Consumer medicine information

Fosamax Plus Once Weekly

Alendronic acid; Colecalciferol

BRAND INFORMATION

Brand name

Fosamax Plus

Active ingredient

Alendronic acid; Colecalciferol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Fosamax Plus Once Weekly.

What is in this leaflet

This leaflet answers some common questions about FOSAMAX PLUS. It is particularly important that you read the sections "When to take it" 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 risks of you taking FOSAMAX PLUS against the benefits they expect it will 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 FOSAMAX PLUS is used for

FOSAMAX PLUS is used to treat osteoporosis and to provide additional vitamin D.

Osteoporosis is caused by changes in the way bone is normally maintained. Vitamin D is an essential nutrient required for calcium absorption and healthy bones.

Understanding bone

Bone is a 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. This balanced process keeps your skeleton healthy and strong. 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.

What should I know about vitamin D?

Vitamin D is an essential nutrient, required for calcium absorption and healthy bones. The main source is through exposure to summer sunlight, which makes vitamin D in our skin. Clothing or sun block can prevent enough sunlight from getting through. In addition, as people age, their skin becomes less able to make vitamin D. Very few foods are natural sources of vitamin D.

Too little vitamin D leads to inadequate calcium absorption and low phosphate-minerals that make bones strong. Even if you are eating a diet rich in calcium or taking a calcium supplement, your body cannot absorb calcium properly unless you have enough vitamin D. Too little vitamin D may lead to bone loss and osteoporosis. Severe vitamin D deficiency may cause muscle weakness which can lead to falls and a higher risk of fracture.

How does FOSAMAX PLUS work?

The alendronate in FOSAMAX PLUS works by slowing down the process of old bone being removed, which allows the bone-forming cells time to rebuild normal bone. Alendronate not only helps prevent the loss of bone but actually helps to rebuild bone and make bone less likely to fracture. Thus, FOSAMAX PLUS reverses the progression of osteoporosis.

FOSAMAX PLUS starts working on the bone cells immediately, but measurable effects on bone mass may not be seen for several months or more.

The alendronate in FOSAMAX PLUS belongs to a group of non-hormonal medicines called bisphosphonates.

In addition to alendronate, FOSAMAX PLUS also contains vitamin D, an essential nutrient required for calcium absorption and healthy bones.

Before you take FOSAMAX PLUS

You should know that in some people, FOSAMAX PLUS can irritate or burn the food pipe (also called oesophagus). The chances of this happening should be reduced when you follow the instructions for 'How to take FOSAMAX PLUS' in this leaflet.

When you must not take it

Do not take FOSAMAX PLUS if:

  • you have an allergy to FOSAMAX PLUS or any of the ingredients listed at the end of this leaflet
  • you have certain disorders of the food pipe (oesophagus) including those that cause difficulty in swallowing
  • you are unable to stand or sit upright for at least 30 minutes
  • your doctor has told you that you currently have low blood calcium
  • your dentist advises you to consult your doctor first

Do not take FOSAMAX PLUS if you are pregnant or breast-feeding. FOSAMAX Plus has not been studied in pregnant or breast-feeding women.

Do not take FOSAMAX PLUS if:

  • the packaging is torn or shows signs of tampering
  • the expiry date on the pack has passed.
    If you take this medicine after the expiry date has passed, it may not work.

If you are not sure whether you should start taking FOSAMAX PLUS, talk to your doctor.

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

Before you start to take it

Tell your doctor if:

  1. you plan to become pregnant or breast-feed
  2. you have any medical conditions, especially the following:
  • kidney disease
  • swallowing or digestive problems, such as ulcers
  1. you have any allergies to any other medicines or any other substances, such as foods, preservatives or dyes
  2. you have dental or jaw-bone problems or are planning to have a course of dental surgery.
  3. you currently smoke or have been a smoker in the past.

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

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines that you buy without a prescription from your 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 FOSAMAX PLUS if taken at the same time. These include:

  • antacids, medicines used to treat indigestion e.g. Gaviscon, Mylanta
  • calcium supplements
  • vitamins

Therefore, take FOSAMAX PLUS 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 any of these medicines.

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

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

How to take FOSAMAX PLUS

How much to take

Take FOSAMAX PLUS only when prescribed by your doctor.

The usual dose of FOSAMAX PLUS is one tablet once a week.

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

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.

When and how to take it

Take FOSAMAX PLUS after getting up for the day and before taking your first food, beverage or other medication. Do not take it at bedtime.

Swallow one tablet whole with a full glass of plain water [not mineral water, not coffee or tea, not juice].

Do not take any food, medicines or drinks other than plain tap water with your FOSAMAX PLUS. It is important to take FOSAMAX PLUS with plain water only, not mineral water. Food, other drugs and mineral water and other drinks, including fruit juices, coffee and tea, will reduce the effect of FOSAMAX PLUS by interfering with the absorption into the body.

Stay upright for at least 30 minutes after swallowing FOSAMAX PLUS 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).

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

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

How long to take it

It is important that you take FOSAMAX PLUS for as long as your doctor prescribes it. FOSAMAX PLUS can only treat your osteoporosis, by helping prevent further loss of bone and continuing to rebuild bone, if you take it every week. Since it is not known how long you should take FOSAMAX PLUS, you should discuss the need to stay on this medication with your doctor periodically to determine if FOSAMAX PLUS is still right for you.

