Consumer medicine information

Alendro Once Weekly

Alendronic acid

BRAND INFORMATION

Brand name

Alendro

Active ingredient

Alendronic acid

Schedule

What is in this leaflet

This leaflet answers some common questions about ALENDRO ONCE WEEKLY.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

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

Talk to your doctor or pharmacist if you have any concerns about taking this medicine.

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

What ALENDRO ONCE WEEKLY are used for

ALENDRO ONCE WEEKLY is used to treat osteoporosis in men and postmenopausal women.

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.

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.

ALENDRO ONCE WEEKLY belongs to a group of medicines called bisphosphonates.

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

Your doctor may have prescribed this medicine for another reason. Ask your doctor if you have any questions about why ALENDRO ONCE WEEKLY has been prescribed for you.

ALENDRO ONCE WEEKLY is available only with a doctor's prescription.

Before you take it

When you must not take it

Do not take ALENDRO ONCE WEEKLY if you are allergic to:

alendronate sodium
any of the ingredients listed at the end of this leaflet.

Do not take ALENDRO ONCE WEEKLY if you:

have certain disorders of the food pipe (also called oesophagus), including those that cause difficulty swallowing
are unable to stand or sit upright for at least 30 minutes
have low levels of calcium in your blood.

Do not take ALENDRO ONCE WEEKLY if you are pregnant or breastfeeding. It has not been studied in pregnant or breastfeeding women, so it is not known whether taking it can affect your baby.

Do not take your medicine if the expiry date (Exp.) printed on the pack has passed. If you take this medicine after the expiry date has passed, it may not work as well.

Do not take it if the packaging shows signs of tampering or the tablets do not look quite right.

Before you start to take it

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives.

Tell your doctor if you plan to become pregnant or to breastfeed.

Tell your doctor if you have, or have had, any medical conditions, especially the following:

kidney problems
swallowing or digestive problems, such as ulcers.

Tell your doctor if you are planning to have any dental procedures or dental surgery. If you know that you need to have any dental work performed, make sure that you discuss this with your doctor as they may decide it is best to delay the commencement of ALENDRO ONCE WEEKLY until the work has been completed.

If you have not told your doctor about any of the above, tell them before you start taking ALENDRO ONCE WEEKLY.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that 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 ALENDRO ONCE WEEKLY if taken at the same time. These include:

antacids
calcium supplements
vitamins.

Therefore, take ALENDRO ONCE WEEKLY at least 30 minutes before taking any of these and other medicines to make sure there is no problem with absorption.

You can take aspirin while you are being treated with this medicine. However, both aspirin and ALENDRO ONCE WEEKLY can increase the chance of a stomach upset.

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist. Your doctor and pharmacist have more information on medicine to be careful with or avoid while taking ALENDRO ONCE WEEKLY.

How to take it

How much to take

Take ALENDRO ONCE WEEKLY only when prescribed by your doctor.

The usual dose is one 70 mg tablet once a week.

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

Follow all directions given to you by your doctor and pharmacist carefully.

When and how to take it

Take ALENDRO ONCE WEEKLY after getting up for the day and before taking your first food, beverage, or other medication.

Do not take it at bedtime.

Swallow ALENDRO ONCE WEEKLY whole with a full glass of plain water. It is important to take ALENDRO ONCE WEEKLY with plain water only, not mineral water. Mineral water and other drinks, including fruit juices, coffee and tea, will reduce the effect of ALENDRO ONCE WEEKLY by interfering with its absorption into the body.

Stay upright for at least 30 minutes after swallowing ALENDRO ONCE WEEKLY and do not take any food, medicines or drinks other than plain 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).

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

Do not chew or suck on a tablet of ALENDRO ONCE WEEKLY. 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 ALENDRO ONCE WEEKLY for as long as your doctor prescribes. ALENDRO ONCE WEEKLY 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.

If you forget to take it

If you forget to take ALENDRO ONCE WEEKLY, take your next dose the following morning. If you take the forgotten tablet after you have eaten or had a drink, ALENDRO ONCE WEEKLY will not work as well as it should. Therefore, it is better to skip the dose that you missed.

Do not take two tablets on the same day to make up for the dose that you missed. 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 take too much (overdose)

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

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 taking it

Things you must do

Before starting any new medicine, tell your doctor or pharmacist that you are taking ALENDRO ONCE WEEKLY.

Tell all the doctors, dentists, oral or facial surgeons and pharmacists who are treating you that you are taking ALENDRO ONCE WEEKLY. It 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.

Ensure that you maintain good oral hygiene while you are taking ALENDRO ONCE WEEKLY, especially following any dental procedure.

If you become pregnant while taking ALENDRO ONCE WEEKLY, stop taking the tablets and tell your doctor.

If you develop difficulty or pain upon swallowing, chest pain, or new or worsening heartburn, stop taking ALENDRO ONCE WEEKLY and tell your doctor.

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.

Things you must not do

Do not use ALENDRO ONCE WEEKLY to treat any other conditions unless your doctor tells you to.

Do not give ALENDRO ONCE WEEKLY to anyone else, even if they have the same condition as 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 ALENDRO ONCE WEEKLY.

Like all other medicines, this one may have unwanted side effects in some people. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

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

Ask your doctor or pharmacist to answer 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, vomiting
constipation, diarrhoea
headache
aching muscles, joints or bones
flu-like symptoms, typically at the start of treatment, such as aching muscles, generally feeling unwell or fever.

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 of the eyes
jaw pain and/or toothache
symptoms of low blood calcium levels including muscle cramps or spasms, or tingling sensation in the fingers or around the mouth
jaw problems, associated with delayed healing and infection, often following a tooth extraction or dental procedure.
If jaw problems develop, tell your dentist as well as your doctor.

If any of the following happen, stop taking ALENDRO ONCE WEEKLY 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.

If any of the following happen, stop taking ALENDRO ONCE WEEKLY and tell your doctor immediately, or go to Accident and Emergency at the nearest hospital:

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 nettlerash
black tar-like and/or bloody stools.

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

After using it

Storage

Keep ALENDRO ONCE WEEKLY where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the blister pack, they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 25°C.

Do not store ALENDRO ONCE WEEKLY or any other medicine in the bathroom or near a sink.

Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Disposal

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

Product description

What it looks like

ALENDRO ONCE WEEKLY comes as a white to off-white, oval tablet marked ‘AN 70’ on one side.

Each blister pack contains 4 tablets.

Ingredients

The active ingredient in ALENDRO ONCE WEEKLY is alendronate sodium.

Each ALENDRO ONCE WEEKLY tablet contains 70 mg of alendronate sodium.

The tablets also contain:

microcrystalline cellulose
croscarmellose sodium
lactose monohydrate
magnesium stearate.

The tablets do not contain gluten, sucrose, tartrazine or any other azo dyes. Contains sugars as lactose.

Sponsor

Arrow Pharma Pty Ltd
15 – 17 Chapel Street
Cremorne VIC 3121

Australian registration number:

ALENDRO ONCE WEEKLY – AUST R 100691

Date of revision: December 2021

Published by MIMS January 2022

BRAND INFORMATION

Brand name

Alendro

Active ingredient

Alendronic acid

Schedule

1 Name of Medicine

Alendronic acid (as alendronate sodium monohydrate).

2 Qualitative and Quantitative Composition

Alendro tablets come in three strengths and contain 10 mg, 40 mg or 70 mg of alendronic acid as alendronate sodium monohydrate.
Alendro tablets contains lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Alendro 10.

White to off-white capsule-shaped tablet embossed with "AN 10" on one side and the Arrow logo on the other.

Alendro 40.

White to off-white triangle shaped tablet embossed with "AN" over "40" on one side and the Arrow logo on the other.

Alendro Once Weekly.

White to off-white oval-shaped tablet embossed with "AN 70" on one side and plain on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

(See Section 4.2 Dose and Method of Administration).
Treatment of osteoporosis, including glucocorticoid induced osteoporosis.
Osteoporosis must be confirmed by the finding of low bone mass of at least two standard deviations below the gender specific mean for young adults, or by the presence of osteoporotic fracture.
Paget's disease of bone.

4.2 Dose and Method of Administration

Alendronate 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).
To facilitate delivery to the stomach and thus reduce the potential for oesophageal irritation, alendronate should only be swallowed upon arising for the day with a full glass of water and patients should not lie down for at least 30 minutes and until after their first food of the day. Alendronate 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 this drug (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 alendronate and consult their doctor.
Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate (see Section 4.4 Special Warnings and Precautions for Use). However, these supplements should not be taken at the same time as alendronate (see above).
No dosage adjustment is necessary for the elderly or patients with mild to moderate renal insufficiency (creatinine clearance 35 to 60 mL/minute). Alendronate is not recommended for patients with more severe renal insufficiency (creatinine clearance < 35 mL/minute).
Although no specific studies have been conducted on the effects of switching patients on another therapy for osteoporosis or Paget's disease 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 alendronate once weekly (70 mg) tablet once weekly or one 10 mg tablet once daily.

Treatment and prevention of glucocorticoid induced osteoporosis.

In postmenopausal women not receiving oestrogen, the recommended dosage is 10 mg once a day (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Glucocorticoid induced osteoporosis).

Paget's disease of bone.

The recommended treatment regimen is 40 mg once daily for up to six months.

Retreatment of Paget's disease.

In clinical studies, during the 12 months following therapy, relapses occurred in only 9% (3 out of 32) of patients who responded to treatment with alendronate. Specific retreatment data with alendronate are not available, although responses to alendronate were similar in patients who had received prior bisphosphonate therapy and those who had not. Retreatment with alendronate may be considered, following a six month post-treatment evaluation period, in patients who have relapsed based on increases in serum alkaline phosphatase.
Retreatment may also be considered in those who failed to normalise their serum alkaline phosphatase.

4.3 Contraindications

Abnormalities of the oesophagus which delay oesophageal 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 this drug (see Section 4.2 Dose and Method of Administration). Doctors should therefore be alert to any signs or symptoms signalling a possible oesophageal reaction. Patients should be instructed to discontinue alendronate and seek medical attention if they develop dysphagia, odynophagia or retrosternal pain.
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 hospitalisation.
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 the dose with a full glass 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 (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience) reports of gastric and duodenal ulcers, some severe and with complications. However, a causal relationship has not been established.
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, gastritis, duodenitis or ulcers.
Causes of osteoporosis other than hypogonadism, ageing and glucocorticoid use should be considered.
If there are clinical reasons to suspect hypocalcaemia and/or vitamin D deficiency, 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, e.g. vitamin D deficiency, should also be effectively treated. Small, asymptomatic decreases in serum calcium and phosphate may occur, especially in patients with Paget's disease, in whom the pretreatment rate of bone turnover may be greatly elevated, and in patients receiving glucocorticoids, in whom calcium absorption may be decreased.
Ensuring adequate calcium and vitamin D intake is especially important in patients with Paget's disease of bone and in patients receiving glucocorticoids.

Dental.

Localised osteonecrosis of the jaw (ONJ), generally associated with tooth extraction and/or local infection with delayed healing, has been reported rarely with oral bisphosphonates including 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 disease, anaemia, coagulopathy, infection). Patients and their dentist should be advised of the reports of osteonecrosis of the jaw so that dental symptoms developing during treatment can be fully assessed before commencing dental procedures. Patients who develop ONJ should receive appropriate care from a dental surgeon.
ONJ after bisphosphonate treatment has been described in a total of 99 cases in two large case series. Until November 2007, the Adverse Drug Reactions Advisory Committee has received twenty two such reports in patients taking alendronate.
Presentation includes jaw pain, toothache, exposed bone and possibly also altered sensation and recurrent soft tissue infection. The condition results in chronic pain and disfigurement and is resistant to treatment. Early diagnosis may reduce morbidity.
A dental examination with appropriate preventative dentistry should be considered prior to treatment with bisphosphonates in patients with possible risk factors (e.g. cancer, chemotherapy, head and neck radiotherapy, corticosteroids, poor oral hygiene, chronic periodontal disease). Patients and their dentist should be advised of the reports of osteonecrosis of the jaw so that dental symptoms developing during treatment can be fully assessed for cause before treatment of the tooth commences.
For patients requiring oral surgery, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. In patients who develop ONJ while on bisphosphate therapy, surgery at the affected area may exacerbate the condition. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/ risk assessment.

