Consumer medicine information

Alendronate Sandoz

Alendronic acid

BRAND INFORMATION

Brand name

Alendronate Sandoz

Active ingredient

Alendronic acid

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Alendronate Sandoz.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Alendronate Sandoz. It is particularly important that you read the section "When and how to take it" before you take this medicine. This leaflet 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 risk of you taking this medicine against the benefits it is expected to have for you.

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

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

WHAT ALENDRONATE SANDOZ IS USED FOR

Alendronate Sandoz is used to treat osteoporosis including osteoporosis caused by a group of medicines known as corticosteroids.

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.

How Alendronate Sandoz works

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. Alendronate Sandoz not only helps prevent the loss of bone but actually helps to rebuild bone and makes bone less likely to fracture. Thus, Alendronate Sandoz reverses the progression of osteoporosis. Alendronate Sandoz starts working on the bone cells immediately, but measurable effects on bone mass may not be seen for several months or more.

Alendronate Sandoz contains the active ingredient alendronate sodium and belongs to a group of non-hormonal medicines called bisphosphonates.

There is no evidence that this medicine is addictive.

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

BEFORE YOU TAKE ALENDRONATE SANDOZ

You should know that Alendronate Sandoz can irritate or burn the food pipe (also called oesophagus) in some people. The chances of this happening should be reduced if you follow the precautions and instructions for taking Alendronate Sandoz.

When you must not take it

Do not take this medicine if:

  • you are allergic to alendronate sodium or any of the inactive ingredients listed at the end of this leaflet under Product Description
  • you have certain disorders of the food pipe 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
  • your dentist advises you to; always consult your doctor first.

Do not give this medicine to a child. Safety and effectiveness in children has not been established.

Do not take this medicine if you are pregnant or breast-feeding. Alendronate Sandoz has not been studied in pregnant or breast-feeding women.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to:

  • any other medicines, especially if they are in the same drug class as Alendronate Sandoz
  • any other substances, including foods, preservatives or dyes.

Tell your doctor if you plan on becoming pregnant or will be breastfeeding while you are taking Alendronate Sandoz.

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

  • kidney disease
  • swallowing or digestive problems, such as ulcers.

Tell your doctor if you are planning to have a course of dental surgery.

If you have not told your doctor about any of the above, tell him/her before you start taking Alendronate Sandoz.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines are likely to interfere with the absorption of Alendronate Sandoz 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 Alendronate Sandoz 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 Alendronate Sandoz. However both aspirin and Alendronate Sandoz may increase the chance of stomach upsets.

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

HOW TO TAKE ALENDRONATE SANDOZ

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

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

How much to take

Take Alendronate Sandoz only when prescribed by your doctor.

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

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

When and how to take it

Take Alendronate Sandoz after getting up for the day. Do not take it at bedtime.

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

Stay upright for at least 30 minutes after swallowing Alendronate Sandoz 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).

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

Do not chew or suck on a tablet of Alendronate Sandoz. Mouth ulcers may occur if the tablet is chewed or dissolved in the mouth.

How long to take Alendronate Sandoz

It is important that you continue taking your medicine for as long as your doctor prescribes. Alendronate Sandoz can only 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 miss a tablet, take one tablet 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 about what to do, talk to your doctor or pharmacist.

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else may have taken too much Alendronate Sandoz. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

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 ALENDRONATE SANDOZ

Things you must do

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

If you become pregnant while taking this medicine, 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 Alendronate Sandoz.

If you require a dental procedure, tell your dentist that you are taking Alendronate Sandoz.

If you develop new or unusual pain in your hip or thigh, tell your doctor. Rarely, patients have experienced fracture in a specific part of the thigh bone.

If you break a bone (have a fracture), tell your doctor that you are taking Alendronate Sandoz.

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 give your medicine to anyone else, even if they have the same condition as you.

Do not take Alendronate Sandoz to treat any other complaint unless your doctor tells you to.

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 Alendronate Sandoz.

Alendronate Sandoz 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.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist 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
  • 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 joints
  • dizziness or spinning sensation
  • unusual tiredness or weakness
  • swelling of hands, ankles or feet
  • hair loss.

Most of these are the common side effects of the medicine. 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
  • new or unusual pain in the hip or thigh
  • jaw problems, associated with delayed healing and infection, often following a tooth extraction.

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

If any of the following happen, stop taking Alendronate Sandoz 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.

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

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

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are rare.