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 FOSAMAX PLUS, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26), or go to accident and emergency at your nearest hospital, if you think that you or anyone else may have taken too much FOSAMAX PLUS. 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 using FOSAMAX PLUS

Things you must do

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

If you become pregnant while taking FOSAMAX PLUS, 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 FOSAMAX PLUS.

If you develop a toothache or require a dental procedure, tell your dentist that you are taking FOSAMAX PLUS.

If you develop new or unusual pain in your hip, leg or other bone, tell your doctor. Rarely, patients have experienced fracture in a specific part of the thigh bone. Patients have experienced fractures in other bones as well.

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 FOSAMAX PLUS to anyone else, even if they have the same condition as you.

Things to be careful of

There have been side effects reported with FOSAMAX PLUS that may affect your ability to drive or operate machinery. Individual responses to FOSAMAX PLUS may vary (see Side Effects).

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 FOSAMAX PLUS.

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

Ask your doctor or pharmacist 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 (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
  • changed sense of taste

Most of these are the more common side effects of FOSAMAX PLUS. 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
  • ear pain
  • 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 your hip or thigh

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

Tell your dentist and doctor immediately if you notice any of the following

  • Jaw-bone or dental problems (including toothache). Jaw-bone problems may include infection, and delayed healing after a tooth extraction or other work that involves drilling into the jaw-bone.

These side effects are rare and may be serious.

If any of the following happen, stop taking FOSAMAX PLUS 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 FOSAMAX PLUS 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 breathing or swallowing
  • pinkish, itchy swellings on the skin, also called hives or nettlerash
  • severe skin reactions
  • black tar-like and/or bloody stools

These may be serious side effects. You may need urgent medical attention. These side effects are rare.

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

Rarely, stomach or duodenal ulcers (some severe) have occurred, but it is not known whether these were caused by FOSAMAX PLUS.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice any other effects.

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

FOSAMAX PLUS is not addictive.

After using FOSAMAX PLUS

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 FOSAMAX PLUS in a cool dry place where the temperature stays below 30°C. Do not freeze the product. Keep the tablets away from light or moisture. Do not store FOSAMAX PLUS 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.

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 FOSAMAX PLUS, or the tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

FOSAMAX PLUS comes in two strengths of tablets, each containing 70mg alendronate but with different strengths of colecalciferol (vitamin D3), either 70 micrograms (2800 IU) or 140 micrograms (5600 IU):

FOSAMAX PLUS (70mg/70 micrograms) comes as a white to off-white, modified capsule-shaped tablet with the outline of a bone image on one side and "710" on the other.

FOSAMAX PLUS 70mg/140 micrograms: comes as a white to off-white, modified-rectangle shaped tablet with "270" on one side and a bone image on the other.

A box of tablets contains 4 tablets (trade pack).

Ingredients

Active ingredients:

FOSAMAX PLUS (70 mg/70 micrograms) Once Weekly Tablets

  • alendronate sodium equivalent to 70 mg alendronic acid per tablet
  • colecalciferol 70 micrograms (2800 IU vitamin D3) per tablet

FOSAMAX PLUS 70mg/140 micrograms

  • alendronate sodium equivalent to 70 mg alendronic acid per tablet
  • colecalciferol 140 micrograms (5600 IU vitamin D3) per tablet

Inactive ingredients:

  • microcrystalline cellulose
  • lactose
  • medium chain triglycerides
  • gelatin
  • croscarmellose sodium
  • sucrose
  • colloidal anhydrous silica
  • magnesium stearate
  • dry vitamin D3 100
  • purified water
  • butylated hydroxytoluene
  • modified food starch
  • aluminium sodium silicate.

FOSAMAX PLUS does not contain gluten, tartrazine or any other azo dyes.

Supplier

FOSAMAX PLUS is supplied in Australia by:-

Organon Pharma Pty Ltd
Building A,
26 Talavera Road,
Macquarie Park NSW 2113

This leaflet was prepared in May 2023

Australian Register Numbers:

FOSAMAX PLUS 70mg/70 micrograms (2800 IU) Once Weekly Tablets:
AUST R 113482.

FOSAMAX PLUS 70mg/140 micrograms (5600 IU) tablets:
AUST R 136846.

WPPI-OG0217A-T-012023

Published by MIMS July 2023

BRAND INFORMATION

Brand name

Fosamax Plus

Active ingredient

Alendronic acid; Colecalciferol

Schedule

S4

 

1 Name of Medicine

Fosamax Plus tablets contain alendronate sodium and colecalciferol (vitamin D3).

2 Qualitative and Quantitative Composition

Alendronate is a white, crystalline, nonhygroscopic powder. It is soluble in water, very slightly soluble in alcohol, and practically insoluble in chloroform.
Colecalciferol is a white, crystalline, odourless powder. Colecalciferol is practically insoluble in water, freely soluble in usual organic solvents, and slightly soluble in vegetable oils.
Each tablet of Fosamax Plus 70 mg/70 microgram contains 91.4 mg of alendronate sodium, which is the molar equivalent to 70 mg of alendronic acid, and 70 microgram of colecalciferol equivalent to 2800 IU vitamin D.
Each tablet of Fosamax Plus 70 mg/140 microgram contains 91.4 mg of alendronate sodium, which is the molar equivalent to 70 mg of alendronic acid, and 140 microgram of colecalciferol equivalent to 5600 IU vitamin D.

List of excipients with known effect.

Lactose, sucrose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Fosamax Plus (alendronate sodium/colecalciferol) 70 mg/ 70 microgram Once Weekly Tablet, providing 2800 IU vitamin D3. White to off-white, modified capsule-shaped tablet with the outline of a bone image on one side and 710 on the other.
Fosamax Plus (alendronate sodium/colecalciferol) 70 mg/ 140 microgram, once weekly tablet, providing 5600 IU vitamin D3. White to off-white, modified rectangle-shaped tablet with "270" on one side and a bone image on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

Fosamax Plus Once Weekly tablet and Fosamax Plus 70 mg/140 microgram are indicated for the treatment of:
Osteoporosis* in select patients where vitamin D supplementation is recommended.
* 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

Fosamax Plus brands (70 mg/70 microgram or 70 mg/140 microgram) 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).
Fosamax Plus brands (70 mg/70 microgram or 70 mg/140 microgram) should only be taken upon arising for the day. To facilitate delivery to the stomach and thus reduce the potential for oesophageal irritation, Fosamax Plus brands (70 mg/70 microgram or 70 mg/140 microgram) tablets should only be swallowed with a full glass of water.
Patients should not lie down for at least 30 minutes and until after their first food of the day. Fosamax Plus brands (70 mg/70 microgram or 70 mg/140 microgram) should not be taken at bedtime or before arising for the day. Failure to follow these instructions may increase the risk of oesophageal adverse experiences (see Section 4.4 Special Warnings and Precautions for Use).
Severe oesophageal ulceration has been reported in patients taking alendronate (see Section 4.4 Special Warnings and Precautions for Use). Patients should be instructed that if they develop symptoms of oesophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or new or worsening heartburn) they should stop taking Fosamax Plus (70 mg/70 microgram or 70 mg/140 microgram) and consult their physician.
In clinical trials, alendronate was administered with appropriate calcium and vitamin D supplementation. The use of vitamin D as the sole treatment of osteoporosis has not been established.
Patients should receive supplemental calcium and/or vitamin D if intake is inadequate (see Section 4.4 Special Warnings and Precautions for Use).
Physicians should consider the vitamin D intake from vitamins and dietary supplements. Fosamax Plus (70 mg/70 microgram) provides 2800 IU (70 microgram) of vitamin D in a single once weekly dose, which is equivalent to seven daily doses of 400 IU (10 microgram). Fosamax Plus (70 mg/140 microgram) provides 140 microgram colecalciferol (5600 IU of vitamin D3) in a single once weekly dose, which is equivalent to seven daily doses of 20 microgram colecalciferol (800 IU vitamin D3). Additional supplements should not be taken at the same time of day as Fosamax Plus (70 mg/70 microgram or 70 mg/140 microgram) (see above).
No dosage adjustment is necessary for the elderly or for patients with mild-to-moderate renal insufficiency (creatinine clearance 35 to 60 mL/min). Fosamax Plus (70 mg/70 microgram or 70 mg/140 microgram) is not recommended for patients with more severe renal insufficiency (creatinine clearance < 35 mL/min).
Although no specific studies have been conducted on the effects of switching patients on another therapy for osteoporosis to Fosamax Plus (70 mg/70 microgram or 70 mg/140 microgram) or on another therapy for Paget's disease, there are no known or theoretical safety concerns related to Fosamax Plus (70 mg/70 microgram or 70 mg/140 microgram) in patients who previously received any other antiosteoporotic or antipagetic therapy.

Fosamax Plus brands (70 mg/70 microgram or 70 mg/140 microgram).

Treatment of osteoporosis in patients where vitamin D supplementation is recommended.
The recommended dose is one tablet of Fosamax Plus (70 mg/70 microgram or 70 mg/140 microgram) once weekly. Fosamax Plus should always be taken on the same day each week.
The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis (see Section 4.8 Adverse Effects (Undesirable Effects), Clinical studies).

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 alendronate. See Section 4.2 Dose and Method of Administration. Physicians should therefore be alert to any signs or symptoms signaling a possible oesophageal reaction. Patients should be instructed to discontinue Fosamax Plus and seek medical attention if they develop dysphagia, odynophagia or retrosternal pain.

General.

Causes of osteoporosis other than hypogonadism, aging and glucocorticoid use should be considered.
If there are clinical reasons to suspect hypocalcaemia and/or vitamin D deficiency (serum levels 25 hydroxyvitamin D < 9 nanomol/L), the appropriate diagnostic tests should be performed. Hypocalcaemia must be corrected before initiating therapy with Fosamax Plus (see Section 4.3 Contraindications). Other disturbances of mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients with these conditions, serum calcium and symptoms of hypocalcaemia should be monitored during therapy with Fosamax Plus. The content of vitamin D in Fosamax Plus (70 mg/70 microgram or 70 mg/140 microgram) is not suitable for correction of vitamin D deficiency.
Fosamax Plus (70 mg/70 microgram or 70 mg/140 microgram) should not be used as sole treatment for osteoporotic patients with a vitamin D deficiency (defined as serum 25-hydroxyvitamin D < 9 nanogram/mL (22.5 nanomol/L) (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Fosamax Plus studies). Fosamax Plus (70 mg/70 microgram or 70 mg/140 microgram) should not be used to treat osteomalacia. Vitamin D should be used to treat osteomalacia. Fosamax Plus (70 mg/70 microgram or 70 mg/140 microgram) has not been studied in patients with vitamin D deficiency.
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.

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 Fosamax Plus and/or who fail to swallow it with the recommended amount of water, and/or who continue to take Fosamax Plus 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 (post-marketing) 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 Fosamax Plus is given to patients with active upper gastrointestinal problems, such as dysphagia, oesophageal diseases (including known Barrett's oesophagus), gastritis, duodenitis, or ulcers.

Colecalciferol.

Vitamin D3 may increase the magnitude of hypercalcaemia and/or hypercalciuria when administered to patients with diseases associated with unregulated overproduction of calcitriol (e.g. leukaemia, lymphoma, sarcoidosis). Urine and serum calcium should be monitored in these patients.
Patients with malabsorption may not adequately absorb vitamin D3.

Dental.

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

Atypical stress fractures.

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

Musculoskeletal pain.

Bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. In post-marketing experience, these symptoms have rarely been severe and/or incapacitating (see Section 4.8 Adverse Effects (Undesirable Effects), Alendronate/Fosamax Plus post-marketing experience). The time to onset of symptoms varied from one day to several months after starting treatment. Most patients had relief of symptoms after stopping treatment. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

Nephrolithiasis and hypercalciuria.

Patients with a history of either nephrolithiasis or hypercalciuria may require special diets that limit their calcium intake.

Dosage instructions for patients.

Fosamax Plus tablets.

To facilitate delivery to the stomach and thus reduce the potential for oesophageal irritation patients should be instructed to swallow each tablet of Fosamax Plus (70 mg/70 microgram or 70 mg/140 microgram) with a full glass of water. Patients should be instructed not to lie down for at least 30 minutes and until after their first food of the day. Patients should not chew or suck on the tablet because of a potential for oropharyngeal ulceration. Patients should be specifically instructed not to take Fosamax Plus (70 mg/70 microgram or 70 mg/140 microgram) 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 Fosamax Plus (70 mg/70 microgram or 70 mg/140 microgram) and consult their physician.
Patients should be instructed that if they miss a dose of Fosamax Plus (70 mg/70 microgram or 70 mg/140 microgram), 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.

Fosamax Plus (70 mg/70 microgram or 70 mg/140 microgram) are not recommended for patients with creatinine clearance < 35 mL/min (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

In controlled trials, there was no age-related difference in the efficacy or safety profiles of Fosamax Plus (70 mg/70 microgram or 70 mg/140 microgram).

Paediatric use.

Fosamax Plus (70 mg/70 microgram or 70 mg/140 microgram) 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 mM) and serum phosphate to ≤ 2.0 mg P/dL (0.65 mM) were similar in both treatment groups.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Alendronate sodium.

If taken at the same time it is likely that calcium supplements, antacids and other oral medications will interfere with absorption of alendronate. Therefore, patients must wait at least one-half hour after taking Fosamax Plus (70 mg/70 microgram or 70 mg/140 microgram) before taking any other oral medication.
No other drug interactions of clinical significance are anticipated though the concomitant medication with two or more bisphosphonates cannot be recommended because of the lack of clinical data.
Concomitant use of 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 mg and 5 mg/day) was used in studies of treatment and prevention of osteoporosis in postmenopausal women, men and glucocorticoid users, with a wide range of commonly prescribed drugs without evidence of clinical adverse interactions. In clinical studies, the incidence of upper gastrointestinal adverse events was increased in patients receiving daily therapy with dosages of alendronate greater than 10 mg and aspirin-containing products. However, this was not observed in studies with alendronate once weekly 70 mg.
Since non steroidal anti-inflammatory drug (NSAID) use is associated with gastrointestinal irritation, caution should be used during concomitant use with alendronate.

Colecalciferol.

Olestra, mineral oils, orlistat, and bile acid sequestrants (e.g. colestyramine, colestipol) may impair the absorption of vitamin D. Anticonvulsants, cimetidine, and thiazides may increase the catabolism of vitamin D.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Alendronate sodium.

Alendronate sodium had no effect on fertility in male and female rats at oral doses of up to 9 and 15 mg/kg/day.
No studies on the effects on fertility have been carried out using the alendronate and colecalciferol combination.
(Category B3)

Alendronate sodium.

Alendronate has not been studied in pregnant women and should not be given to them. In studies with pregnant rats, oral alendronate doses of 2 mg/kg/day and above resulted in dystocia due to maternal hypocalcaemia. Foetal weight was reduced in rats at maternal doses greater than 5 mg/kg/day. No teratogenic effects were seen in rats or rabbits at oral doses up to 25 and 35 mg/kg/day, respectively.

Colecalciferol.

No data are available for colecalciferol (vitamin D3). Intramuscular administration of high doses (≥ 10,000 IU/every other day) of ergocalciferol (vitamin D2) to pregnant rabbits resulted in higher incidence of foetal aortic stenosis compared to controls. Administration of vitamin D2 (40,000 IU/day) to pregnant rats resulted in neonatal death, decreased foetal weight, and impaired osteogenesis of long bones postnatally.
No studies on the reproductive toxicity potential of the alendronate and colecalciferol combination have been carried out in animals.
 Fosamax Plus (70 mg/70 microgram or 70 mg/140 microgram) have not been studied in breast-feeding women and should not be given to them. No studies using the combination of alendronate and colecalciferol have been carried out in lactating animals.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. However, certain adverse reactions that have been reported with Fosamax Plus may affect some patients' ability to drive or operate machinery. Individual responses to Fosamax Plus may vary (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Clinical studies.

