Consumer medicine information

Alendrobell Tablets

Alendronic acid

BRAND INFORMATION

Brand name

Alendrobell Tablets

Active ingredient

Alendronic acid

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Alendrobell Tablets.

What is in this leaflet

This leaflet answers some common questions about Alendrobell (alendronate).

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Alendrobell against the benefits they expect it will have for you.

If you have any concerns about using/taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with this medicine. You may need to read it again

What Alendrobell is used for

Alendrobell contains alendronate tablets.

Alendrobell is used to treat osteoporosis.

This condition is caused by changes in the way bone is normally maintained.

Understanding bone

Bone is living, growing tissue. Throughout life, our bodies are breaking down old bone and rebuilding new bone in a continuous cycle. Until our late 20s, while bones are still developing, we gain bone by building more than we lose. From then until about age 35 the process is usually in balance, so that the amount of bone lost is about equal to the amount that is replaced. After about age 35 this balance is disturbed, with bone loss occurring at a slightly faster rate than it can be replaced. In women, after menopause, hormonal changes cause bone loss at an even faster rate. When bone loss is excessive, bones can become thinner and weaker, and therefore are more likely to break.

Osteoporosis

Osteo means bone, and porosis means something that has holes in it, like a sponge. Therefore, osteoporosis is a disease, which causes bones to become more porous, gradually making them weaker, more brittle and likely to break.

Osteoporosis is common in postmenopausal women. The menopause occurs when the ovaries virtually stop producing the female hormone, oestrogen, or are removed (which may occur, for example, at the time of a hysterectomy). At this time, bone is removed faster than it is formed, so bone loss occurs and bones become weaker. The earlier a woman reaches the menopause, the greater the risk of osteoporosis.

Osteoporosis also occurs in men but is less common than in women.

Osteoporosis can also occur in people receiving corticosteroid medicines. If taken in high doses or for a long period of time, corticosteroid medicines can cause bone to be removed faster than it is formed. This causes loss of bone and therefore, bones become weaker and are more likely to break.

Maintaining bone mass and preventing further bone loss are important to keep your skeleton healthy.

Early on, osteoporosis usually has no symptoms. However, if left untreated it can result in broken bones, also called fractures. Although fractures usually cause pain, fractures of the bones of the spine may go unnoticed until they cause height loss. Fractures may occur during normal, everyday activity, such as lifting, or from minor injury that would not ordinarily fracture normal bone. Fractures usually occur at the hip, spine, or wrist and can lead not only to pain, but also to considerable deformity and disability, such as stooped posture from curvature of the spine, and loss of mobility.

How does Alendrobell work?

In osteoporosis, it works by slowing down the process of old bone being removed, which allows the bone-forming cells time to rebuild normal bone. Alendrobell not only helps prevent the loss of bone but also actually helps to rebuild bone and makes bone less likely to fracture. Thus, Alendrobell prevents or reverses the progression of osteoporosis. Alendronate starts working on the bone cells immediately, but measurable effects on bone mass may not be seen for several months or more.

Alendronate belongs to a group of non-hormonal medicines called bisphosphonates.

Before you take Alendrobell

You should know that Alendrobell can irritate or burn the food pipe in some people. The chances of this happening should be reduced if you follow the precautions and instructions for taking Alendrobell.

When you must not take it

You have an allergy to Alendrobell or any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include skin rash, itching, shortness of breath, swelling of the tongue or face.

Do not take if any of the following applies to you:

  • You have certain disorders of the food pipe (also called oesophagus) including those that cause difficulty in swallowing
  • You are unable to stand or sit upright for at least 30 minutes
  • Your doctor has told you that you currently have low blood calcium

Do not take Alendrobell after the expiry date printed on the pack.

If you take it after the expiry date has passed, it may not work as well or may cause harm. Do not take Alendrobell if the tablets do not look quite right.

Do not take Alendrobell if the packaging is torn or shows signs of tampering.

Tell your doctor if you have allergies to:

  • any other medicines
  • any other substances, such as foods, preservatives or dyes

Do not take Alendrobell if you are pregnant or breast-feeding.

Alendrobell has not been studied in pregnant or breast-feeding women.

Tell your doctor if you are pregnant or planning to become pregnant.

Like many other medicines, Alendrobell may affect your developing baby if you take it during pregnancy.

Tell your doctor if you are breast-feeding or planning to breast-feed.

Your doctor will discuss the possible risks and benefits of using Alendrobell during breastfeeding.

Tell your doctor if:

  • you plan to become pregnant or breast-feed
  • you have any medical conditions, especially the following:
  • kidney disease
  • swallowing or digestive problems, such as ulcers
  • you have any allergies to any other medicines or any other substances, such as foods, preservatives or dyes.
  • you have gum disease
  • you have a planned dental extraction

A dental examination should be considered before you start treatment with Alendrobell if you have any of the conditions listed below.

  • you have cancer
  • you are undergoing chemotherapy or radiotherapy
  • you are taking steroids
  • you don’t receive routine dental care
  • you have gum disease
  • you suffer from anaemia
  • you have a blood clotting disorder

If you suffer from any of the above, your doctor may recommend that you undergo dental treatment to prevent jaw-bone problems, before you start your treatment with Alendrobell.

Your doctor may decide to discontinue Alendrobell treatment if you are scheduled for oral surgery.

If you have not told your doctor about any of the above, tell him/her before you take Alendrobell.

There is no change in the dose of Alendrobell when given to elderly patients.

Do not give Alendrobell to a child. Alendrobell has not been studied in children

Avoid alcoholic beverages until you have discussed their use with your doctor.

Tell your doctor if you plan to have blood/urine test.

If you need a laboratory investigation such as blood test or urine test, do inform your doctor about the medicine you are taking.

You will need to undergo blood tests for monitoring your sugar levels at regular intervals.

If you have not told your doctor about any of the above, tell them before you take Alendrobell.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines you buy without a prescription from a pharmacy, supermarket or health food shop. Some medicines may affect the way other medicines work.

Some medicines are likely to interfere with the absorption of Alendrobell if taken at the same time. These include:

  • antacids, such as Algicon, Almacarb, Alu-tab, Amphojel, De witt's antacid, Eno powder,Gastrobom, Gastrogel, Gelusil, Meracote, Mucaine, Mylanta, Rennie, Salvital, Simeco, Titralac
  • calcium supplements
  • vitamins

Therefore, take Alendrobell at least 30 minutes before taking any of these or other medicines to make sure there is no problem with absorption. Check with your doctor or pharmacist if you are not sure whether you are taking an antacid.

You can take aspirin while you are being treated with Alendrobell. However, both aspirin and Alendrobell may increase the chance of stomach upsets.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking Alendrobell.

These medicines may be affected by Alendrobell, or may affect how well it works. You may need to use different amounts of your medicine or you may need to take different medicines. Your doctor or pharmacist will be able to tell you what to do when taking/being given Alendrobell with other medicines.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking Alendrobell.

