Document: Alendropol Veckotablett 70 mg tablet ENG SmPC change

• Alendropol Veckotablett 70 mg tablet SmPC
• Alendropol Veckotablett 70 mg tablet ENG SmPC

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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Alendropol Veckotablett 70 mg tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Every tablet contains 70 mg alendronate (as alendronate sodium (trihydrate)).

Excipientwith known effect:lactose monohydrate.

Each tablet contains 128.64 mg lactose monohydrate.

For the full list of excipients, see section 6.1

3. PHARMACEUTICAL form

Tablet.

Tablets are white, oblong and biconvex.

4. Clinical particulars

4.1 Therapeutic indications

Treatment of postmenopausal osteoporosis. Alendronate minimises the risk of hip and spinal fractures.

4.2 Posology and method of administration

Posology:

Recommended dosage is one 70 mg tablet once a week.

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 on an individual patient basis, particularly after 5 or more years of use.

In order to achieve satisfactory absorption of alendronate:

Alendropol Veckotablettshould only be taken with normal water a minimum of 30 minutes before the day’s first meal, drink or other medicinal products. Other drinks (including mineral water), food and certain medicinal products are likely to reduce the absorption of alendronate (see section 4.5).

In order to facilitate the transportation to the stomach and therefore minimise the risk of irritation/side-effects locally and in the oesophagus (see section 4.4):

• Alendropol Veckotablett should only be swallowed with the help of a glass of water (not less than 200 ml) upon getting up.

• Patients should only swallow Alendropol Veckotablett whole. The patient should not crush or chew the tablet or allow the tablet to dissolve in the mouth due to the risk of ulcers in the mouth/throat.

• The patient should not lie down before the day’s first meal, which should be a minimum of 30 minutes after taking the tablet.

• The patient should not lie down within 30 minutes after taking the Alendropol Veckotablett.

The patient should take calcium and vitamin D supplements, if the dietary intake is not sufficient (see section 4.4).

Use by the elderly:

Clinical studies have shown no age related difference concerning the effects or safety profiles of alendronate. Therefore no adjustment of the dose is required for the elderly.

Use in renal impairment:

No adjustment of the dose is required for patients with a glomerular filtration rate (GFR) over 35 ml/min. Alendronate is not recommended for patients with a reduced kidney function where the GFR is under 35 ml/min, due to a lack of experience with this condition.

Peadiatric population:

Alendronate sodium is not recommended for use in children 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).

Alendropol Veckotablett has not been examined for the treatment of corticosteroid induced osteoporosis.

4.3 Contraindications

• Abnormalities of the oesophagus and other factors that delay oesophageal emptying, such as strictures or achalasia.

• Inability to stand or sit upright for a minimum of 30 minutes.

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Hypocalcaemia

4.4 Special warnings and precautions for use

Alendronate can cause local irritation in the mucous membrane in the upper part of the gastrointestinal tract. As there is a risk of aggravating the underlying illness, care should be taken when alendronate is given to patients with active problems in the upper gastrointestinal tract, such as dysphagia, oesophageal illness, gastritis, duodenitis, ulcers or who have recently (during the last year) experienced severe gastrointestinal illness such as stomach ulcers, active gastrointestinal bleeding or surgical intervention in 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.

Oesophageal adverse reaction/experience (in certain cases severe and requiring hospital care) such as oesophagitis, oesophageal ulcers and oesophageal erosion, in exceptional cases followed by oesophageal stricture have been reported in patients being treated with alendronate. Doctors should therefore pay attention to every sign or symptom of possible oesophageal reaction. The patients should be instructed to stop taking alendronate and seek medical attention if they develop symptoms of oesophageal irritation such as dysphagia, odynophagia, retrosternal pain or newly developed or aggravated heartburn.

The risk of severe oesophageal adverse reaction/experience 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 the 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.

Although no increased risk has been observed in extensive clinical studies, rare occurrences have been reported of gastric and duodenal ulcers since approval, some of which have been severe and with complications.