Fosamax.

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

Postmenopausal women.

Alendronate has been evaluated for safety in clinical studies in approximately 5000 postmenopausal patients. In two three-year, placebo controlled, double blind multicentre studies, discontinuation of therapy due to any clinical adverse experience occurred in 4.1% of 196 patients treated with alendronate 10 mg/day and 6.0% of 397 patients treated with placebo. Adverse experiences reported by the investigators as possibly, probably or definitely drug related in ≥ 1% of patients treated with either alendronate 10 mg/day or placebo are presented in Table 1.
Rarely, rash and erythema have occurred.
In the two-year extension (treatment years 4 and 5) of the above studies, the overall safety profile of alendronate 10 mg/day was similar to that observed during the three-year placebo-controlled period. Additionally, the proportion of patients who discontinued alendronate 10 mg/day due to any clinical adverse experience was similar to that during the first three years of the study.
In the Fracture Intervention Trial, discontinuation of therapy due to any clinical adverse experience occurred in 9.1% of 3236 patients treated with alendronate 5 mg/day for 2 years and 10 mg/day for either one or two additional years and 10.1% of 3223 patients treated with placebo. Discontinuations due to upper gastrointestinal adverse experiences were: alendronate, 3.2%; placebo, 2.7%. The overall adverse experience profile was similar to that seen in other studies with alendronate 5 or 10 mg/day.
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 Fosamax 10 mg daily in 146 men was generally similar to that seen in postmenopausal women.

Other studies in men and women.

In a ten-week endoscopy study in men and women (n = 277; mean age 55 years) no difference was seen in upper gastrointestinal tract lesions between alendronate once weekly 70 mg and placebo.
In an additional one-year study in men and women (n = 335; mean age 50 years) the overall safety and tolerability profiles of alendronate once weekly 70 mg were similar to that of placebo and no difference was seen between men and women.
Prevention of osteoporosis. The safety of alendronate in postmenopausal women 40-60 years of age has been evaluated in three double-blind, placebo-controlled studies involving over 1,400 patients randomised to receive alendronate for either two or three years. In these studies, the safety and tolerability profile of alendronate 5 mg/day (n=642) was similar to that of placebo (n=648). The only adverse experience reported by the investigators as possibly, probably, or definitely drug related in ≥ 1% of patients treated with alendronate 5 mg/day and at a greater incidence than placebo was dyspepsia (alendronate, 1.9% vs. placebo, 1.7%).
Treatment and prevention of glucocorticoid-induced osteoporosis. In two, one-year, placebo-controlled, double-blind, multicentre studies in patients receiving glucocorticoid treatment, the overall safety and tolerability profiles of alendronate 5 and 10 mg/day were generally similar to that of placebo. Adverse experiences reported by the investigators as possibly, probably or definitely drug related in ≥ 1% of patients treated with either alendronate 5 mg/day, 10 mg/day or placebo are presented in Table 3.
Paget's disease of bone. In clinical studies (Paget's disease and osteoporosis), adverse experiences reported in patients taking alendronate 40 mg/day for 3-12 months were similar to those in postmenopausal women treated with alendronate 10 mg/day. However, there was an apparent increased incidence of upper gastrointestinal adverse experiences in patients taking alendronate 40 mg/day. Isolated cases of oesophagitis and gastritis resulted in discontinuation of treatment.
Additionally, musculoskeletal pain (bone, muscle or joint), which has been described in patients with Paget's disease treated with other bisphosphonates, was reported by the investigators as possibly, probably or definitely drug related in approximately 6% of patients treated with alendronate 40 mg/day versus approximately 1% of patients treated with placebo, but rarely resulted in discontinuation of therapy.

Fosamax Plus.

In a 15-week, double-blind, multinational study in osteoporotic postmenopausal women (n=682) and men (n=35), the safety profile of once weekly alendronate 70 mg/colecalciferol 70 microgram was similar to that of alendronate once weekly 70 mg. In the 24-week double-blind extension study in women (n=619) and men (n=33), the safety profile of alendronate 70 mg/ colecalciferol 70 microgram (vitamin D3 2800 IU) administered with an additional colecalciferol 70 microgram for a total of 140 microgram colecalciferol (5600 IU vitamin D3) was similar to that of alendronate 70 mg/ colecalciferol 70 microgram (2800 IU vitamin D3). The primary endpoint was the proportion of patients who developed hypercalciuria at Week 39, with 4.2% noted in the colecalciferol 140 microgram group and 2.8% in the colecalciferol 70 microgram group, which was not statistically significant. Overall, the safety profile of alendronate 70 mg/ colecalciferol 70 microgram administered with 70 microgram additional colecalciferol for a total of 140 microgram colecalciferol was similar to that of alendronate/colecalciferol 70 microgram.

Alendronate/Fosamax Plus post-marketing experience.

The following adverse reactions have been reported in post-marketing use with alendronate:

Body as a whole.