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

Rare cases of stomach and duodenal ulcers (some severe) have occurred in some people, but it is not known whether these were caused by Alendronate Sandoz.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

AFTER TAKING ALENDRONATE SANDOZ

Storage

Keep your tablets in the blister 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 medicine in a cool dry place where the temperature stays below 25°C. Do not freeze the product.

Do not store Alendronate Sandoz or any other medicine in the bathroom or near a sink. Do not leave it in the car or on a window sill. Heat and dampness can destroy some medicines.

Keep it 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.

Disposal

If your doctor tells you to stop taking this medicine, or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

PRODUCT DESCRIPTION

What it looks like

Alendronate Sandoz 70 mg tablets: white, round with "ALN 70" marked on one side. Available in blisters of 4 tablets.

Ingredients

Active Ingredient:

Alendronate Sandoz 70 mg tablet - contains 70 mg of alendronic acid as alendronate sodium.

Inactive Ingredients:

  • microcrystalline cellulose
  • croscarmellose sodium
  • colloidal anhydrous silica
  • magnesium stearate
  • Film coat consists of (microcrystalline cellulose, carrageenan, macrogol 8000).

This medicine does not contain any lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

Alendronate Sandoz is supplied in Australia by:

Sandoz Pty Ltd.
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Australia
Tel: 1800 726 369

This leaflet was revised in February 2021.

Australian Register Number

Alendronate Sandoz 70 mg tablets:
AUST R 134981 (blister)

# Trademarks

Published by MIMS April 2021

BRAND INFORMATION

Brand name

Alendronate Sandoz

Active ingredient

Alendronic acid

Schedule

S4

 

1 Name of Medicine

Alendronate sodium.

2 Qualitative and Quantitative Composition

Each Alendronate Sandoz tablet contains 91.4 mg of alendronate sodium, which is the molar equivalent to 70 mg of alendronic acid.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Alendronate Sandoz 70 mg tablets: White, round, bi-convex film-coated tablet, debossed with "ALN 70" on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Alendronate Sandoz is indicated for the treatment of osteoporosis, including glucocorticoid induced osteoporosis. 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.

4.2 Dose and Method of Administration

Dosage.

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 therapy.

Adults.

Treatment of osteoporosis.

The recommended dosage is one 70 mg tablet once weekly.
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 Alendronate Sandoz and consult their doctor.
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 intake is inadequate (see Section 4.4 Special Warnings and Precautions for Use). Doctors should consider the vitamin D intake from vitamins and dietary supplements. Additional supplements should not be taken at the same time of day as Alendronate Sandoz (see below).
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 below).

Method of administration.

Compatibility to meals and fluids.

Alendronate Sandoz 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).
Alendronate Sandoz should only be taken upon arising for the day. Alendronate Sandoz should be swallowed with a full glass of water to facilitate delivery to the stomach and thus reduce the potential for oesophageal irritation.
Patients should not lie down for at least 30 minutes and until after their first food of the day. Alendronate Sandoz 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).

Dosage adjustment.

Renal impairment.

No dosage adjustment is necessary for patients with mild to moderate renal insufficiency (creatinine clearance 35 to 60 mL/min). Alendronate Sandoz is not recommended for patients with more severe renal insufficiency (creatinine clearance < 35 mL/min).

Elderly.

No dosage adjustment is necessary for the elderly.

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). Physicians should therefore be alert to any signs or symptoms signaling a possible oesophageal reaction. Patients should be instructed to discontinue Alendronate Sandoz and seek medical attention if they develop dysphagia, odynophagia or retrosternal pain.

General.

Causes of osteoporosis other than oestrogen deficiency, 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 Sandoz (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 hypocalcemia should be monitored during therapy with Alendronate Sandoz.
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 the bone and in patients receiving glucocorticoids.

Alendronate.

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 it 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 (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 Sandoz is given to patients with active upper gastrointestinal problems, such as dysphagia, oesophageal diseases, gastritis, duodenitis, or ulcers. In patients with known Barrett's oesophagus, prescribers should consider the benefits and potential risks of alendronate on an individual patient basis.

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 Sandoz (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience). Most reported cases of bisphosphonate associated ONJ have been in cancer patients treated with intravenous bisphosphonates. Known risk factors for ONJ include:
Potency of the bisphosphonate (highest for zoledronic acid).
A diagnosis of cancer, concomitant therapies (e.g. chemotherapy, radiotherapy, corticosteroids), smoking.
Poor oral hygiene and comorbid disorders (e.g. pre-existing periodontal disease, anaemia, coagulopathy, infection, parodontitis, poorly fitting dentures).
Patients who develop ONJ should receive appropriate care by an oral surgeon.
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 Nov 2006, the Australian Adverse Drug Reactions Advisory Committee has received 25 reports of ONJ in patients receiving alendronate.
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 dentists 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 and their dentists should be advised of the risk of osteonecrosis of the jaw so that any toothache 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. However, consideration should be given to discontinuation of bisphosphonate therapy.
While on treatment, these patients should avoid invasive dental procedures if possible.
In patients who develop ONJ while on bisphosphonate 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.
During bisphosphonate treatment, all patients should be encouraged to maintain good oral hygiene, receive routine dental checkups, and report any oral symptoms such as dental mobility, pain, or swelling.
Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms including chronic ear infections.