Osteonecrosis of the jaw generally associated with tooth extraction and/or a local infection (including osteomyelitis) has been reported in patients with cancer undergoing a treatment regime that is comprised mainly of intravenously administered biphosphonates.

Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral biphosphonates.

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, and 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.

During treatment these patients should avoid invasive dental intervention, if possible.For patients who develop osteonecrosis in the jaw during ongoing biphosphonate treatment, dental surgery can aggravate the condition. For patients who need to undergo dental intervention, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw.

Clinical evaluation by the attending doctor shall guide the treatment plan for every patient based on risk/benefit assessment for the individual patient.

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.

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.

Bone, joint and/or muscle pain has been reported in patients who take biphosphonates.After approval these symptoms have on rare occasions been reported as severe and/or impact on the ability to perform everyday activities (see section 4.8). The time to onset of symtoms varied from one day to several months after starting the treatment. The majority of patients experienced relief from the symptoms upon cessation of treatment. A sub-category experienced recurring symptoms with repeated exposure to the same medicinal product or another biphosphonate.

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.

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

Patients should be instructed that if they miss a dose of Alendropol Veckotablett, 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 on the day that they originally chose.

Alendronate is not recommended for patients with a reduced kidney function where the GFR is lower than 35 ml/min (see section 4.2).

Other causes of osteoporosis than oestrogen deficiency and ageing should be considered.

Hypocalcaemia must be corrected before starting treatment with alendronate (see section 4.3). Other disturbances in mineral metabolism (such as vitamin D deficiency and hypothyroidism) should also be treated effectively. Patients with these conditions should have serum calcium and symptoms of hypocalcaemia monitored during treatment with alendronate.

Due to the positive effect of alendronate on the increase of bone mineralisation, reductions of serum calcium and serum 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 reports of symptomatic hypocalcaemia that have occasionally been severe and have often occurred in patients with a predisposing condition (for example hypoparathyroidism, vitamin D deficiency and calcium malabsorption). It is therefore particularly important to make sure that patients who use glucocortoids have a sufficient intake of calcium and vitamin D.

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

It is likely that food and drink (including mineral water), calcium supplements, antacids and certain oral medicinal products affect the absorption of alendronate when taken at the same time. Therefore the patients must wait a minimum of 30 minutes after taking alendronate before taking any other oral medicinal products (see sections 4.2 and 5.2).

The incidence of upper gastrointestinal adverse events increases in patients receiving concomitant therapy with daily doses of alendronate greater than 10 mg and acetylsalicylic acid - containing products.

Since Nonsteroidal Anti-inflammatory Drugs use is associated with gastrointestinal irritation, caution should be used during concomitant use with alendronate.

No other clinically significant pharmaceutical interactions are anticipated.

A number of patients in the clinical studies received oestrogen (intravaginal, transdermal or orally) at the same time as alendronate. No side effects could be connected to the combined treatment.

Specific interaction studies have not been carried out, but alendronate has been used in clinical studies at the same time as a quantity of other generally 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 adequate data from the use of alendronate in pregnant women.Animal studies 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).

Breastfeeding

It is unknown if alendronate is excreted in breast milk in humans. Alendronate should not be used by women who are breastfeeding.

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 alendronate may affect some patients' ability to drive or operate machinery. Individual responses to alendronate may vary (see section 4.8 ).

4.8 Undesirable effects

In a one-year study of postmenopausal women with osteoporosis the overall safety profiles for alendronate (weekly tablet 70 mg) once a week (n=519) and alendronate 10 mg daily (n=370) were comparable.