How Alendrobell is given

How much to take

Take Alendrobell 70 mg only when prescribed by your doctor.

The usual dose of Alendrobell 70 mg is one tablet (containing 70 mg of alendronate) once a week.

Choose the day of the week that best fits your schedule. Every week, take one tablet of Alendrobell 70mg on your chosen day.

Follow all directions given to you by your doctor carefully. They may differ from the information contained in the leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

When and how to take it

Take Alendrobell 70mg, once a week, after getting up for the day on your chosen day and at least 30 minutes before taking your first food, beverage, or any other medication. Do not take it at bedtime.

Take Alendrobell 70 mg on the same day of the week every week.

Swallow Alendrobell whole with a full glass of plain water only.

It is important to take Alendrobell with plain water only, not mineral water. Mineral water and other drinks, including fruit juices, coffee and tea, will reduce the effect of Alendrobell by interfering with the absorption into the body.

Stay upright for at least 30 minutes after swallowing Alendrobell and do not take any food, medicines or drinks other than plain tap water during this time.

Do not lie down immediately after swallowing it.

It is important to stay upright (sitting, standing or walking around) for at least 30 minutes after swallowing your tablet. It is also very important to stay upright until after you have eaten your first food of the day. These actions will help make sure your tablet reaches your stomach quickly and help reduce the potential for irritation to your food pipe (oesophagus).

Alendrobell is effective only if taken when your stomach is empty. Food, drinks other than plain water, and other medicines will lessen the effect of Alendrobell by interfering with its absorption into the body.

Do not chew or suck on a tablet of Alendrobell.

Mouth ulcers may occur if the tablet is chewed or dissolved in the mouth.

How long to take it

It is important that you continue taking Alendrobell for as long as your doctor prescribes. Alendrobell can only prevent or treat your osteoporosis, by helping prevent further loss of bone and continuing to rebuild bone, if you take it every week.

Do not let yourself run out of medicine over the weekend or on holidays.

If you forget to take it

If you miss a tablet, take one 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 are not sure what to do, talk to your doctor or pharmacist.

If you have trouble remembering to take your tablets, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26), or go to accident and emergency at your nearest hospital, if you think that you or anyone else may have taken too much Alendrobell. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention. Keep these telephone numbers handy

If you take too many tablets at one time, drink a full glass of milk. Do not induce vomiting. Do not lie down.

While you are using Alendrobell

Things you must do

Take Alendrobell Tablets exactly as your doctor tells you to.

If you develop difficulty or pain upon swallowing, chest pain, or new or worsening heartburn, stop taking Alendrobell and call your doctor.

Visit your doctor regularly for check ups.

If you become pregnant while taking Alendrobell, stop taking the tablets and tell your doctor.

If you are about to be started on any new medicine tell your doctor and pharmacist that you are taking Alendrobell.

Make sure you have an adequate intake of calcium in your diet.

Your doctor, dietician or pharmacist can tell you what foods you should eat.

Appropriate preventative dental care and oral hygiene, as recommended by the dentist, should be followed during treatment.

Tell all doctors, dentists and pharmacists who are treating you that you are taking Alendrobell .

Tell your doctor if you are to undergo any blood or urine test.

Things you must not do

Do not give Alendrobell to anyone else, even if they have the same condition as you.

Do not use alendronate to treat other complaints unless your doctor tells you to.

Do not stop taking Alendrobell, or change the dosage, without checking with your doctor.

Be careful driving or operating machinery until you know how Alendrobell affects you.

Things that would be helpful for your osteoporosis

Some self help measures suggested below may help your osteoporosis. Talk to your doctor or pharmacist about these measures and for more information.

  • Exercise - can be helpful in building and maintaining strong bones. Regular exercise such as a brisk walk is a good idea. Talk to your doctor before you begin any exercise program.
  • Diet - eat a balanced diet. You may need to increase the amount of calcium in your diet by eating calcium-rich foods or taking a calcium supplement. Your doctor will advise you.
  • Smoking - appears to increase the rate at which you lose bone and, therefore, may increase your risk of fracture. Your doctor may ask you to stop smoking or at least cut down.
  • Alcohol - your doctor may advise you to cut down the amount of alcohol you drink. If you drink excessively on a regular basis, you may increase your risk of developing osteoporosis.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Alendrobell.

Alendrobell helps most people with osteoporosis, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • stomach pain, gas in the stomach or bowel, wind
  • an uncomfortable feeling in the stomach or belching after eating, also called dyspepsia, or heartburn
  • feeling sick (nausea), vomiting
  • constipation, diarrhoea
  • headache, dizziness
  • aching muscles, joints and/or bones, which rarely can be severe
  • flu-like symptoms, typically at the start of treatment, such as aching muscles, generally feeling unwell, and rarely, fever.
  • swelling of hands and feet

Most of these are the more common side effects of Alendrobell. For the most part, these have been mild.

Tell your doctor immediately if you notice any of the following

  • skin rash or redness of the skin, sometimes made worse by sunlight, itchiness
  • mouth ulcers
  • blurred vision, pain or redness in the eye
  • symptoms of low blood calcium levels including muscle cramps or spasms or tingling sensation in the fingers or around the mouth.
  • Swelling or pain in the jaw with/without infections of the gums/teeth that take a long time to heal. Alendrobell may cause jaw-bone problems in some people. Jaw-bone problems may include infection and delayed healing after teeth are pulled out or other work that involves drilling into the jaw.

These side effects are rare, and very rarely, may be serious

If any of the following happen, stop taking Alendrobell and tell your doctor immediately:

  • difficulty or pain upon swallowing
  • chest pain
  • new or worsening heartburn

These side effects may be due to irritation or ulceration of the food pipe. They may worsen if you continue taking the tablets. Rarely, these side effects may be serious.

Tell your doctor immediately or go to Emergency department at your nearest hospital if you notice any of the following:

  • swelling of the face, lips, mouth, throat or tongue which may cause difficulty in breathing or swallowing
  • pinkish, itchy swellings on the skin, also called hives or nettle rash
  • severe skin reactions
  • black tar-like and/or bloody stools

These are very serious side effects. You may need urgent medical attention or hospitalization. All these side effects are very rare.

If you have the swelling described above, you may be having a serious allergic reaction to Alendrobell.

Uncommon episodes of irregular heartbeat have been reported. Rarely, stomach or duodenal ulcers (some severe) have occurred, but it is not known whether these were caused by Alendrobell.

Other side effects not listed above may also occur in some patients. Tell you doctor if you notice anything else that is making you feel unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Alendrobell is not addictive.

After using Alendrobell

Storage

Keep this medicine where young children cannot reach it.

Keep your tablets in the blister pack until it is time to take them.

If you take the tablets out of the bottle or the blister pack they may not keep well.

Keep your Alendrobell in a cool, dry place where it stays below 25°C.

Do not store it, or any other medicine, in the bathroom or near a sink.

Do not leave it in the car on hot days.