Atypical stress fractures.

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate treated patients who has sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. 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 patients experienced prodromal pain in the affected area, often associated with imaging features of stress fracture, weeks to months before a complete fracture occurred. The number of reported cases of this condition is very low (some 40 reported cases worldwide). 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 increase 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.
During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.

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 analyis 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.

Information 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 Sandoz with a full glass of water. Patients should be instructed not to lie down for at least 30 minutes and until after they first take food on the day. Patients should be warned not to 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 Alendronate Sandoz, 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 Sandoz tablets are 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 Sandoz tablets have 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 millimolar) and serum phosphate to ≤ 2.0 mg P/dL (0.65 millimolar) 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 and a half hours after taking Alendronate Sandoz before taking any other oral medication.
Since NSAID use is associated with gastrointestinal irritation, caution should be used during concomitant use with alendronate.
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 hormone replacement therapy (HRT) (oestrogen ± progestin) and alendronate was assessed in two clinical studies of one and 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 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.

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.
Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. The amount of bisphosphonate incorporated into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on foetal risk in humans. However, there is a theoretical risk of foetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on the risk has not been studied.
(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. Fetal 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.
 It is not known whether alendronate is excreted into human breast milk. Alendronate Sandoz tablets have not been studied in breastfeeding women and should not be given to them.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive or use machines have been performed. However some adverse reactions that have been reported with alendronate may affect some patients' ability to drive or operate machinery. Individual responses to alendronate may vary.

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 observed 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 3.2% with alendronate and 2.7% with placebo. 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 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 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 once weekly 70 mg were similar to that of placebo and no difference was seen between men and women.

Treatment 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.

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 hypocalcemia has occurred, generally in association with predisposing conditions. Rarely, peripheral oedema.

Gastrointestinal.

Nausea, vomiting, oesophagitis, oesophageal erosions, 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). Localised osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection, often with delayed healing, has been reported rarely (see Section 4.4 Special Warnings and Precautions for Use).

Musculoskeletal.

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

Nervous system.

Dizziness, vertigo, dysgeusia.

Skin and subcutaneous tissue disorders.

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

Special senses.

Rarely uveitis, scleritis or episcleritis. Cholesteatoma of the external auditory canal (focal osteonecrosis) has been reported rarely.

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 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. On account of the risk of oesophageal irritation, vomiting should not be induced and the patient should be kept in an upright position.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (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 Section 5.1 Pharmacodynamic Properties, 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 6,000-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 characterized 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 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. 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 administered once weekly (70 mg) for the treatment of osteoporosis.

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. The graph in 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 (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 below). 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 (FIT) consisted of two studies in postmenopausal women: a three year study of patients who had at least one baseline vertebral (compression) fracture; and a 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 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%) 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 ≤ -2 at the femoral neck and ≤ -1 at the lumbar spine or 2) a baseline osteoporotic fracture and a BMD T-score of ≤ -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.

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 crosslinked 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 = 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 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% 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.
After administration of replicate single oral doses of alendronate 70 mg to healthy male adults, the accumulated urinary excreted amount in 72 hours were 304.19 microgram and 298.06 microgram for the respective single oral doses. The maximum rate of excretion during this period was 92.24 microgram/hour and 85.15 microgram/hour respectively.
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).

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 millimolar) 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

Microcrystalline cellulose, colloidal anhydrous silica, croscarmellose sodium and magnesium stearate. The film coat consists of microcrystalline cellulose, carrageenan and macrogol 8000.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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

Supplied in Al/Al blister packs of 4 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Alendronate sodium is a white or almost white crystalline powder. It is soluble in water, very slightly soluble in methanol and practically insoluble in methylene chloride.

Chemical structure.


Chemical name: (4-amino-1-hydroxybutylidene) bisphosphonic acid monosodium salt trihydrate.
Molecular formula: C4H12NNaO7P2.3H2O.
Molecular weight: 325.12.

CAS number.

121268-17-5.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes