if
taken at the same time. Therefore, it is important that you follow the advice given in section 3. HOW
TO TAKE FOSAVANCE.
Pregnancy and breast-feeding
FOSAVANCE is only intended for use in postmenopausal women. You should not take
FOSAVANCE if you are or think you may be pregnant, or if you are breast-feeding.
Driving and using machines
There have been side effects (for example blurred vision, dizziness and severe bone, muscle or joint
pain) reported with FOSAVANCE that may affect your ability to drive or operate machinery. (See
POSSIBLE SIDE EFFECTS.) If you experience any of these side effects you should not drive until
you feel better.
Important information about some of the ingredients of FOSAVANCE
FOSAVANCE contains lactose and sucrose. If you have been told by your doctor that you have an
intolerance to some sugars, contact your doctor before taking this medicine.
3.
HOW TO TAKE FOSAVANCE
Always take FOSAVANCE exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
Take one FOSAVANCE tablet once a week.
Follow these instructions carefully to make sure you will benefit from FOSAVANCE.
1) Choose the day of the week that best fits your schedule. Every week, take one FOSAVANCE
tablet on your chosen day.
It is very important to follow instructions 2), 3), 4) and 5) to help the FOSAVANCE tablet reach your
stomach quickly and help reduce the chance of irritating your gullet (oesophagus - the tube that
connects your mouth with your stomach).
49
2) After getting up for the day and before taking any food, drink, or other medicine, swallow your
FOSAVANCE tablet whole with a full glass of water only (not mineral water) (not less than
200 ml or 7 fl. oz.).
•
Do not take with mineral water (still or sparkling).
•
Do not take with coffee or tea.
•
Do not take with juice or milk.
Do not crush or chew the tablet or allow it to dissolve in your mouth.
3) Do not lie down — stay fully upright (sitting, standing or walking) — for at least 30 minutes
after swallowing the tablet. Do not lie down until after your first food of the day.
4) Do not take FOSAVANCE at bedtime or before getting up for the day.
5) If you develop difficulty or pain upon swallowing, chest pain, or new or worsening heartburn,
stop taking FOSAVANCE and contact your doctor.
6) After swallowing your FOSAVANCE tablet, wait at least 30 minutes before taking your first
food, drink, or other medicine of the day, including antacids, calcium supplements and vitamins.
FOSAVANCE is effective only if taken when your stomach is empty.
If you take more FOSAVANCE than you should
If you take too many tablets by mistake, drink a full glass of milk and contact your doctor
immediately. Do not make yourself vomit, and do not lie down.
If you forget to take FOSAVANCE
If you miss a dose, just take one tablet on the morning after you remember.
Do not take two tablets on
the same day.
Return to taking one tablet once a week, as originally scheduled on your chosen day.
If you stop taking FOSAVANCE
It is important that you continue taking FOSAVANCE for as long as your doctor prescribes the
medicine. FOSAVANCE can treat your osteoporosis only if you continue to take the tablets.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, FOSAVANCE can cause side effects, although not everybody gets them.
The frequency of possible side effects listed below is defined using the following convention:
very common (affects more than 1 user in 10)
common (affects 1 to 10 users in 100)
uncommon (affects 1 to 10 users in 1,000)
rare (affects 1 to 10 users in 10,000)
very rare (affects less than 1 user in 10,000)
not known (frequency cannot be estimated from the available data).
Common:
•
heartburn; difficulty swallowing; pain upon swallowing; ulceration of the gullet (oesophagus -
the tube that connects your mouth with your stomach) which can cause chest pain, heartburn or
difficulty or pain upon swallowing,
•
bone, muscle and/or joint pain,
•
abdominal pain; uncomfortable feeling in the stomach or belching after eating; constipation; full
or bloated feeling in the stomach; diarrhoea; flatulence,
•
headache.
50
Uncommon:
•
nausea; vomiting,
•
irritation or inflammation of the gullet (oesophagus – the tube that connects your mouth with
your stomach) or stomach,
•
black or tar-like stools,
•
rash; itching; redness of the skin.
Rare:
•
allergic reactions such as hives; swelling of the face, lips, tongue and/or throat, possibly causing
difficulty breathing or swallowing,
•
symptoms of low blood calcium levels including muscle cramps or spasms and/or tingling
sensation in the fingers or around the mouth,
•
stomach or peptic ulcers (sometimes severe or with bleeding),
•
narrowing of the gullet (oesophagus – the tube that connects your mouth with your stomach),
•
blurred vision, pain or redness in the eye,
•
rash made worse by sunlight,
•
severe bone, muscle and/or joint pain,
•
mouth ulcers when the tablets have been chewed or sucked,
•
transient flu-like symptoms, such as aching muscles, generally feeling unwell and sometimes
with fever usually at the start of treatment.
Very rare:
•
severe skin reactions.
During post-marketing experience the following side effects have been reported (frequency not
known):
•
dizziness,
•
changed sense of taste,
•
joint swelling,
•
tiredness,
•
hair loss,
•
jaw problems associated with delayed healing and infection, often following tooth extraction,
•
swelling in the hands or legs,
•
fracture of the thigh bone in patients on long-term treatment with FOSAVANCE. Thigh pain,
weakness or discomfort may be an early indication of a possible fracture of the thigh bone.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
It will help if you make a note of what you experienced, when it started and how long it lasted.
5.
HOW TO STORE FOSAVANCE
Keep out of the reach and sight of children.