Disposal

If your doctor tells you to stop taking Alendrobell or you find that they have passed their expiry date, ask your pharmacist what to do with any tablets that are left over.

Product description

What it looks like

Alendrobell 70mg tablets are available in a pack of 4 tablets.

Alendrobell 70mg are white to off-white circular tablets, debossed with “A” on one side and “4” on other side.

Ingredients

Active ingredient:

Alendronate sodium

Inactive ingredients

Mannitol

Croscarmellose sodium

Magnesium stearate

Purified Talc

Colloidal Anhydrous Silica

Sponsor

Alendrobell 70mg Tablets are supplied in Australia by:

Generic Health Pty Ltd
Level 1, 1102Toorak Road
Camberwell VIC 3124

Australian Registration Number

Alendrobell 70mg tablet blister pack: AUST R 130163

Alendrobell 5mg tablet blister pack: AUST R 130160 *

Alendrobell 10mg tablet blister pack: AUST R 130162 *

* Not marketed

This leaflet was updated in February 2015

BRAND INFORMATION

Brand name

Alendrobell Tablets

Active ingredient

Alendronic acid

Schedule

S4

 

1 Name of Medicine

Alendronate sodium.

6.7 Physicochemical Properties

Alendronate sodium anhydrous is a white or almost white, crystalline, nonhygroscopic powder. It is soluble in water, very slightly soluble in alcohol, and practically insoluble in chloroform. Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxyapatite found in bone. Alendronate is a bisphosphonate that acts as a potent, specific inhibitor of osteoclast mediated bone resorption.
Chemical Name: (4-amino-1-hydroxybutylidene) bisphosphonic acid monosodium salt.
Molecular Formula: C4H12NO7P2Na.
Molecular Weight: 271.1.

Chemical structure.


CAS number.

129318-43-0.

2 Qualitative and Quantitative Composition

Each Alendrobell 10 mg tablet contains alendronate sodium equivalent to 10 mg alendronic acid.
Each Alendrobell 70 mg tablet contains alendronate sodium equivalent to 70 mg alendronic acid.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Alendrobell 10 mg tablets are white to off-white tablets, debossed with "A3" on one side and with a deep breakline on other side.
Alendrobell 70 mg tablets are white to off-white circular tablets, debossed with "A" on one side and "4" on other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Alendronate is a bisphosphonate that, in animal studies, localizes preferentially to sites of bone resorption, specifically under osteoclasts, and inhibits osteoclastic bone resorption with no direct effect on bone formation. Since bone formation and bone resorption are coupled, bone formation is also reduced, but less so than resorption, leading to progressive gains in bone mass (See Section 5.1 Pharmacodynamic Properties, Clinical trials for details). Following exposure to alendronate, normal bone is formed that incorporates alendronate into its matrix where it is pharmacologically inactive.
The relative inhibitory activities on bone resorption and mineralization of alendronate and etidronate were compared in growing rats. The lowest dose of alendronate that interfered with bone mineralisation (leading to osteomalacia) was 6000-fold the antiresorptive dose. The corresponding safety margin for etidronate was one to one. These data indicate that, unlike etidronate, alendronate administered in therapeutic doses is highly unlikely to induce osteomalacia.

Osteoporosis.

WHO utilises the definition of osteoporosis as a disease characterised by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk. The diagnosis may be confirmed by the finding of low bone mass (for example, at least 2 standard deviations below the gender specific mean for young adults) or by the presence or history of osteoporotic fracture. It occurs in both males and females but is most common among women following the menopause, when bone turnover increases and the rate of bone resorption exceeds that of bone formation, leading to loss of bone mass.

Osteoporosis in postmenopausal women.

Daily oral doses of alendronate in postmenopausal women produced biochemical changes indicative of dose dependent inhibition of bone resorption, including decreases in urinary calcium and urinary markers of bone collagen degradation (such as hydroxyproline, deoxypyridinoline, and cross linked N-telopeptides of type I collagen). These biochemical changes returned toward baseline values as early as three weeks following the discontinuation of alendronate despite the long retention of alendronate in the skeleton.
Long-term treatment of osteoporosis with alendronate 10 mg/day (for up to five years) reduced urinary excretion of markers of bone resorption, deoxypyridinoline and cross linked N-telopeptides of type I collagen, by approximately 50% and 70%, respectively, to reach levels similar to those seen in healthy premenopausal women. Similar decreases were seen in patients in osteoporosis prevention studies who received alendronate 5 mg/day. The decrease in the rate of bone resorption indicated by these markers was evident as early as one month and at three to six months reached a plateau that was maintained for the entire duration of treatment with alendronate. In osteoporosis treatment studies alendronate 10 mg/day decreased the markers of bone formation, osteocalcin and total serum alkaline phosphatase, by approximately 50% and 25-30%, respectively, to reach a plateau after 6 to 12 months. Similar though slightly lower reductions in the rate of bone turnover were observed in postmenopausal women during one year studies with alendronate once weekly 70 mg for the treatment of osteoporosis. In osteoporosis prevention studies alendronate 5 mg/day decreased these markers by approximately 40% and 15%, respectively.

Osteoporosis in men.

Even though osteoporosis is less prevalent in men than in postmenopausal women, a significant proportion of osteoporotic fractures occur in men. The prevalence of vertebral deformities appears to be similar in men and women. All men with osteoporosis should be investigated for hypogonadism and, if necessary, treated for this condition. Treatment of men with osteoporosis with alendronate 10 mg/day for two years reduced urinary excretion of cross linked N-telopeptides of type I collagen by approximately 60% and bone specific alkaline phosphatase by approximately 40%. Similar reductions in cross linked N-telopeptides of type I collagen were seen in men receiving alendronate 70 mg once weekly.

Clinical trials.

Treatment of osteoporosis - postmenopausal women.

Effect on bone mineral density.

The efficacy of alendronate 10 mg once daily in postmenopausal women with osteoporosis was demonstrated in two large three year multicentre studies of virtually identical design, one performed in the United States and the other in 15 different countries (Multinational), which enrolled 478 and 516 patients, respectively. Figure 1 shows the mean increases in bone mineral density (BMD) of the lumbar spine, femoral neck and trochanter in patients receiving alendronate 10 mg/day relative to placebo treated patients at three years for each of these studies.
The increases were highly significant relative both to baseline and placebo at each measurement site in each study. Increases in BMD were evident as early as three months and continued throughout the entire three years of treatment (see Figure 2 for lumbar spine results). In the two year extension of these studies, treatment with alendronate 10 mg/day resulted in continued increases in BMD at the lumbar spine and trochanter (absolute additional increases between years 3 and 5: lumbar spine 0.94%; trochanter 0.88%). BMD at the femoral neck, forearm and total body were maintained. Thus, alendronate appears to reverse the progression of osteoporosis as assessed by increased bone mineral density. Alendronate was similarly effective regardless of age, race, baseline rate of bone turnover, renal function and use of concomitant medications.
In patients with postmenopausal osteoporosis treated with alendronate 10 mg/day for one or two years the effects of treatment withdrawal were assessed. Following discontinuation, there were no further increases in bone mass and the rates of bone loss were similar to those in the placebo groups. These data indicate that continuous treatment with alendronate is required to produce progressive increases in bone mass.
The therapeutic equivalence of alendronate once weekly 70 mg (n = 519) and alendronate 10 mg daily (n = 370) was demonstrated in a one year, double blind, multicentre study of postmenopausal women with osteoporosis. The mean increases from baseline in lumbar spine BMD at one year were 5.1% (4.8, 5.4%; 95% CI) in the 70 mg once weekly group and 5.4% (5.0, 5.8%; 95% CI) in the 10 mg daily group. The two treatment groups were also similar with regard to BMD increases at other skeletal sites. While there are no placebo controlled fracture data for the once weekly 70 mg tablet, the increases in bone density support the expectation that alendronate once weekly 70 mg will have effects to reduce the incidence of fractures similar to those of the 10 mg daily treatment (see Table 4). The study was not designed to evaluate the relative compliance of alendronate once weekly 70 mg and 10 mg daily.