Hypersensitivity reactions including urticaria and rarely angioedema. Transient symptoms as in an acute-phase response (myalgia, malaise, asthenia and rarely, fever) have been reported with alendronate, typically in association with initiation of treatment. Rarely, symptomatic 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 and/or stomatitis; rarely, gastric or duodenal ulcers, some severe and with complications (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration). Localised osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis), often with delayed healing, has been reported rarely.

Musculoskeletal.

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

Nervous system.

Dizziness, vertigo, dysgeusia.

Skin.

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

Special senses.

Rarely uveitis, scleritis or episcleritis. 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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Alendronate sodium.

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.

Colecalciferol.

Vitamin D toxicity has not been documented during chronic therapy in generally healthy adults at a dose less than 10,000 IU/day. In a clinical study of healthy adults, a 4000 IU daily dose of vitamin D3 for up to five months was not associated with hypercalciuria or hypercalcemia.
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 sodium.

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 for details). Following exposure to alendronate, normal bone is formed that incorporates alendronate into its matrix where it is pharmacologically inactive.
The relative inhibitory activities on bone resorption and 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.

Colecalciferol.

Vitamin D3 is produced in the skin by photochemical conversion of 7-dehydrocholesterol to previtamin D3 by ultraviolet light. This is followed by non-enzymatic isomerisation to vitamin D3. In the absence of adequate sunlight exposure, vitamin D3 is an essential dietary nutrient. Vitamin D3 in skin and dietary vitamin D3 (absorbed into chylomicrons) is converted to 25-hydroxyvitamin D3 in the liver. Conversion to the active calcium-mobilising hormone 1,25-dihydroxyvitamin D3 (calcitriol) in the kidney is stimulated by both parathyroid hormone and hypophosphataemia. The principal action of 1,25-dihydroxyvitamin D3 is to increase intestinal absorption of both calcium and phosphate as well as regulate serum calcium, renal calcium and phosphate excretion, bone formation and bone resorption.
Vitamin D3 is required for normal bone formation. Optimal serum levels of 25-hydroxyvitamin D are unknown. Vitamin D insufficiency may be seen with serum levels below 30 - 50 nanomol/L. Severe vitamin D deficiency is commonly associated with levels < 12.5 nanomol/L. Vitamin D insufficiency develops when both sunlight exposure and dietary intake are inadequate. Insufficiency is associated with negative calcium balance, bone loss, and increased risk of skeletal fracture. In severe cases, deficiency results in secondary hyperparathyroidism, hypophosphataemia, proximal muscle weakness and osteomalacia, further increasing the risk of falls and fractures in osteoporotic individuals. Supplemental vitamin D is associated with reduced risk of vitamin D insufficiency as defined by serum hydroxyvitamin D of < 37.5 nanomol/L.

Osteoporosis.

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

Osteoporosis in postmenopausal women.

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

Osteoporosis in men.

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

Clinical trials.

Treatment of osteoporosis.

Fosamax Plus studies. The effect of alendronate 70 mg/colecalciferol 70 microgram on vitamin D status was demonstrated in a 15-week, double-blind, multinational study of 717 osteoporotic postmenopausal women and men (serum 25-hydroxyvitamin D at baseline: mean, 22.2 nanogram/mL [56 nanomol/L]; range, 9-90 nanogram/mL [22.5-225 nanomol/L]). Patients received alendronate 70 mg/colecalciferol 70 microgram (2800 IU) (n=350 women, 10 men) or alendronate (alendronate 70 mg (n=332 women, 25 men) once a week; additional vitamin D supplements were prohibited. Patients who were vitamin D deficient [defined as serum 25-hydroxyvitamin D < 9 nanogram/mL (22.5 nanomol/L)] at baseline were excluded. Patients with vitamin D insufficiency at baseline were defined as having serum 25-hydroxyvitamin D levels between 9 nanogram/mL (22.5 nanomol/L) and 15 nanogram/mL (37.5 nanomol/L).
The percentage of patients with serum 25-hydroxyvitamin D ≥ 15 nanogram/mL (37.5 nanomol/L) was significantly higher with alendronate 70 mg/colecalciferol 70 microgram vs. alendronate only (89% vs. 68%, respectively). The percentage of patients with serum 25-hydroxyvitamin D ≥ 9 nanogram/mL (22.5 nanomol/L) was significantly higher with alendronate 70 mg/colecalciferol 70 microgram vs. alendronate only (99% vs. 87%, respectively). There were no differences in mean serum calcium, phosphate or 24-hour urine calcium between treatment groups. The final levels of 25-hydroxyvitamin D at week 15 are summarised in Table 4.
The effect of alendronate 70 mg/colecalciferol 70 microgram with an additional 70 microgram colecalciferol (2800 IU vitamin D3) for a total of 140 microgram colecalciferol (5600 IU vitamin D3) once weekly was compared to 70 mg/colecalciferol 70 microgram weekly in a 24-week, extension study that enrolled 652 osteoporotic men and post-menopausal women who completed the above 15-week study. Patients in the colecalciferol 70 microgram group received alendronate 70 mg/colecalciferol 70 microgram (n=305 women, 21 men) and those in the colecalciferol 140 microgram group received alendronate 70 mg/colecalciferol 70 microgram with an additional 70 microgram colecalciferol (n=314 women, 12 men) once a week; additional vitamin D supplements were allowed. The primary endpoint was incidence of hypercalciuria, defined as an increase of greater than 25% from baseline in 24-hour urine calcium and to a value greater than the upper limit of normal (300 mg in women, 350 mg in men). The rate of hypercalciuria was 13/311 (4.2%) for the colecalciferol 140 microgram group and 9/317 (2.8%) for the colecalciferol 70 microgram group, relative risk 1.48 (95% CI 0.64, 3.40).
Secondary endpoints included 25 hydroxyvitamin D levels. The proportions of patients with vitamin D insufficiency (< 37.5 nanomol/L) after 39 weeks was 10/321 (3.1%) in the colecalciferol 140 microgram group and 18/320 (5.6%) in the colecalciferol 70 microgram group.
The percentage of patients with serum 25-hydroxyvitamin D ≥ 15 nanogram/mL (37.5 nanomol/L) was higher with the colecalciferol 140 microgram group vs. the colecalciferol 70 microgram group (96.9% vs. 94.4%, respectively), although not statistically significant.
There were no differences detected between mean serum calcium, mean serum phosphate, or mean 24-hour urine calcium between groups. The distribution of the final levels of 25-hydroxyvitamin D at week 39 is summarised in Table 5.
Alendronate studies. 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 following graph 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. See Figure 1.
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 once weekly 70 mg (n = 519) and alendronate 10 mg daily (n = 370) was demonstrated in a one-year, double-blind, multicentre study of postmenopausal women with osteoporosis. The mean increases from baseline in lumbar spine BMD at one year were 5.1% (4.8, 5.4%; 95% CI) in the 70 mg once weekly group and 5.4% (5.0, 5.8%; 95% CI) in the 10 mg daily group. The two treatment groups were also similar with regard to BMD increases at other skeletal sites. While there are no placebo-controlled fracture data for the once weekly 70 mg tablet, the increases in bone density support the expectation that alendronate once weekly 70 mg will have effects to reduce the incidence of fractures similar to those of the 10 mg daily treatment (see 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: the Three-Year Study of patients who had at least one baseline vertebral (compression) fracture and the Four-Year Study of patients with low bone mass but without baseline vertebral fracture.