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

Side effects reported by the investigators as possibly, probably or definitively drug-related are presented below if they occur in 1% in either treatment groups in the one year study or in 1% of the patients treated with alendronate 10 mg/daily and with an incidence higher than in patients treated with the placebo in the three year studies:

	One year study		Three year studies
	Alendronate	Alendronate	Alendronate	Placebo
	70 mg weekly mg tablets«	10 mg daily	10 mg daily
	(n=519)	(n=370)	(n=196)	(n=397)
	%	%	%	%
Gastrointestinal 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 distension	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 ulcers	0.0	1.1	0.0	0.0
Oesophageal ulcers	0.0	0.0	1.5	0.0
Musculoskeletal and connective tissue disorders connective tissue disorders
Musculoskeletal pain (bones, muscles or joints)	2.9	3.2	4.1	2.5
Muscular cramp	0.2	1.1	0.0	1.0
Nervous system disorders
Headache	0.4	0.3	2.6	1.5

The following side effects have also been reported in clinical studies and/or after approval:

Side effects are given in descending order of severity within each category.

[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 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†
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)⊥ Very rare: Osteonecrosis of the external auditory canal (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.

Osteonecrosis in the jaw has been reported in patients treated with biphosphonates. The majority of the reports concern cancer patients, but similar cases have also been reported in patients who are being treated for osteoporosis. Osteonecrosis in the jaw is generally associated with tooth extraction and/or local infection (including osteomyelitis). A cancer diagnosis, chemotherapy, radiation treatment, corticosteroids as well as poor oral hygiene are also considered to be risk factors; (see 4.4 Special warnings and precautions for use).

Reporting of suspected adverse reactions

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

4.9 Overdose

Hypocalcaemia, hypophosphatemia and upper gastrointestinal side effects such as upset stomach, heartburn, oesophagitis, gastritis or ulcers can occur with oral overdosing.

Specific information regarding overdosing with alendronate is not available. Milk or antacids should be given in order to bind the alendronate. Due to the risk of oesophageal irritation, vomiting should not be induced and the patient kept in an upright position.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Biphosphonates, medicinal products for the treatment of skeletal illnesses.

ATC code: M05BA04

Mechanism of action

The active substance in Alendropol Veckotablett, sodium alendronate trihydrate, is a biphosphonate which retards the bone resorption of osteoclasts without any direct effect on osteogenesis. Preclinical studies have demonstrated a preference for the localisation of alendronate to the places where active resorption takes place. Osteoclast activity is retarded, but the formation and binding of osteoclasts is not affected. Bone which is formed during treatment with alendronate is of normal quality.

Clinical efficacy and safety

Treatment of postmenopausal osteoporosis

Osteoporosis is defined as bone density (BMD) of the spine or hips with a standard deviation (SD) of 2.5 under the mean value for a normal young population or as an earlier low energy fracture, regardless of bone density.

The therapeutic equivalence of alendronate (weekly tablet 70 mg) (n=519) and alendronate 10 mg daily (n=370) was shown in a one year multi centred study of postmenopausal women with osteoporosis. The mean increase from the base value of the bone density (BMD) in the spine after one year was 5.1% (95% confidence interval (CI): 4.8, 5.4%) in the group who received 70 mg once a week and 5.4% (95% CI: 5.0, 5.8%) in the group who received 10 mg daily. The average increase in bone density in the group that received 70 mg once a week as well as the one that received 10 mg daily, was 2.3% and 2.9% in the femoral neck and 2.9% and 3.1% over the entire hip bone. The two treatment groups were also similar in relation to increased bone density in other parts of the skeleton.

The effects of alendronate on bone density (BMD) and incidences of fractures in postmenopausal women were examined in two Primary Phase III studies of identical design (n=994), as well as in the Fracture Intervention Trial (FIT n=6459).

The increase in bone density (BMD) with alendronate 10 mg daily, compared to placebo in the two Primary Phase III studies after three years, was 8.8%, 5.9% and 7.8% in the spine, femoral neck and trochanter respectively. The total bone density in the body also increased significantly. In the patients treated with alendronate, the percentage who received one or more spinal fractures decreased by 48% (alendronate 3.2% compared with the placebo 6.2%). In the two year extension of these studies, bone density continued to increase in the spine and trochanters. Moreover, the increase in bone density in the femoral neck and total body was sustained.