Effect on fracture incidence.

Although the US and Multinational studies (see above) were not designed to assess fracture rates as the primary endpoint, preplanned analysis of the data pooled across once daily doses at three years revealed a statistically significant and clinically meaningful 48% reduction in the proportion of patients treated with alendronate experiencing one or more vertebral fractures (3.2%) relative to those treated with placebo (6.2%). Furthermore, of patients who sustained any vertebral fracture, those treated with alendronate experienced less height loss (5.9 mm vs 23.3 mm) due to a reduction in both the number and severity of fractures.
The fracture intervention trial consisted of two studies in postmenopausal women: the three year study of patients who had at least one baseline vertebral (compression) fracture and the four year study of patients with low bone mass but without baseline vertebral fracture.

Fracture intervention trial: three year study (patients with at least one baseline vertebral fracture).

This randomised, double blind, placebo controlled 2027 patient study, (alendronate n = 1022; placebo, n = 1005) demonstrated that treatment with alendronate resulted in clinically significant reductions in fracture incidence at three years as shown in Table 4. Data also showed statistically significant reductions in painful vertebral fractures and clinical fractures at other sites. Similar reductions of hip and wrist fractures were seen in five pooled osteoporosis treatment studies of two or three years duration.
Furthermore, in this population of patients with baseline vertebral fracture, treatment with alendronate significantly reduced the incidence of hospitalisations resulting from any cause (25.0% vs. 30.7%, a 20% relative risk reduction). This difference appears to be related, at least in part, to the reduction in fracture incidence.

Fracture intervention trial: four year study (patients with low bone mass but without a baseline vertebral fracture).

This randomised, double blind, placebo controlled, 4432 patient study (alendronate, n = 2214; placebo, n = 2218) further demonstrated the reduction in fracture incidence due to alendronate. The intent of the study was to recruit women with osteoporosis, i.e. with a baseline femoral neck BMD at least two standard deviations below the mean for young adult women. However, due to subsequent revisions to the normative values for femoral neck BMD, 31% of patients were found not to meet this entry criterion and thus this study included both osteoporotic and nonosteoporotic women. The results are shown in Table 5 for the patients with osteoporosis.

Consistency of fracture results.

The reductions in the incidence of vertebral fractures (alendronate vs. placebo) in the three and four year studies of FIT were consistent with that in the combined US and Multinational (US/Mult) treatment studies (see Table 5), in which 80% of the women did not have a vertebral fracture at baseline. During these studies, treatment with alendronate reduced the proportion of women experiencing at least one new vertebral fracture by approximately 50% (three year FIT: 47% reduction, p < 0.001; four year FIT: 44% reduction, p = 0.001 US/Mult, 48% reduction, p = 0.034). In addition, alendronate reduced the proportion of women experiencing multiple (two or more) new vertebral fractures by approximately 90% in US/Mult and three year FIT studies (p < 0.001). Thus, alendronate reduced the incidence of vertebral fractures whether or not patients had experienced a previous vertebral fracture.
Overall, these results demonstrate the consistent efficacy of alendronate in reducing the incidence of fractures, including those of the spine and hip, which are the sites of osteoporotic fracture associated with greatest morbidity.

Bone histology.

Bone histology in 270 postmenopausal patients with osteoporosis treated with alendronate at doses ranging from 1 to 20 mg/day for one, two or three years revealed normal mineralisation and structure, as well as the expected decrease in bone turnover relative to placebo. These data, together with the normal bone histology and increased bone strength observed in ovariectomised rats and baboons exposed to long-term alendronate treatment, indicate that bone formed during therapy with alendronate is of normal quality.

Concomitant use with estrogen/hormone replacement therapy.

The effects on BMD of treatment with alendronate 10 mg once daily and conjugated estrogen (0.625 mg/day) either alone or in combination were assessed in a two year, double blind, placebo controlled study of hysterectomised postmenopausal osteoporotic women (n = 425). At two years, the increases in lumbar spine BMD from baseline were significantly greater with the combination (8.3%) than with either estrogen or alendronate alone (both 6.0%).
The effects on BMD when alendronate was added to stable doses (for at least one year) of HRT (estrogen ± progestin) were assessed in a one year, double blind, placebo controlled study in postmenopausal osteoporotic women (n = 428). The addition of alendronate 10 mg once daily to HRT produced, at one year, significantly greater increases in lumbar spine BMD (3.7%) vs. HRT alone (1.1%).
In these studies, significant increases or favourable trends in BMD for combined therapy compared with HRT alone were seen at the total hip, femoral neck, and trochanter. No significant effect was seen for total body BMD.

Men.

The efficacy of alendronate 10 mg once daily in men with osteoporosis was demonstrated in a two year, double blind, placebo controlled, multicentre study, which enrolled 241 osteoporotic men between the ages of 31 and 87 years. All patients in the study (97.5% of whom were Caucasian) had either: 1) a BMD T-score less than or equal to -2 at the femoral neck and less than or equal to -1 at the lumbar spine or 2) a baseline osteoporotic fracture and a BMD T-score of less than or equal to -1 at the femoral neck. At two years the mean increases relative to placebo in BMD in men receiving alendronate 10 mg daily were; lumbar spine 5.3%; femoral neck 2.6%; trochanter 3.1%; and total body 1.6% (all p ≤ 0.001). Alendronate was effective regardless of age, gonadal function, baseline rate of bone turnover, or baseline BMD. Consistent with the much larger studies in postmenopausal women, in these men alendronate 10 mg daily reduced the incidence of new vertebral fracture (post hoc analysis; assessment by quantitative radiography) relative to placebo (0.8% vs 7.1%, respectively; p = 0.017) and correspondingly, also reduced height loss (-0.6 vs -2.4 mm, respectively; p = 0.022).
The effects of discontinuation of alendronate treatment have not been studied in this population.

Prevention of osteoporosis.

For the prevention of osteoporosis, alendronate may be considered in postmenopausal women who are at risk of developing osteoporosis and for whom the desired clinical outcome is to maintain bone mass and to reduce the risk of future fracture.
Bone loss is particularly rapid in postmenopausal women younger than age 60. Risk factors often associated with the development of postmenopausal osteoporosis include early menopause; moderately low bone mass (for example, at least 1 standard deviation below the mean for healthy young adult women; thin body build and family history of osteoporosis). The presence of such risk factors may be important when considering the use of alendronate for prevention of osteoporosis.
Prevention of bone loss was demonstrated in both a two year (n = 1609) and a three year (n = 447) study of women 40-60 years of age who were at least 6 months postmenopausal. In these studies, alendronate or matching placebo was administered once daily to nonosteoporotic women (overall baseline spine BMD approximately one SD lower that the premenopausal mean BMD).
As expected, in the placebo treated patients BMD losses of approximately 1% per year were seen at the spine, hip (femoral neck and trochanter) and total body. In contrast, alendronate 5 mg/day effectively prevented bone loss, and induced highly significant increases in bone mass at each of these sites. The mean percent increase in BMD from baseline at the lumbar spine, femoral neck, trochanter and total body at the end of the two year study were 3.46%, 1.27%, 2.98% and 0.67%, respectively, and those at the end of the three year study were 2.89%, 1.10%, 2.71% and 0.32%, respectively (see Figure 3).
In addition, alendronate 5 mg/day reduced the rate of bone loss in the forearm by approximately half relative to placebo. Alendronate 5 mg/day was similarly effective in this population regardless of age, time since menopause, race and baseline rate of bone turnover.
In the two year study (n = 1609), of 435 women willing to be randomised to an open label estrogen/progestin therapy subgroup, 55 in the US centres received conjugated equine estrogens 0.625 mg daily (Premarin) in combination with medroxyprogesterone acetate 5 mg daily (Provera), whilst 55 in the European centres received higher doses of estrogen given as 17β-estradiol 2 mg daily in combination with norethisterone acetate 1 mg daily (10 days per 28 day cycle) (Trisequens). Only women in the European centres using Trisequens experienced increases in BMD at the spine, hip and total body that were different from those in women using alendronate 5 mg. At these centres, two year increases in BMD at the lumbar spine were 5.1% and 3.3%, femoral neck 2.4% and 1.4%, trochanter 4.8% and 2.8%, and total body 2.6% and 0.6% in the Trisequens and alendronate 5 mg groups, respectively. Increases with Premarin and Provera in the US centres were not statistically different to those obtained with alendronate 5 mg. Both alendronate 5 mg and estrogen/progestin therapy prevented bone loss in these nonosteoporotic women.
Bone histology was normal in the 28 patients biopsied at the end of three years who received alendronate doses of up to 10 mg/day.

Glucocorticoid induced osteoporosis.

Sustained use of glucocorticoids is commonly associated with development of osteoporosis and resulting fractures (especially vertebral, hip and rib). It occurs both in males and females of all ages. Bone loss occurs as a result of a lower rate of bone formation relative to that of bone resorption. Alendronate decreases bone resorption without directly inhibiting bone formation.
In clinical studies of one year's duration, alendronate 5 and 10 mg/day reduced cross linked N-telopeptides of type 1 collagen (a marker of bone resorption) by approximately 60% and reduced bone specific alkaline phosphatase and total serum alkaline phosphatase (markers of bone formation) by approximately 25% to 30% and 12% to 15%, respectively. As a result of inhibition of bone resorption, alendronate 5 and 10 mg/day induced asymptomatic decreases in serum calcium (approximately 1%) and serum phosphate (approximately 2 to 7%).
The efficacy of alendronate 5 and 10 mg once daily in men and women receiving glucocorticoids (at least 7.5 mg/day of prednisone or equivalent) was demonstrated in two, one year placebo controlled, double blind, multicentre studies (n: total = 560, males = 176) of virtually identical design. Most of the patients were ambulant, Caucasian and nonsmokers. The study population included patients with rheumatoid arthritis, polymyalgia rheumatica, systemic lupus erythematosus, pemphigus, asthma, myositis, inflammatory bowel disease, giant cell arteritis, sarcoidosis, myasthenia gravis, chronic obstructive pulmonary disease and nephrotic syndrome. The range and duration of prior corticosteroid use in the studies was 0 to 538 months with a mean of 43.6 months and a median of 12 months. The range of prednisone dose at study commencement was 5 to 135 mg/day with a mean of 18.4 mg and a median of 10 mg daily. Fifty seven percent (57%) of patients had osteopenia/osteoporosis at study commencement. Patients received supplemental calcium and vitamin D. At one year, the mean increases relative to placebo in BMD in patients receiving alendronate 5 mg/day from the combined studies were: lumbar spine, 2.41%; femoral neck, 2.19%; and trochanter, 1.65%. These increases were significant at each site. Total body BMD was maintained with alendronate 5 mg/day indicating that the increase in bone mass of the spine and hip did not occur at the expense of other sites. The increases in BMD with alendronate 10 mg/day were similar to those with alendronate 5 mg/day in all patients except for postmenopausal women not receiving estrogen therapy. In these women, the increases (relative to placebo) with alendronate 10 mg/day were greater than those with alendronate 5 mg/day at the lumbar spine (4.11% vs. 1.56%) and trochanter (2.84% vs. 1.67%), but not at other sites. Alendronate was effective regardless of dose or duration of glucocorticoid use. In addition, alendronate was similarly effective regardless of age (< 65 vs. ≥ 65 years), race (Caucasian vs. other races), gender, baseline BMD, baseline bone turnover, and use with a variety of common medications.
Bone histology was normal in the 49 patients biopsied at the end of one year who received alendronate at doses of up to 10 mg/day.

5.2 Pharmacokinetic Properties

Absorption.

Relative to an intravenous (IV) reference dose, the mean oral 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. There was substantial variability both within and between patients, coefficient of variation 63% and 77%, respectively. Oral bioavailability in men (0.6%) was similar to that in women.
Bioavailability was decreased similarly (by approximately 40%) whether alendronate was administered one or one half hour before a standardised breakfast. In osteoporosis and Paget's disease 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 normal subjects, oral prednisone (20 mg three times daily for five days) did not substantially alter the oral bioavailability of alendronate (alendronate alone, 0.73%; alendronate plus prednisone, 0.87%).

Distribution.

Preclinical studies show that alendronate transiently distributes to soft tissues following 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 L in humans. Concentrations of alendronate in plasma following therapeutic oral doses are generally below the limits of quantification (less than 5 nanogram/mL). Protein binding in human plasma is approximately 78%.

Metabolism.

There is no evidence that alendronate is metabolised in animals or humans.

Excretion.