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

This randomised, double-blind, placebo-controlled 2027-patient study, (alendronate n=1022; placebo, n=1005) demonstrated that treatment with Fosamax resulted in clinically significant reductions in fracture incidence at three years as shown in Table 6. 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 non-osteoporotic women. The results are shown in Table 7 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.

Prevention of osteoporosis.

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

Glucocorticoid-induced osteoporosis.

Sustained use of glucocorticoids is commonly associated with development of osteoporosis and resulting fractures (especially vertebral, hip and rib). It occurs both in males and females of all ages. Bone loss occurs as a result of a lower rate of bone formation relative to that of bone resorption. Alendronate decreases bone resorption without directly inhibiting bone formation.
In clinical studies of one year's duration, alendronate 5 and 10 mg/day reduced cross-linked N-telopeptides of type 1 collagen (a marker of bone resorption) by approximately 60% and reduced bone-specific alkaline phosphatase and total serum alkaline phosphatase (markers of bone formation) by approximately 25 to 30% and 12 to 15%, respectively. As a result of inhibition of bone resorption, alendronate 5 and 10 mg/day induced asymptomatic decreases in serum calcium (approximately 1%) and serum phosphate (approximately 2 to 7%).
The efficacy of alendronate 5 and 10 mg once daily in men and women receiving glucocorticoids (at least 7.5 mg/day of prednisone or equivalent) was demonstrated in two, one-year placebo-controlled, double-blind, multicentre studies (n: total = 560, males = 176) of virtually identical design. Most of the patients were ambulant, Caucasian and non-smokers. 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.

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 4 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 ≥ 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. Fosamax 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.

Alendronate sodium.

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.
In two two-period cross-over studies, the alendronate in the Fosamax Plus (70 mg/70 microgram and 70 mg/140 microgram) tablet was shown to be bioequivalent to the alendronate in the alendronate 70 mg tablet.
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%).

Colecalciferol.

Following administration of Fosamax Plus (70 mg/70 microgram) Once Weekly Tablet after an overnight fast and two hours before a standard meal, the baseline unadjusted mean area under the serum-concentration-time curve (AUC0-120 hrs) for vitamin D3 was 296.4 nanogram-hr/mL (Geometric Mean Ratio [{GMR} Fosamax Plus 70 mg/70 microgram/vitamin D3 only]: 0.88; 90% CI: 0.81, 0.95). The baseline unadjusted mean maximal serum concentration (Cmax) of vitamin D3 was 5.9 nanogram/mL, [GMR (Fosamax Plus 70 mg/70 microgram/vitamin D3 only): 0.89; 90% CI: 0.84, 0.95] and the median time to maximal serum concentration (Tmax) was 12 hrs. The bioavailability of the 70 microgram (2800 IU) vitamin D3 in Fosamax Plus (70 mg/70 microgram) is similar to 70 microgram (2800 IU) vitamin D3 administered alone (using the AUC0-120 hr and Cmax GMR values).
Following administration of Fosamax Plus 70 mg/140 microgram after an overnight fast and two hours before a standard meal, the mean area under the serum-concentration-time curve (AUC0-80 hrs) (unadjusted for endogenous vitamin D3 levels) for vitamin D3 was 490.2 nanogram-hr/mL (Geometric Mean Ratio [{GMR} Fosamax Plus 70 mg/140 microgram/ vitamin D3 only]: 0.94; 90% CI 0.89, 1.00). The baseline unadjusted mean maximal serum concentration (Cmax) of vitamin D3 was 12.2 nanogram/mL, [GMR (Fosamax Plus 70 mg/140 microgram/ vitamin D3 only 0.94; 90% CI: 0.88, 1.00] and the median time to maximal serum concentration (Tmax) was 10.6 hrs. The bioavailability of the 140 microgram (5600 IU) vitamin D3 in Fosamax Plus 70 mg/140 microgram is similar to 140 microgram (5600 IU) vitamin D3 administered alone (using the AUC0-80 hr and Cmax GMR values).

Distribution.

Alendronate sodium.

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%.

Colecalciferol.

Following absorption, vitamin D3 enters the blood as part of chylomicrons. Vitamin D3 is rapidly distributed mostly to the liver where it undergoes metabolism to 25-hydroxyvitamin D3, the major storage form. Lesser amounts are distributed to adipose and muscle tissue and stored as vitamin D3 at these sites for later release into the circulation. Circulating vitamin D3 is bound to vitamin D-binding protein.

Metabolism.

Alendronate sodium.

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

Colecalciferol.

Vitamin D3 is rapidly metabolised by hydroxylation in the liver to 25-hydroxyvitamin D3, and subsequently metabolised in the kidney to 1,25-dihydroxyvitamin D3, which represents the biologically active form. Further hydroxylation occurs prior to elimination. A small percentage of vitamin D3 undergoes glucuronidation prior to elimination.

Excretion.

Alendronate sodium.

Following a single 10 mg IV dose of [14C] alendronate, approximately 50% of the radioactivity was excreted in the urine within 72 hours and little or no radioactivity was recovered in the faeces; the renal clearance of alendronate was 71 mL/min. Plasma concentrations fell by more than 95% within 6 hours following IV administration, due to distribution to the bone and excretion in the urine. The terminal half-life in humans is estimated to exceed 10 years, reflecting release of alendronate from the skeleton. Alendronate is not excreted through the acidic or basic transport systems of the kidney in rats, and thus it is not anticipated to interfere with the excretion of other drugs by those systems in humans.
Preclinical studies show that the alendronate 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).

Colecalciferol.

When radioactive vitamin D3 was administered to healthy subjects, the mean urinary excretion of radioactivity after 48 hours was 2.4%, and the mean faecal excretion of radioactivity after 4 days was 4.9%. In both cases, the excreted radioactivity was almost exclusively as metabolites of the parent. The mean half-life of vitamin D3 in the serum following an oral dose of alendronate 70 mg/colecalciferol 70 microgram is approximately 24 hours.

5.3 Preclinical Safety Data

Genotoxicity.

Alendronate sodium.

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

Colecalciferol.

Calcitriol, the active hormonal metabolite of colecalciferol, was not genotoxic in the microbial mutagenesis assay with or without metabolic activation, or in an in vivo micronucleus assay in mice.
No studies on the genotoxic potential have been carried out using the alendronate and colecalciferol combination.

Carcinogenicity.

Alendronate sodium.

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.
The carcinogenic potential of colecalciferol alone or the alendronate and colecalciferol combination has not been studied.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each Fosamax Plus 70 mg/70 microgram and 70 mg/140 microgram tablet contains the following inactive ingredients: microcrystalline cellulose, lactose, medium chain triglycerides, gelatin, croscarmellose sodium, sucrose, colloidal anhydrous silica, magnesium stearate, dry vitamin D3 100, purified water, butylated hydroxytoluene, modified food starch and aluminium sodium silicate.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 30°C.
Protect Fosamax Plus (70 mg/ 70 microgram and 70 mg/ 140 microgram) tablets from moisture and light, and store tablets in original blister package until use.

6.5 Nature and Contents of Container

Fosamax Plus 70 mg/ 70 microgram Once Weekly Tablet are supplied in blister packs of 1* and 4 tablets.
Fosamax Plus 70 mg/ 140 microgram once weekly tablet are supplied in blister packs of 1* and 4 tablets.
* Supplied as starter packs only.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Alendronate sodium.

Alendronate sodium is a bisphosphonate that acts as a potent, specific inhibitor of osteoclast-mediated bone resorption. Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxyapatite found in bone.
Alendronate sodium is described chemically as: (4-amino-1-hydroxybutylidene) bisphosphonic acid monosodium salt trihydrate. The empirical formula is C4H12NNaO7P2.3H2O. The formula weight is 325.12.

Colecalciferol.

Colecalciferol (vitamin D3) is a secosterol that is the natural precursor of the calcium regulating hormone calcitriol (1,25-dihydroxyvitamin D3).
The chemical name of colecalciferol is (3β,5Z,7E)-9,10-secocholesta- 5,7,10(19)-trien-3-ol. The empirical formula of colecalciferol is C27H44O and its molecular weight is 384.6.

Chemical structure.

The structural formula of alendronate sodium is:
The structural formula of colecalciferol is:

CAS number.

The CAS Registry Numbers are 121268-17-5 (alendronate sodium); 67-97-0 (colecalciferol).

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (S4).

Summary Table of Changes