The FIT studies included two placebo controlled studies where alendronate was given daily (5 mg daily for two years and 10 mg daily for an additional either one or two years):

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.

Laboratory values

In clinical studies asymptomatic, moderate and temporary reductions of serum calcium and serum phosphate were observed in patients on 10 mg/kg per day alendronate.

Serum calcium was reduced in 18% of patients on alendronate as compared to 12% of patients on placebo, while serum phosphate was reduced in 10% of patients on alendronate as compared to 3% of patients on placebo. Nonetheless, reductions of serum calcium to 2.0 mmol/l and serum phosphate to 0.65 mmol/l were comparable in both groups.

5.2 Pharmacokinetic properties

Absorption

Compared with an intravenous reference dose, the preparation bioavailability of alendronate in women was 0.64% with doses from 5 to 70 mg given after a night fasting and two hours before a standard breakfast. The bioavailability reduced to an estimated 0.46% and 0.39% when alendronate was given an hour or a half hour before a standard breakfast. In an osteoporosis study, alendronate was effective when given a minimum of 30 minutes before the first meal or drink of the day.

Bioavailability was negligible irrespective of if alendronate was given with or up to two hours after a standard breakfast. Simultaneous administration of alendronate and coffee or orange juice reduced the bioavailability by around 60%.

In healthy people, prednisolon taken orally (20 mg three times daily for five days) did not give any clinically meaningful change to the oral bioavailability of alendronate (an increase from 20% to 44%).

Distribution

Studies on rats showed that alendronate was initially distributed to soft tissue after intravenous administration of 1 mg/kg but was then soon redistributed to bone or excreted in the urine. The mean value for the distribution volume at a steady state, excluding bones, is a minimum of 28 litres in humans. Concentrations of the medicinal product in plasma after therapeutic oral dosage are too low for analytical detection (<5 ng/ml). The binding to plasma proteins in humans is around 78%.

Biotransformation

There is no evidence of alendronate metabolising in animals or people.

Elimination

After an intravenous single dose of (¹⁴C) alendronate, approximately 50% of the radioactivity was excreted in the urine within 72 hours and little or no radioactivity was found in the faeces. After an intravenous single dose of 10 mg, the kidney clearance of alendronate 71 ml/min and systematic clearance did not exceed 200 ml/min. Plasma concentrations reduced by more than 95% within 6 hours after intravenous administration. The overall half-life period in humans is estimated to exceed ten years, which reflects the excretion of alendronate from bones. Alendronate is not excreted via the acid-base-transport system in the kidneys in rats and therefore assumed not to affect the excretion of other medicinal products via this system in humans.

Patent characteristics

Preclinical studies show that medicinal products that are not stored in bones are quickly excreted in the urine. In animals no sign of saturation of the uptake in bones could be seen after chronic dosing with cumulative intravenous doses up to 35 mg/kg. Even if no clinical information is available it is likely that, as in animals, elimination of alendronate via the kidneys will be reduced in patients with reduced kidney function. Therefore a somewhat higher accumulation of alendronate in bones is expected in patients with reduced kidney function (see 4.2 Posology and method of administration).

5.3 Preclinical safety data

Current studies in relation to general toxicity, genotoxicity and carcinogenic potential do not show any special risks to humans. Studies on female rats have shown that treatment with alendronate during pregnancy is connected with dystocia during partus which relates to hypocalcaemia. Studies where rats were given high doses showed an increased incidence of insufficient bone development in the foetus. The relevance for humans is unknown.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate

Microcrystalline cellulose

Croscarmellose sodium

Silica colloidal anhydrous

Magnesium stearate

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

Pack sizes of 2, 4, 8, 12 or 40 tablets are supplied 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

Date of first authorisation: [To be completed nationally]

Date of latest renewal: [To be completed nationally]

10. DATE OF REVISION OF THE TEXT

2016-06-03