Following a single 10 mg IV 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; the renal clearance of alendronate was 71 mL/min. Plasma concentrations fell by more than 95% within 6 hours following IV administration, due to distribution to the bone and excretion in the urine. The terminal half-life in humans is estimated to exceed 10 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 drugs by those systems in humans.
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 over three weeks in rats, with a cumulative IV dose of 35 mg/kg. 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 Dose and Method of Administration).
A bioequivalence study, specific to Alendrobell, was conducted comparing Alendrobell tablets with Fosamax tablets, administered as a single oral dose of 70 mg, taken as one 70 mg tablet. Urinary excretion rates were the same for both formulations (see Table 6). Thus, Alendrobell tablets are shown to be bioequivalent to Fosamax tablets and may be used interchangeably. The acceptance criteria for the confidence intervals of the pharmacokinetic parameters in these studies were 80-125%.
No bioavailability or pharmacokinetic data are available for Alendrobell 5 mg and 10 mg tablets.

5.3 Preclinical Safety Data

Genotoxicity.

Alendronate did not cause gene mutations in bacteria or in mammalian cells in vitro, nor did it cause DNA damage in rat hepatocytes in vitro (alkaline elution assay). In assays of chromosomal damage, alendronate was weakly positive in an in vitro assay using Chinese hamster ovary cells at cytotoxic concentrations (5 mM and above), but was negative at IV doses up to 25 mg/kg/day (75 mg/m2) in an in vivo assay (chromosomal aberrations in mouse bone marrow).

Carcinogenicity.

No evidence of carcinogenic effect was observed in a 105 week study in rats receiving oral doses up to 3.75 mg/kg/day and in a 92 week study in mice receiving oral doses up to 10 mg/kg/day.

4 Clinical Particulars

4.1 Therapeutic Indications

Alendrobell is indicated for the treatment of osteoporosis, including glucocorticoid induced osteoporosis (see Section 4.2 Dose and Method of Administration).
Prior to treatment, osteoporosis must be confirmed by:
the finding of low bone mass of at least 2 standard deviations below the gender specific mean for young adults; or by
the presence of osteoporotic fracture.
Alendrobell is also indicated for the prevention of:
osteoporosis in postmenopausal women with low bone mass (at least 1 standard deviation below the mean for young adults);
glucocorticoid induced osteoporosis in those patients on long-term corticosteroid therapy (see Section 4.2 Dose and Method of Administration for specific uses of Alendrobell tablets).

4.3 Contraindications

Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia.
Inability to stand or sit upright for at least 30 minutes.
Hypersensitivity to any component of this product.
Hypocalcaemia (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Severe oesophageal ulceration has been reported in patients taking alendronate (see Section 4.2 Dose and Method of Administration). Physicians should therefore be alert to any signs or symptoms signaling a possible oesophageal reaction. Patients should be instructed to discontinue Alendrobell and seek medical attention if they develop dysphagia, odynophagia or retrosternal pain.

General.

Causes of osteoporosis other than hypogonadism, aging and glucocorticoid use should be considered.
If there are clinical reasons to suspect hypocalcaemia and/or vitamin D deficiency (serum levels 25 hydroxyvitamin D < 9 nanomol/L), the appropriate diagnostic tests should be performed. Hypocalcaemia must be corrected before initiating therapy with alendronate (see Section 4.3 Contraindications). Other disturbances of mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients with these conditions, serum calcium and symptoms of hypocalcaemia should be monitored during therapy with alendronate.
Small, asymptomatic decreases in serum calcium and phosphate may occur, especially in patients receiving glucocorticoids, in whom calcium absorption may be decreased.
Ensuring adequate calcium and vitamin D intake is especially important in patients receiving glucocorticoids.
Alendronate, like other bisphosphonates, may cause local irritation of the upper gastrointestinal mucosa.
Oesophageal adverse experiences, such as oesophagitis, oesophageal ulcers and oesophageal erosions, rarely followed by oesophageal stricture or perforation, have been reported in patients receiving treatment with alendronate. In some cases these have been severe and required hospitalization.
The risk of severe oesophageal adverse experiences appears to be greater in patients who lie down after taking alendronate and/or who fail to swallow it with the recommended amount of water, and/or who continue to take alendronate after developing symptoms suggestive of oesophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient (see Section 4.2 Dose and Method of Administration).
While no increased risk was observed in extensive clinical trials, there have been rare (postmarketing) reports of gastric and duodenal ulcers, some severe and with complications.
Because of possible irritant effects of alendronate on the upper gastrointestinal mucosa and 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 diseases (including known Barrett's oesophagus), gastritis, duodenitis, or ulcers.

Dental.

Localised osteonecrosis of the jaw (ONJ), generally associated with tooth extraction and/or local infection (including osteomyelitis) with delayed healing, has been reported rarely with oral bisphosphonates including alendronate (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience). As of May 2004, ONJ after bisphosphonate treatment has been described in a total of 99 cases in two large case series, 7 of which were taking oral bisphosphonates. As of 3 November 2006, the Australian Adverse Drug Reactions Advisory Committee has received 25 reports of ONJ in patients receiving alendronate. Most reported cases of bisphosphonate associated ONJ have been in cancer patients treated with intravenous bisphosphonates. Known risk factors for ONJ include a diagnosis of cancer, concomitant therapies (e.g. chemotherapy, radiotherapy, corticosteroids), poor oral hygiene, and comorbid disorders (e.g. pre-existing periodontal and/or other pre-existing dental disease, anaemia, coagulopathy, infection) and smoking.
Prior to treatment with bisphosphonates, a dental examination with appropriate preventative dentistry should be considered in patients with possible risk factors.
Before commencing invasive dental procedures, patients and their dentist should be advised of the risks and reports of osteonecrosis of the jaw so that dental symptoms including toothache, developing during treatment can be fully assessed for cause before treatment of the tooth commences.
For patients requiring oral surgery (e.g. tooth extraction, dental implants), there are no definitive data available to establish whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Therefore, clinical judgment of the treating physician and/or surgeon should guide the management plan, including discontinuation of bisphosphonate treatment, of each patient based on individual benefit/risk assessment.
In patients who develop ONJ while on bisphosphonate therapy, the clinical judgment of the treating physician should guide the management plan to include appropriate care by an oral surgeon and discontinuation of bisphosphonate therapy should be based on individual benefit/risk assessment. Surgery at the affected area may exacerbate the condition.

Atypical stress fractures.

A small number of long-term (usually longer than three years) alendronate treated patients developed stress fractures of the proximal femoral shaft (also known as insufficiency fractures), some of which occurred in the absence of apparent trauma. Some patients experienced prodromal pain in the affected area, often associated with imaging features of stress fracture, weeks to months before a complete fracture occurred. Approximately one third of these fractures were bilateral; therefore the contralateral femur should be examined in patients who have sustained a femoral shaft stress fracture. The number of reported cases of this condition is very low (some 40 reported cases worldwide in connection with alendronate as of 2008). Patients with suspected stress fractures should be evaluated, including evaluation for known causes and risk factors (e.g. vitamin D deficiency, malabsorption, glucocorticoid use, previous stress fracture, lower extremity arthritis or fracture, extreme or increased exercise, diabetes mellitus, chronic alcohol abuse), and receive appropriate orthopaedic care. Discontinuation of bisphosphonate therapy in patients with stress fractures is advisable pending evaluation of the patient, based on individual benefit/risk assessment. A cause and effect relationship between bisphosphonate use and stress fractures has not been excluded.

