iMeds.se

Alendronate Bioeq Pharma Veckotablett

Document: Alendronate bioeq pharma Veckotablett 70 mg tablet ENG SmPC change


SUMMARY OF PRODUCT CHARACTERISTICS


1. NAME OF THE MEDICINAL PRODUCT


Alendronate bioeq pharma Veckotablett 70 mg tablets


2. QUALITATIVE AND QUANTITATIVE COMPOSITION


Each tablet contains the equivalent of 70 mg alendronic acid as 91.36 mg of alendronate sodium trihydrate.


Excipient with known effect:

Each tablet contains 128.64 mg of lactose anhydrous


For thefull list of excipients, see section 6.1


3. PHARMACEUTICAL form


Tablet


White, oblong, biconvex tablets.


4. Clinical particulars


4.1 Therapeutic indications


Alendronate bioeq pharma Veckotablett is indicated in adults for the treatment of post-menopausal osteoporosis.

Alendronate bioeq pharma Veckotablett reduces the risk of vertebral and hip fractures.


4.2 Posology and method of administration


Posology

The recommended dosage is one 70 mg tablet once weekly. The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of Alendronate bioeq pharma Veckotablett on an individual patient basis, particularly after 5 or more years of use.


Elderly:

In clinical studies there was no age-related difference in the efficacy or safety profiles of alendronate. Therefore no dosage adjustment is necessary for the elderly.


Renal impairment:

No dosage adjustment is necessary for patients with GFR greater than 35 ml/min. Alendronate is not recommended for patients with renal impairment where GFR is less than 35 ml/min, due to lack of experience.


Paediatric population:

Alendronate sodium is not recommended for use inchildren under the age of 18 years due to insufficient data on safety and efficacy in conditions associated with paediatric osteoporosis (also see section 5.1).


Method of administration

Oral use


To permit adequate absorption of alendronate:

Alendronate bioeq pharma Veckotablett must be taken at least 30 minutes before the first food, beverage or other medicinal product of the day with plain water only. Other beverages (including mineral water), food and some medicinal products are likely to reduce the absorption of alendronate (see section 4.5).


To facilitate delivery to the stomach and thus reduce the potential for local and oesophageal

irritation/adverse experiences (see section 4.4)



Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate (see section 4.4).


Alendronate bioeq pharma Veckotablett 70 mg has not been investigated in the treatment of glucocorticoid-induced osteoporosis.


4.3 Contraindications



4.4 Special warnings and precautions for use


Upper gastrointestinal adverse reactions

Alendronate can cause local irritation of the upper gastro-intestinal mucosa. Because there is a potential for worsening of the underlying illness, caution should be used when alendronate is given to patients with active upper gastro-intestinal problems such as dysphagia, oesophageal disease, gastritis, duodenitis, ulcers or with a recent history (within the previous year) of major gastro-intestinal disease such as peptic ulcer, or active gastro-intestinal bleeding, or surgery of the upper gastro-intestinal 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.


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.


The risk of severe oesophageal adverse experiences appears to be greater in patients who fail to take alendronate properly and/or continue to take alendronate after developing symptoms suggestive of oesophageal irritation. It is very important that full dosing instructions are provided to and 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, there have been rare (post-marketing) reports of gastric and duodenal ulcers, some severe and with complications.


Osteonecrosis of the jaw

Osteonecrosis of the jaw generally associated with tooth extraction and/or a local infection (including osteomyelitis) has been reported in patients with cancer 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.


The following risk factors should be considered when evaluating an individual’s risk of developing osteonecrosis of the jaw:

• potency of the bisphosphonate (highest for zoledronic acid), route of administration (see

above) and cumulative dose

• cancer, chemotherapy, radiotherapy, corticosteroids, smoking

• a history of dental disease, poor oral hygiene, periodontal disease, invasive dental

procedures and poorly fitting dentures


A dental examination with appropriate preventive dentistry should be considered prior to treatment with oral bisphosphonates in patients with poor dental status.

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 risk/benefit assessment.


During bisphosphonate treatment, all patients should be encouraged to maintain good oral hygiene,

receive routine dental check-ups, and report any oral symptoms such as dental mobility, pain, or

swelling.


Osteonecrosis of the external auditory canal

Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms including chronic ear infections.


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.

A sub-set had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.


Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique, fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are 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 has also been reported. Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment.


During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.


Skin reactions

In post-marketing experience, there have been rare reports of severe skin reactions including Stevens Johnson syndrome and toxic epidermal necrolysis.


Missed dose

Patients should be instructed that if they miss a dose of Alendronate bioeq pharma Veckotablett they should take the 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.


Renal impairment

Alendronate is not recommended for patients with renal impairment where the GFR is less than 35 ml/min (see section 4.2).


Bone and mineral metabolism

Causes of osteoporosis other than oestrogen deficiency and ageing should be considered.

Hypocalcaemia must be corrected before initiating therapy with alendronate (see section 4.3). Other disorders affecting mineral metabolism (such as vitamin D deficiency and hypoparathyroidism) should also be effectively treated. In patients with these conditions serum calcium and symptoms of hypocalcaemia should be monitored during treatment with Alendronate bioeq pharma Veckotablett


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 have often occurred in patients with predisposing conditions (e.g. hypoparathyroidism, vitamin D deficiency and calcium malabsorption).


Ensuring adequate calcium and vitamin D intake is particularly important in patients receiving glucocorticoids.


Excipients

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.


4.5 Interaction with other medicinal products and other forms of interaction


If taken at the same time, it is likely that food and beverages (including mineral water), calcium supplements, antacids and some other medicinal products will interfere with the absorption of alendronate. Therefore, patients must wait at least 30 minutes after taking alendronate before taking any other oral medicinal product (see section 4.2 and 5.2).


No other interactions with medicinal products of clinical significance are anticipated. A number of patients in the clinical trials received oestrogen (intravaginal, transdermal or oral) while taking alendronate. No adverse experiences attributable to their concomitant use were identified.


Since NSAID use is associated with gastrointestinal irritation, caution should be used during concomitant use with alendronate.


Although specific interaction studies were not performed, in clinical studies alendronate was used concomitantly with a wide range of commonly prescribed medicinal products without evidence of clinically adverse interactions.


4.6 Fertility, Pregnancy and lactation


Pregnancy

Alendronate should not be used during pregnancy. There are no or limited amount of data from the use of alendronate in pregnant women. Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonic/fetal development or postnatal development. Alendronate given during pregnancy in rats caused dystocia related to hypocalcaemia (see section 5.3).


Breast-feeding

It is unknown whether alendronate/metabolites are excreted into human milk.A risk to the newborns/infants cannot be excluded. Alendronateshould not be used during breast-feeding.


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 atheoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing acourse 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.


4.7 Effects on ability to drive and use machines


No studies on the effects on the ability to drive and use machines have been performed. However, certain adverse reactions that have been reported with alendronatemay affect some patients' ability to drive or operate machinery. Individual responses to Alendronate bioeq pharma Veckotablett may vary (see section 4.8).


4.8 Undesirable effects


Summary of the safety profile

In a one-year study of post-menopausal women with osteoporosis the overall safety profiles of alendronate (weekly tablet 70 mg) once a week (n=519) and alendronate 10 mg/day (n=370) were similar.


In two three-year studies of virtually identical design, in post-menopausal women (alendronate 10 mg: n=196, placebo: n=397) the overall safety profiles of alendronate 10 mg/day and placebo were similar.


Adverse experiences reported by the investigators as possibly, probably or definitively drug-related are presented below if they occurred in 1% in either treatment group in the one-year study or in 1% of the patients treated with alendronate 10 mg/day and at a greater incidence than in patients given placebo in the three-year studies:

One-year study

Three-year studies

alendronate mg

alendronate

alendronate

Placebo

70 mg weekly


mg tablets«

10 mg/day

10 mg/day

(n=519)

(n=370)

(n=196)

(n=397)

%

%

%

%

Gastro-intestinal disorders



Abdominal pain

3.7

3.0

6.6

4.8

Dyspepsia

2.7

2.2

3.6

3.5

Acid regurgitation

1.9

2.4

2.0

4.3

Nausea

1.9

2.4

3.6

4.0

Abdominal distention

1.0

1.4

1.0

0.8

Constipation

0.8

1.6

3.1

1.8

Diarrhoea

0.6

0.5

3.1

1.8

Dysphagia

0.4

0.5

1.0

0.0

Flatulence

0.4

1.6

2.6

0.5

Gastritis

0.2

1.1

0.5

1.3

Gastric ulcer

0.0

1.1

0.0

0.0

Oesophageal ulcer

0.0

0.0

1.5

0.0

Musculoskeletal




Musculoskeletal (bone, muscle or joint) pain

2.9

3.2

4.1

2.5

Muscle cramp

0.2

1.1

0.0

1.0

Neurological



Headache

0.4

0.3

2.6

1.5

Tabulated list of adverse reactions

The following adverse experiences have also been reported during clinical studies and/or post-marketing use:


Frequencies are defined as : Very common (>1/10), Common (>1/100, < 1/10), Uncommon (>1/1,000, < 1/100), Rare (>1/10,000, < 1/1,000), Very rare (< 1/10,000 including isolated cases)]


Immune system disorders:

Rare: hypersensitivity reactions including urticaria and angioedema

Metabolism and nutrition disorders:

Rare: symptomatic hypocalcaemia, often in association with predisposing conditions §

Nervous system disorders:

Common: headache, dizziness†

Uncommon: dysgeusia†

Eye disorders:

Uncommon: eye inflammation (uveitis, scleritis, episcleritis)

Ear and labyrinth disorders:

Common: vertigo†

Very rare: Osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction).

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) §

Skin and subcutaneous tissue disorders:

Common: alopecia†, pruritus†

Uncommon: rash, erythema

Rare: rash with photosensitivity, severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis‡

Musculoskeletal and connective tissue disorders:

Very common: musculoskeletal (bone, muscle or joint) pain which is sometimes severe†§

Common: joint swelling†

Rare: Osteonecrosis of the jaw‡§; atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction)⊥

General disorders and administration site conditions:

Common: asthenia†, peripheral oedema†

Uncommon: transient symptoms as in an acute-phase response (myalgia, malaise and rarely, fever), typically in association with initiation of treatment†.

§See section 4.4

†Frequency in Clinical Trials was similar in the drug and placebo group.

*See sections 4.2 and 4.4

‡This adverse reaction was identified through post-marketing surveillance. The frequency of rare was estimated based on relevant clinical trials.

⊥Identified in postmarketing experience.

Reporting of suspected adverse reactions

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


4.9 Overdose


Symptoms

Hypocalcaemia, hypophosphatemia and upper gastro-intestinal adverse effects such as upset stomach, heartburn, oesophagitis, gastritis or ulcer may result from oral overdosage.


Management

No specific information is available on the treatment of overdosage with alendronate. Milk or antacids should be given to bind the alendronate. Due to the risk of oesophageal irritation, vomiting should not be induced and the patient must remain fully upright.


5. PHARMACOLOGICAL PROPERTIES


5.1 Pharmacodynamic properties


Pharmacotherapeutic group: Bisphosphonate, for the treatment of bone diseases.

ATC code: M05BA04


Mechanism of action

The active ingredient of Alendronate bioeq pharma Veckotablett, alendronate sodium trihydrate, 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 the recruitment or attachment of osteoclasts is not affected. The bone formed during treatment with alendronate is of normal quality.


Clinical efficacy and safety

Treatment of post-menopausal osteoporosis


Osteoporosis is defined as BMD of the spine or hip 2.5 SD belowthe mean value ofa normal young population or as a previous fragilityfracture, irrespectiveof BMD.


The therapeutic equivalence of alendronate (weekly tablet 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=6459).


In the initial efficacy studies, the mean bone mineral density (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 was 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 found in the analysis of the subgroups of osteoporotic women (37% of the global population 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.


Paediatric population:

Alendronate sodium has been studied in a small number of patients with osteogenesis imperfecta under the age of 18 years. Results are insufficient to support the use of alendronate sodium in paediatric patients with osteogenesis imperfecta.


5.2 Pharmacokinetic properties


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.


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 any 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 drug 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 14C] 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 kidneys in rats and thus it is not anticipated to interfere with the excretion of other medicinal products by those systems in humans.


Renal impairment

Preclinical studies show that the drug 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 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 fetal ossification. The relevance to humans is unknown.


6. PHARMACEUTICAL PARTICULARS


6.1 List of excipients


Lactose monohydrate

Microcrystalline cellulose (E460)

Croscarmellose sodium

Silica colloidal anhydrous

Magnesium stearate (E572)


6.2 Incompatibilities


Not applicable.


6.3 Shelf life


3 years.


6.4 Special precautions for storage


This medicinal product does not require any special storage conditions.


6.5 Nature and contents of container


Cartons containing 2, 4, 8, 12 or 40 tablets in aluminium/PVC blister packs.


Not all pack sizes may be marketed.


6.6 Special precautions for disposal and other handling


No special requirements.


7. MARKETING AUTHORISATION HOLDER


[To be completed nationally]


8. MARKETING AUTHORISATION NUMBER(S)


[To be completed nationally]


9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION


DD month YYYY


10. DATE OF REVISION OF THE TEXT


2016-09-12