Do not use FOSAVANCE after the expiry date which is stated on the carton and the wallet after EXP.
The expiry date refers to the last day of that month.
Store in the original blister in order to protect from moisture and light.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
51
6.
FURTHER INFORMATION
What FOSAVANCE contains
The active substances are alendronic acid and colecalciferol (vitamin D
3
). Each tablet contains 70 mg
alendronic acid as alendronate sodium trihydrate and 140 micrograms (5600 IU) colecalciferol
(vitamin D
3
).
The other ingredients are microcrystalline cellulose (E460), lactose anhydrous, medium chain
triglycerides, gelatin, croscarmellose sodium, sucrose, colloidal silicon dioxide, magnesium stearate
(E572), butylated hydroxytoluene (E321), modified starch (maize), and sodium aluminium silicate
(E554).
What FOSAVANCE looks like and contents of the pack
FOSAVANCE 70 mg/5600 IU tablets are available as modified rectangle-shaped, white to off-white
tablets marked with an outline of a bone image on one side and ‘270’ on the other.
The tablets are supplied in wallets with sealed aluminium blisters in cartons in the following pack
sizes
•
2 tablets (1 wallet containing 2 tablets in aluminium blisters)
•
4 tablets (1 wallet containing 4 tablets in aluminium blisters)
•
12 tablets (3 wallets each containing 4 tablets in aluminium blisters).
•
40 tablets (10 wallets each containing 4 tablets in aluminium blisters).
Not all pack sizes may be marketed.
Marketing Authorisation Holder
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
Manufacturer
Merck Sharp & Dohme BV
Waarderweg 39
2031 BN, Haarlem, Netherlands
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
Belgique/België/Belgien
Merck Sharp & Dohme B.V.
Succursale belge/Belgisch bijhuis
Tél/Tel: +32 (0) 800 38693
MSDBelgium_info@merck.com
Luxembourg/Luxemburg
Merck Sharp & Dohme B.V.
Succursale belge
Tél: +32 (0) 800 38693
MSDBelgium_info@merck.com
България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3740
info-msdbg@merck.com
52
Česká republika
Merck Sharp & Dohme IDEA, Inc., org. sl.
Tel.: +420 233 010 111
msd_cr@merck.com
Malta
Merck Sharp & Dohme Cyprus Limited
Tel: +357 22866700
malta_info@merck.com
Danmark
Merck Sharp & Dohme
Tlf: +45 43 28 77 66
dkmail@merck.com
Nederland
Merck Sharp & Dohme BV
Tel: +31 (0) 23 5153153
msdbvnl@merck.com
Deutschland
MSD SHARP & DOHME GMBH
Tel: +49 (0) 89 4561 2612
Infocenter@msd.de
Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no
Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 613 9750
msdeesti@merck.com
Österreich
Merck Sharp & Dohme Ges.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com
Eλλάδα
BIANEΞ Α.Ε
Τηλ: +3 0210 80091 11
Mailbox@vianex.gr
Polska
MSD Polska Sp.z o.o.
Tel.: +48 22 549 51 00
msdpolska@merck.com
España
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
Fosavance@msd.es
Portugal
Merck Sharp & Dohme, Lda
Tel: + 351 214 465 700
informacao_doente@merck.com
France
Laboratoires Merck Sharp & Dohme – Chibret
Tél: +33 (0)1 47 54 87 00
Contact@msd-france.com
România
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com
Ireland
Merck Sharp and Dohme Ireland (Human Health)
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com
Slovenija
Merck Sharp & Dohme, inovativna zdravila
d.o.o.
Tel: + 386 1 5204201
msd_slovenia@merck.com
Ísland
Icepharma hf.
Sími: +354 540 8000
ISmail@merck.com
Slovenská republika
Merck Sharp & Dohme IDEA, Inc.
Tel.: +421 2 58282010
msd_sk@merck.com
Ιtalia
Merck Sharp & Dohme (Italia) S.p.A.
Tel: +39 06 361911
doccen@merck.com
Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0) 9 804650
info@msd.fi
Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ: +357 22866700
cyprus_info@merck.com
Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 (0) 8 626 14 00
medicinskinfo@merck.com
53
Latvija
SIA “Merck Sharp & Dohme Latvija”
Tel: +371 67364 224
msd_lv@merck.com
United Kingdom
Merck Sharp and Dohme Limited
Tel: +44 (0) 1992 467272
medinfo_uk@merck.com
Lietuva
UAB “Merck Sharp & Dohme”
Tel.: +370 5 278 02 47
msd_lietuva@merck.com
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency website:
http://www.ema.europa.eu
54
ANNEX IV
GROUNDS FOR ONE ADDITIONAL RENEWAL
55
GROUNDS FOR ONE ADDITIONAL RENEWAL
Based upon the data that have become available since the granting of the initial Marketing
Authorisation, the CHMP considers that the benefit-risk balance of Fosavance remains positive, but
considers that its safety profile is to be closely monitored for the following reasons:
There are a number of ongoing safety issues for alendronate for which post-marketing studies are
ongoing or planned, the results of which are expected to yield important new safety data which could
impact on the benefit-risk balance of the product. These studies pertain to oesophageal adverse effects
and stress fractures. In particular for stress fractures, there are significant uncertainties at present, and
more information should become available in the next 5 years.
Therefore, based upon the safety profile of Fosavance, which requires the submission of 3-yearly
PSURs, the CHMP concluded that the MAH should submit one additional renewal application in 5
years time.
56
Source: European Medicines Agency
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