Alendro is indicated in adults for the treatment of postmenopausal osteoporosis. It reduces the risk of
vertebral and hip fractures.

Posology
The recommended dosage is one 70 mg tablet once weekly.
Patients should be instructed that if they miss a dose of Alendro Once Weekly, 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.
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.

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 creatinine clearance greater than 35 ml/min.
Alendronate is not recommended for patients with renal impairment where creatinine clearance is less
than 35 ml/min, due to lack of experience.

Paediatric population
The safety and efficacy of Alendronate in children less than 18 years of age has not been established.
This medicinal product should not be used in children less than 18 years of age. Currently available
data for alendronic acid in the paediatric population is described in section 5.1.
Method of administration
Oral use.
To permit adequate absorption of alendronate:

Alendronate must be taken at least 30 minutes before the first food, beverage, or 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):
- Alendronate should only be swallowed upon arising for the day with a full glass of water (not less
than 200 ml).
- Patients should only swallow Alendronate 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 for at least 30 minutes after taking Alendronate and until after the first
food of the day.
- Alendronate should not be taken at bedtime or before arising for the day.
Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate (see section 4.4).
Alendronate Once Weekly 70 mg has not been investigated in the treatment of glucocorticoid-induced osteoporosis.

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Abnormalities of the esophagus and other factors which delay esophageal emptying such as stricture or achalasia. - Inability to stand or sit upright for at least 30 minutes. - Hypocalcaemia.

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 disease, 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, new or worsening heartburn (see section 4.8).

The risk of severe oesophageal adverse experiences 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
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 (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.

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, angiogenesis inhibitors, 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 benefit/risk 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 such as pain or discharge, or 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 treatment. A subset had recurrence of symptoms when rechallenged
with the same medicinal product 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 complete 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.
Renal impairment
Alendronate is not recommended for patients with renal impairment where creatinine clearance 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 before starting this medicinal product. In patients with these conditions,
serum calcium and symptoms of hypocalcaemia should be monitored during therapy with Alendronate.
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).
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.

 

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).

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
clinical adverse interactions.

Pregnancy
There are no or limited amount of data from the use of alendronate in pregnant women. Studies in
animals have shown reproductive toxicity. Alendronate given during pregnancy in rats caused dystocia
related to hypocalcaemia (see section 5.3).
Alendronate should not be used during pregnancy.
Breast-feeding
It is unknown whether alendronate/metabolites are excreted in human milk. A risk to the
newborns/infants cannot be excluded. Alendronate should 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 foetal risk in humans. However, there is a
theoretical risk of foetal 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.

Alendronate has no or negligible direct influence on the ability to drive and use machines. Patients may
experience certain adverse reactions (for example blurred vision, dizziness and severe bone muscle or
joint pain (see section 4.8)) that may influence the ability to drive and use machines.

Summary of the safety profile
In a one-year study in postmenopausal women with osteoporosis the overall safety profiles of
Alendronate Once Weekly 70 mg (n=519) and alendronate 10 mg/day (n=370) were similar.

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/day and placebo were similar.

Adverse experiences reported by the investigators as possibly, probably or definitely drug-related are
presented below if they occurred in ≥1% in either treatment group in the one-year study, or in ≥1% of
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 Once Weekly 70mg (n=519) %	Alendronate 10 mg/day (n=370) %	Alendronate 10 mg/day (n=196) %	Placebo (n=397) %
Gastro-intestinal
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 postmarketing
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)

System organ class	Frequency	Adverse reactions
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, dizzinesst
	Uncommon	dysgeusiat
Eye disorders	Uncommon	eye inflammation (uveitis, scleritis, or 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 medicinal product 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.

To report any side effect(s):
• Saudi Arabia:
The National Pharmacovigilance and Drug Safety
Centre (NPC)
o Fax: +966-11-205-7662
o Call NPC at +966-11-2038222,
Ext: 2317-2356-2340.
o Reporting hotline: 19999
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc
• Other GCC States:
− Please contact the relevant competent authority

 

Symptoms
Hypocalcaemia, hypophosphataemia and upper gastro-intestinal adverse reactions, such as upset
stomach, heartburn, oesophagitis, gastritis, or ulcer, may result from oral overdose.

Management
No specific information is available on the treatment of overdose with alendronate. 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.

Pharmacotherapeutic group: Bisphosphonate, for the treatment of bone diseases
ATC Code: M05B A04
Mechanism of action
The active ingredient of Alendronate, 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 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 postmenopausal osteoporosis

Osteoporosis is defined as BMD of the spine or hip 2.5 SD below the mean value of a normal
young population or as a previous fragility fracture, irrespective of BMD.
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 postmenopausal 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 postmenopausal 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 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 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.

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.

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 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
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 kidney 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).

 

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.

Microcrystalline cellulose
Lactose
Croscarmellose sodium
Magnesium stearate
Colloidal Silicon Dioxide

Not applicable.

3 years.

Do not store above 30°C

Aluminum/aluminum blisters.

No special requirements.