Musculoskeletal pain.

Bone, joint and/or muscle pain has been reported in patients taking bisphosphonates. In 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.

Adynamic bone disease.

Severely depressed bone turnover has been reported in connection with long-term use, manifesting as delayed or absent fracture healing. All patients had spontaneous atraumatic nonspinal fractures. These patients had received alendronate for 3 to 9 years at doses of 10 mg per day or 70 mg per week. Three women had received oestrogen therapy. Histomorphometric analysis of the cancellous bone in 9 patients (8 women, 1 man) showed suppressed bone formation, with reduced or absent osteoblastic surface in most patients, low or low normal osteoclastic surface in 8 patients and eroded surface was decreased in 4 patients. Four of nine patients showed satisfactory fracture healing within 8 months. No new fractures occurred after cessation of alendronate. The presence of spontaneous nonspinal fractures, e.g. of femoral shaft, in patients who have received alendronate long-term may be indicative of adynamic bone disease.

Instructions to patients.

To facilitate delivery to the stomach and thus reduce the potential for oesophageal irritation, patients should be instructed to swallow alendronate with a full glass of water and 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 rising 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, e.g. difficulty or pain upon swallowing, retrosternal pain or new or worsening heartburn, they should stop taking alendronate and consult their doctor.
Patients should be instructed that if they miss a dose of alendronate once weekly (70 mg), 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 less than 35 mL/minute (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 less than or equal 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 the 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 although the concomitant medication with two or more bisphosphonates cannot be recommended because of the lack of clinical data.
Concomitant use of HRT (oestrogen ± 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 oestrogen/ hormone replacement therapy).
Specific interaction studies were not performed. Alendronate (10 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).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Respective oral alendronate doses of up to 9 and 15 mg/kg/day had no effect on fertility in male and female rats.
(Category B3)
Alendronate has not been studied in pregnant women and should not be given to them. In studies with pregnant rats, oral doses of alendronate 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.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Clinical studies.

In clinical studies alendronate was generally well tolerated. In studies 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 greater than or equal to 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 two 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.
In a one year, double blind, multicentre study, the overall safety and tolerability profiles of alendronate 70 mg (once weekly) (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 greater than or equal to 1% of patients treated with either patient group are presented in Table 2.

Concomitant use with oestrogen/ 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 oestrogen ± 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 70 mg (once weekly) were similar to that of placebo and no difference was seen between men and women.
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 greater than or equal to 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 to 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 (bone, muscle and joint) pain, 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.

Body as a whole.

Hypersensitivity reactions including urticaria and, rarely, angioedema. Transient symptoms as in an acute phase response (myalgia, malaise and, rarely, fever) have been reported with alendronate, typically in association with initiation of treatment. Rarely, symptomatic hypocalcaemia 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; 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). Stomatitis is a possible adverse event. 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, Instructions to patients); joint swelling.

Nervous system.

Dizziness, vertigo.

Skin.

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

Special senses.

Rarely uveitis, rarely scleritis or episcleritis.

Bioequivalence studies.

The following events were reported during the bioequivalence study and classified as probably related to the study drug.

Gastrointestinal.

Nausea, vomiting, gastritis, diarrhoea, dyspepsia, bloating, gastric ulcer.

Musculoskeletal.

Musculoskeletal pain.

Nervous system.

Tremor, headache.

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.

4.9 Overdose

No specific information is available on the treatment of alendronate overdosage. 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).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Alendronate is a bisphosphonate that, in animal studies, localises 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 Clinical trials). 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 mineralisation 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. The World Health Organization (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 (e.g. at least two 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 to 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.

These 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 70 mg (once weekly formulation) (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 alendronate 70 mg (once weekly) tablet, the increases in bone density support the expectation that alendronate 70 mg (once weekly) will have effects to reduce the incidence of fractures similar to those of the 10 mg daily treatment (see below). The study was not designed to evaluate the relative compliance of alendronate 70 mg (once weekly) 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 versus 23.3 mm) due to a reduction in both the number and severity of fractures.
The fracture intervention trial (FIT) 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 2,027 patient study, (alendronate n = 1,022; placebo n = 1,005) 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% versus 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, 4,432 patient study (alendronate, n = 2,214; placebo, n = 2,218) 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 versus 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 above), 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 the 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 oestrogen/ hormone replacement therapy. The effects on BMD of treatment with alendronate 10 mg once daily and conjugated oestrogen (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 oestrogen or alendronate alone (both 6.0%).
The effects on BMD when alendronate was added to stable doses (for at least one year) of HRT (oestrogen ± 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%) versus 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 less than or equal to 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 versus 7.1%, respectively; p = 0.017) and, correspondingly, also reduced height loss (-0.6 versus -2.4 mm, respectively; p = 0.022).
The effects of discontinuation of alendronate treatment have not been studied in this population.
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 I 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. 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 oestrogen 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 versus 1.56%) and trochanter (2.84 versus 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 versus greater than or equal to 65 years), race (Caucasian versus 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.

Paget's disease of bone.

Paget's disease of bone is a chronic focal skeletal disorder characterised by greatly increased and disorderly bone remodelling. Excessive osteoclastic bone resorption is followed by osteoblastic new bone formation, leading to the replacement of the normal bone architecture by disorganised, enlarged and weakened bone structure.
Alendronate decreases the rate of bone resorption directly, which leads to an indirect decrease in bone formation. Alendronate 40 mg once daily for six months produced highly significant decreases in serum alkaline phosphatase, an objective measure of disease severity. Furthermore, normal lamellar bone was produced during treatment with alendronate, even where pre-existing bone was woven and disorganised. As a result of the inhibition of bone resorption, alendronate induced generally mild, transient and asymptomatic decreases in serum calcium and phosphate.
The efficacy of alendronate 40 mg once daily for six months was demonstrated in two double blind clinical studies of male and female patients with moderate to severe Paget's disease (alkaline phosphatase at least twice the upper limit of normal) - a placebo controlled multinational study and a US comparative study with etidronate disodium 400 mg/day. Figure 3 shows the mean percent changes from baseline in serum alkaline phosphatase for up to six months of randomised treatment.

At six months, the mean percent suppression from baseline in serum alkaline phosphatase in patients treated with alendronate (-79% and -73% in the two studies) was significantly greater than that achieved with etidronate disodium 400 mg/day (-44%) and contrasted with the complete lack of response in placebo treated patients (+8.0%). Response (defined as either normalisation of serum alkaline phosphatase or decrease from baseline greater than or equal to 60%) occurred in approximately 85% of patients treated with alendronate in the combined studies versus 30% in the etidronate group and 0% in the placebo group. Alendronate was similarly effective irrespective of age, gender, race, renal function, concomitant medications, prior use of other bisphosphonates or baseline alkaline phosphatase.

5.2 Pharmacokinetic Properties

Absorption.

Relative to an intravenous 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 hour or 30 minutes 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 (< 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 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; the renal clearance of alendronate was 71 mL/minute. Plasma concentrations fell by more than 95% within six hours following intravenous administration, due to distribution to the bone and excretion in the urine. 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 drugs by those systems in humans.
Two bioequivalence studies, specific to Alendro, were conducted comparing Alendro tablets with Fosamax tablets. When administered either as a single oral dose of 40 mg, taken as four 10 mg tablets, or as a single oral dose of 70 mg, taken as one 70 mg tablet, urinary excretion rates were the same for both formulations (see Tables 6 and 7). Thus, alendronic acid tablets are shown to be bioequivalent with Fosamax and may be used interchangeably. The acceptance criteria for the confidence intervals of the pharmacokinetic parameters in these studies were 0.70-1.43.

No bioavailability or pharmacokinetic data are available for Alendro 40.
Preclinical studies show that any 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 intravenous 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).

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 (greater than or equal to 5 mM) but was negative at intravenous 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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Alendro tablets contain the following excipients: croscarmellose sodium, microcrystalline cellulose, lactose monohydrate and magnesium stearate. The tablets are gluten free.

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.