Musculoskeletal pain.

Bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. In postmarketing experience, these symptoms have rarely been severe and/or incapacitating (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience). 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 drug or another bisphosphonate.

Nephrolithiasis and hypercalciuria.

Patients with a history of either nephrolithiasis or hypercalciuria may require special diets that limit their calcium intake. The calcium content of BoneCal should be considered when these diets are prescribed.

Dosing instructions for patients.

To facilitate delivery to the stomach and thus reduce the potential for oesophageal irritation patients should be instructed to swallow each tablet of alendronate with a full glass of water. Patients should be instructed not to lie down for at least 30 minutes and until after their first food of the day. Patients should not chew or suck on the tablet because of a potential for oropharyngeal ulceration. Patients should be specifically instructed not to take alendronate at bedtime or before arising for the day. Patients should be informed that failure to follow these instructions may increase their risk of oesophageal problems. Patients should be instructed that if they develop symptoms of oesophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or new or worsening heartburn) they should stop taking alendronate and consult their physician.
Patients should be instructed that if they miss a dose of Alendrobell, 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.

Use in renal impairment.

Alendronate is not recommended for patients with creatinine clearance < 35 mL/min (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

In controlled trials, there was no age related difference in the efficacy or safety profiles of alendronate.

Paediatric use.

Alendronate has not been studied in children and should not be given to them.

Effects on laboratory tests.

In double blind, multicentre, controlled studies, asymptomatic, mild and transient decreases in serum calcium and phosphate were observed in approximately 18% and 10%, respectively, of patients taking alendronate versus approximately 12% and 3% of those taking placebo. However, the incidences of decreases in serum calcium to < 8.0 mg/dL (2.0 mm) and serum phosphate to ≤ 2.0 mg P/dL (0.65 mm) were similar in both treatment groups.

4.5 Interactions with Other Medicines and Other Forms of Interactions

If taken at the same time it is likely that calcium supplements, antacids and other oral medications will interfere with absorption of alendronate. Therefore, patients must wait at least one-half hour after taking alendronate before taking any other oral medication.
No other drug interactions of clinical significance are anticipated though the concomitant medication with two or more bisphosphonates cannot be recommended because of the lack of clinical data.
Concomitant use of hormone replacement therapy (HRT) (estrogen ± progestin) and alendronate was assessed in two clinical studies of one or two years duration in postmenopausal osteoporotic women. Combined use of alendronate and HRT resulted in greater increases in bone mass, together with greater decreases in bone turnover, than seen with either treatment alone. In these studies, the safety and tolerability profile of the combination was consistent with those of the individual treatments (see Section 4.8 Adverse Effects (Undesirable Effects), Clinical studies, Concomitant use with estrogen/hormone replacement therapy).
Specific interaction studies were not performed. Alendronate (10 mg and 5 mg/day) was used in studies of treatment and prevention of osteoporosis in postmenopausal women, men and glucocorticoid users, with a wide range of commonly prescribed drugs without evidence of clinical adverse interactions. In clinical studies, the incidence of upper gastrointestinal adverse events was increased in patients receiving daily therapy with dosages of alendronate greater than 10 mg and aspirin containing products. However, this was not observed in studies with alendronate once weekly 70 mg.
Since nonsteroidal anti-inflammatory drug (NSAID) use is associated with gastrointestinal irritation, caution should be used during concomitant use with alendronate.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Alendronate sodium had no effect on fertility in male and female rats at oral doses of up to 9 and 15 mg/kg/day.
(Category B3)2
Alendronate has not been studied in pregnant women and should not be given to them. In studies with pregnant rats, oral alendronate doses of 2 mg/kg/day and above resulted in dystocia due to maternal hypocalcaemia. Foetal weight was reduced in rats at maternal doses greater than 5 mg/kg/day. No teratogenic effects were seen in rats or rabbits at oral doses up to 25 and 35 mg/kg/day, respectively.
 Alendronate has not been studied in breastfeeding women and should not be given to them.
2 Australian categorisation definition of Category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals have shown evidence of an increased occurrence of foetal damage, the significance of which is considered uncertain in humans.

4.8 Adverse Effects (Undesirable Effects)

Clinical studies.

In clinical studies alendronate was generally well tolerated. In studies of up to five years in duration, side effects, which usually were mild, generally did not require discontinuation of therapy.

Treatment of osteoporosis - postmenopausal women.

Alendronate has been evaluated for safety in clinical studies in approximately 5000 postmenopausal patients. In two three year, placebo controlled, double blind multicentre studies, discontinuation of therapy due to any clinical adverse experience occurred in 4.1% of 196 patients treated with alendronate 10 mg/day and 6.0% of 397 patients treated with placebo. Adverse experiences reported by the investigators as possibly, probably or definitely drug related in ≥ 1% of patients treated with either alendronate 10 mg/day or placebo are presented in Table 1.
Rarely, rash and erythema have occurred.
In the two year extension (treatment years 4 and 5) of the above studies, the overall safety profile of alendronate 10 mg/day was similar to that observed during the three year placebo controlled period. Additionally, the proportion of patients who discontinued alendronate 10 mg/day due to any clinical adverse experience was similar to that during the first three years of the study.
In the Fracture Intervention Trial, discontinuation of therapy due to any clinical adverse experience occurred in 9.1% of 3236 patients treated with alendronate 5 mg/day for 2 years and 10 mg/day for either one or two additional years and 10.1% of 3223 patients treated with placebo. Discontinuations due to upper gastrointestinal adverse experiences were: alendronate, 3.2%; placebo, 2.7%. The overall adverse experience profile was similar to that seen in other studies with alendronate 5 or 10 mg/day.
The overall risk of atrial fibrillation adverse events in the Fracture Intervention Trial over 5 years, was similar between alendronate (2.5%) and placebo (2.2%). However, there was a small excess incidence of serious atrial fibrillation 1.5% of alendronate patients compared to 1.0% of placebo treated patients (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In a one year, double blind, multicentre study, the overall safety and tolerability profiles of alendronate once weekly 70 mg (n = 519) and alendronate 10 mg daily (n = 370) were similar. Adverse experiences reported by the investigators as possibly, probably or definitely drug related in ≥ 1% of patients treated with either patient group are presented in Table 2.

Concomitant use with estrogen/hormone replacement therapy.

In two studies (of one and two years duration) of postmenopausal osteoporotic women (total: n = 853), the safety and tolerability profile of combined treatment with alendronate 10 mg once daily and estrogen ± progestin (n = 354) was consistent with those of the individual treatments.

Men.

In a two year, placebo controlled, double blind, multicentre study, the safety profile of alendronate 10 mg daily in 146 men was generally similar to that seen in postmenopausal women.

Other studies in men and women.

In a ten week endoscopy study in men and women (n = 277; mean age 55 years) no difference was seen in upper gastrointestinal tract lesions between alendronate once weekly 70 mg and placebo.
In an additional one year study in men and women (n = 335; mean age 50 years) the overall safety and tolerability profiles of alendronate once weekly 70 mg were similar to that of placebo and no difference was seen between men and women.

Prevention of osteoporosis.

The safety of alendronate in postmenopausal women 40-60 years of age has been evaluated in three double blind, placebo controlled studies involving over 1400 patients randomised to receive alendronate for either two or three years. In these studies, the safety and tolerability profile of alendronate 5 mg/day (n = 642) was similar to that of placebo (n = 648). The only adverse experience reported by the investigators as possibly, probably, or definitely drug related in ≥ 1% of patients treated with alendronate 5 mg/day and at a greater incidence than placebo was dyspepsia (alendronate, 1.9% vs. placebo, 1.7%).

Treatment and prevention of glucocorticoid induced osteoporosis.

In two, one year, placebo controlled, double blind, multicentre studies in patients receiving glucocorticoid treatment, the overall safety and tolerability profiles of alendronate 5 and 10 mg/day were generally similar to that of placebo. Adverse experiences reported by the investigators as possibly, probably or definitely drug related in ≥ 1% of patients treated with either alendronate 5 mg/day, 10 mg/day or placebo are presented in Table 3.

Paget's disease of bone.

In clinical studies (Paget's disease and osteoporosis), adverse experiences reported in patients taking alendronate 40 mg/day for 3-12 months were similar to those in postmenopausal women treated with alendronate 10 mg/day. However, there was an apparent increased incidence of upper gastrointestinal adverse experiences in patients taking alendronate 40 mg/day. Isolated cases of oesophagitis and gastritis resulted in discontinuation of treatment.
Additionally, musculoskeletal pain (bone, muscle or joint), which has been described in patients with Paget's disease treated with other bisphosphonates, was reported by the investigators as possibly, probably or definitely drug related in approximately 6% of patients treated with alendronate 40 mg/day versus approximately 1% of patients treated with placebo, but rarely resulted in discontinuation of therapy.

Postmarketing experience.

The following adverse reactions have been reported in postmarketing use with alendronate.

Body as a whole.

Hypersensitivity reactions including urticaria and rarely angioedema. Transient symptoms as in an acute phase response (myalgia, malaise, asthenia and rarely, fever) have been reported with alendronate, typically in association with initiation of treatment. Rarely, symptomatic hypocalcemia has occurred, generally in association with predisposing conditions. Rarely, peripheral oedema.

Gastrointestinal.

Nausea, vomiting, oesophagitis, oesophageal erosions, oesophageal ulcers, rarely oesophageal stricture or perforation, and oropharyngeal ulceration and/or stomatitis; rarely, gastric or duodenal ulcers, some severe and with complications (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).
Localised osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection, often with delayed healing, has been reported rarely.

Musculoskeletal.

Bone, joint, and/or muscle pain, rarely severe and/or incapacitating (see Section 4.4 Special Warnings and Precautions for Use); joint swelling, atypical stress fracture (see Section 4.4 Special Warnings and Precautions for Use).

Nervous system.

Dizziness, vertigo.

Skin.

Rash (occasionally with photosensitivity), pruritus, alopecia, rarely severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Special senses.

Rarely uveitis, scleritis or episcleritis.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Alendrobell must be taken at least 30 minutes before the first food, beverage, or medication of the day with plain water only. Other beverages (including mineral water), food and some medications are likely to reduce the absorption of alendronate (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Alendrobell should only be taken upon arising for the day. To facilitate delivery to the stomach and thus reduce the potential for oesophageal irritation, an Alendrobell tablet should be swallowed with a full glass of water.
Patients should not lie down for at least 30 minutes and until after their first food of the day. Alendrobell should not be taken at bedtime or before arising for the day. Failure to follow these instructions may increase the risk of oesophageal adverse experiences (see Section 4.4 Special Warnings and Precautions for Use).
Severe oesophageal ulceration has been reported in patients taking alendronate (see Section 4.4 Special Warnings and Precautions for Use). Patients should be instructed that if they develop symptoms of oesophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or new or worsening heartburn) they should stop taking Alendrobell and consult their physician.
In clinical trials, alendronate was administered with appropriate calcium and vitamin D supplementation. The use of vitamin D as the sole treatment of osteoporosis has not been established.
Patients should receive supplemental calcium and/or vitamin D, if dietary intake is inadequate (see Section 4.4 Special Warnings and Precautions for Use). Physicians should consider the vitamin D intake from vitamins and dietary supplements. Additional supplements should not be taken at the same time as Alendrobell (see above).
No dosage adjustment is necessary for the elderly or for patients with mild to moderate renal insufficiency (creatinine clearance 35 to 60 mL/min). Alendrobell is not recommended for patients with more severe renal insufficiency (creatinine clearance < 35 mL/min).
Although no specific studies have been conducted on the effects of switching patients on another therapy for osteoporosis to alendronate, there are no known or theoretical safety concerns related to alendronate in patients who previously received any other antiosteoporotic or antipagetic therapy.

Treatment of osteoporosis.

The recommended dosage is one Alendrobell 70 mg tablet once weekly or one Alendrobell 10 mg tablet once daily.

Prevention of osteoporosis in postmenopausal women.

The recommended dosage is one Alendrobell 5 mg1 tablet once a day.

Treatment and prevention of glucocorticoid induced osteoporosis.

In selected patients, the recommended dosage is 5 mg1 once a day, except for postmenopausal women not receiving estrogen, for whom the recommended dosage is 10 mg1 once a day (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Glucocorticoid induced osteoporosis).
The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
1 Note that Alendrobell is not available in 5 mg or 10 mg strengths. Other brands should be used if these dose strengths are required.

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 Adverse Effects (Undesirable Effects)).

4.9 Overdose

No specific information is available on the treatment of overdosage with alendronate. Hypocalcaemia, hypophosphataemia and upper gastrointestinal adverse events, such as upset stomach, heartburn, oesophagitis, gastritis, or ulcer, may result from oral overdosage. Administration of milk or antacids, to bind alendronate, should be considered.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Alendrobell tablets contain following inactive ingredients: mannitol, croscarmellose sodium, magnesium stearate, purified talc, colloidal anhydrous silica.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

The tablets are supplied in a PA/Al/PVC/Al blister pack containing 30 tablets for the 10 mg strength.
The tablets are supplied in a PA/Al/PVC/Al blister pack containing 4 tablets for the 70 mg strength.
Not all strengths are currently marketed.

Australian registration numbers.

Alendrobell 10 mg tablets: AUST R 130163.
Alendrobell 70 mg tablets: AUST R 130163.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes