Consumer medicine information

Alendronate Plus D3 APOTEX

Alendronic acid; Colecalciferol

BRAND INFORMATION

Brand name

Alendronate Plus D3 APOTEX

Active ingredient

Alendronic acid; Colecalciferol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Alendronate Plus D3 APOTEX.

What is in this leaflet

This leaflet answers some common questions about Alendronate Plus D3 APOTEX. It does not contain all the available information. It does not take the place of talking to your doctor and pharmacist.

All medicines have risks and benefits. Your doctor will have weighed the risks of you taking this medicine 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 this medicine is used for

Alendronate Plus D3 APOTEX contains both alendronate and colecalciferol (vitamin D). It is used to treat osteoporosis and to provide additional vitamin D.

Alendronate belongs to a group of medicines called bisphosphonates. Vitamin D is an essential nutrient required for calcium absorption and healthy bones.

Understanding bone

Throughout life, old bone is being broken down and rebuilt as 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 age 35 this balance is disturbed, with bone loss occurring at a slightly faster rate than it can be replaced. After menopause, hormonal changes in women cause bone loss at an even faster rate. Excessive bone loss causes bones to become thinner and weaker, and therefore more likely to break.

Osteoporosis

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 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 osteoporosis usually has no symptoms. However, if left untreated it can result in broken bones or fractures. Spinal bone fractures may go unnoticed until they cause height loss. Fractures may occur during everyday activities, 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 to pain, deformity and disability, such as stooped posture from curvature of the spine, and loss of mobility.

What should I know about vitamin D?

The main source of vitamin D is through exposure to the sun, 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. Vitamin D deficiency may cause bone loss, osteoporosis and muscle weakness, which can lead to falls and a higher risk of fracture.

How it works

Alendronate works by slowing down the process of old bone being removed, which allows the bone-forming cells time to rebuild normal bone. This reverses the progression of osteoporosis by helping to prevent the loss of bone, rebuild bone and make bone less likely to fracture. Alendronate starts working on the bone cells immediately, but measurable effects on bone mass may not be seen for several months or more.

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

This medicine is not addictive.

This medicine is available only with a doctor’s prescription.

There is not enough information to recommend the use of this medicine in children.

Before you take this medicine

When you must not take it

Do not take this medicine if you have an allergy to:

  • alendronate
  • colecalciferol (vitamin D)
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take this medicine if you have certain disorders of the food pipe (oesophagus) including those that cause difficulty in swallowing.

Alendronate can irritate or burn the food pipe (oesophagus). The chances of this happening should be reduced when you follow the instructions in this leaflet.

Do not take this medicine if you are unable to stand or sit upright for at least 30 minutes.

Do not take this medicine if your doctor has told you that you currently have low blood calcium.

Do not take this medicine if your dentist advises you to consult your doctor first.

Do not take this medicine if you are pregnant or breast-feeding. This medicine has not been studied in pregnant or breastfeeding 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 it has expired or is damaged, return it to your pharmacist for disposal.

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 any allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have kidney disease or swallowing or digestive problems, such as ulcers.

Tell your doctor if you have dental or jaw-bone problems or are planning to have dental surgery.

Tell your doctor if you 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 this medicine.

Taking other medicines

Tell your doctor and 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 may interfere with the absorption of alendronate if taken at the same time. These include:

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

Therefore, this medicine should be taken at least 30 minutes before taking any of the above medicines.

You can take aspirin while you are taking this medicine, however, this combination may increase the risk of stomach upsets.

These medicines may be affected by this medicine or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

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

How to take this medicine

Follow all directions given to you by your doctor or pharmacist carefully. They may differ to 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

The usual dose is one tablet taken once a week on the same day each week. Choose the day of the week that best fits your schedule.

How to take it

Swallow one tablet whole with a full glass of plain water.

Stay upright (sitting, standing or walking around) for at least 30 minutes after swallowing the tablet and until after you have eaten your first food of the day.

Do not lie down immediately after swallowing it.

Do not take any food, medicines or drinks other than plain tap water during this time.

These actions will help make sure your tablet reaches your stomach quickly and help reduce the potential for irritation to your food pipe (oesophagus).

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

When to take it

Take this medicine once a week on the same day each week.

This medicine should be taken after getting up for the day. Do not take it at bedtime.

This medicine should be taken on empty stomach. Food, drinks (other than plain water), and other medicines will lessen the effect of this medicine by interfering with its absorption into the body.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

It is important to keep taking your medicine even if you feel well.

If you forget to take it

If you miss a tablet, take one tablet on the morning after you remember. Return to taking one tablet once a week on your original chosen day.

Do not take two tablets on the same 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 of this medicine. 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 once:

  • drink a full glass of milk
  • do not induce vomiting
  • do not lie down

While you are using this medicine

Things you must do

If you are about to be started on a new medicine, remind your doctor and pharmacist that you are taking this medicine.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately.

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

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

Tell your doctor if you develop new or unusual pain in your leg. Rarely, patients have experienced fracture in the thigh bone.

Make sure you have an adequate intake of calcium in your diet. Your doctor, dietician or pharmacist can suggest suitable foods to eat.

Things you must not do

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

Do not take your medicine to treat any other complaints unless your doctor tells you to.

Do not stop taking your medicine or change the dosage without first discussing it with your doctor.

Things to be careful of

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

Things that may be helpful for your osteoporosis

Talk to your doctor or pharmacist about the self-help measures suggested below for more information:

  • Regular exercise can be helpful in building and maintaining strong bones, such as a brisk walk.
  • Eat a balanced diet. Your doctor may advise to increase the amount of calcium in your diet by eating calcium-rich foods or taking a calcium supplement.
  • 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 or reduce smoking.
  • Your doctor may advise you to reduce the amount of alcohol you drink. Drinking excessively on a regular basis may increase the risk of osteoporosis.

Side effects

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

This medicine 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 attention if you get some of the side effects.

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

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

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

  • stomach complaints, such as pain, wind, feeling sick, vomiting, constipation, diarrhoea
  • an uncomfortable feeling in the stomach or belching after eating (dyspepsia or heartburn)
  • headache
  • aching muscles, joints or bones
  • flu-like symptoms at the start of treatment, such as aching muscles, feeling unwell and fever
  • joint swelling, swelling of hands, ankles or feet
  • dizziness or spinning sensation, unusual tiredness or weakness
  • hair loss
  • changed sense of taste

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

Tell your doctor immediately if you notice any of the following:

  • skin rash, redness of the skin, sometimes made worse by sunlight, itchiness
  • mouth ulcers
  • blurred vision, eye pain or redness
  • muscle cramps or spasms, tingling sensation in the fingers or around the mouth (low blood calcium levels)
  • new or unusual pain in your hip or thigh
  • stomach or duodenal ulcers
  • pinkish, itchy swellings on the skin (hives or nettle rash)
  • jaw-bone or dental problems, including toothache, infection, and delayed healing after a tooth extraction or other work that involves drilling into the jawbone

The above list includes rare serious side effects that may require medical attention.

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

  • difficulty or pain upon swallowing, new or worsening heartburn, chest pain
  • severe skin reactions
  • shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue, or other parts of the body, rash, itching or hives on the skin (signs of an allergic reaction)
  • black, tar-like bloody stools

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

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

Storage and Disposal

Storage

Keep your medicine in the pack until it is time to take it. Protect from light and moisture. If you take your medicine out of the pack it may not keep well.

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

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

Keep this medicine 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

70 mg/70 microgram tablets: White to off- white, modified capsule shaped uncoated tablet, debossed with 'ADC' on one side and '28' on the other side. AUST R 308732.

70 mg/140 microgram tables: white to off- white, modified capsule shaped uncoated tablet, debossed with 'ADC' on one side and '56' on the other side. AUST R 308733.

Available in blister packs of 1 and 4 tablets.

*Not all strengths and pack types may be available.

Ingredients

Each tablet contains 70 mg of alendronate sodium and either 70 or 140 micrograms of colecalciferol as the active ingredients.

It also contains the following:

  • microcrystalline cellulose
  • medium chain triglycerides
  • gelatin
  • croscarmellose sodium
  • sucrose
  • colloidal anhydrous silica
  • magnesium stearate
  • butylated hydroxytoluene
  • povidone

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

Sponsor

Dr Reddy’s Laboratories (Australia) Pty Ltd
Melbourne, VIC 3004

Distributed by:

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park, NSW 2113

This leaflet was prepared in July 2019.

Published by MIMS April 2021

BRAND INFORMATION

Brand name

Alendronate Plus D3 APOTEX

Active ingredient

Alendronic acid; Colecalciferol

Schedule

S4

 

1 Name of Medicine

Alendronate sodium and colecalciferol.

2 Qualitative and Quantitative Composition

Each tablet of Alendronate Plus D3 70 mg/70 microgram APOTEX contains 91.37 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 Alendronate Plus D3 70 mg/140 microgram APOTEX contains 91.37 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.

Excipients with known effect.

Sucrose.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Alendronate Plus D3 70 mg/70 microgram APOTEX once weekly tablet is a white to off-white, modified capsule-shaped uncoated tablet, debossed with 'ADC' on one side and '28' on the other side.
Alendronate Plus D3 70 mg/140 microgram APOTEX once weekly tablet is a white to off-white, modified capsule-shaped uncoated tablet, debossed with 'ADC' on one side and '56' on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Alendronate Plus D3 70 mg/70 microgram APOTEX and Alendronate Plus D3 70 mg/140 microgram APOTEX 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

Alendronate Plus D3 (70 mg/70 microgram or 70 mg/140 microgram).

Treatment of osteoporosis in patients where vitamin D3 supplementation is recommended.

The recommended dose is one tablet of Alendronate Plus D3 (70 mg/70 microgram or 70 mg/140 microgram) once weekly.
The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
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 sodium with colecalciferol (70 mg/70 microgram or 70 mg/140 microgram) and consult their physician.
Alendronate Plus D3 (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).
Alendronate Plus D3 (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, alendronate sodium with colecalciferol 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. Alendronate sodium with colecalciferol (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).
In clinical trials, alendronate was administered with appropriate calcium and vitamin D3 supplementation. The use of vitamin D3 as the sole treatment of osteoporosis has not been established.
Patients should receive supplemental calcium and/or vitamin D3, if intake is inadequate (see Section 4.4 Special Warnings and Precautions for Use).
Physicians should consider the vitamin D3 intake from vitamins and dietary supplements. Alendronate sodium with colecalciferol (70 mg/70 microgram) provides 2800 IU (70 microgram) of vitamin D3 in a single once weekly dose, which is equivalent to seven daily doses of 400 IU (10 microgram). Alendronate sodium with colecalciferol (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 alendronate sodium with colecalciferol (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). Alendronate sodium with colecalciferol (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 alendronate sodium with colecalciferol (70 mg/70 microgram or 70 mg/140 microgram), or on another therapy for Paget's disease to alendronate, there are no known or theoretical safety concerns related to alendronate sodium with colecalciferol (70 mg/70 microgram or 70 mg/140 microgram) in patients who previously received any other antiosteoporotic or antipagetic therapy.

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 alendronate sodium with colecalciferol and seek medical attention if they develop dysphagia, odynophagia or retrosternal pain.

General.

Causes of osteoporosis other than hypogonadism, aging and glucocorticoid use should be considered. If there are clinical reasons to suspect hypocalcaemia and/or vitamin D deficiency (serum levels 25 hydroxyvitamin D < 9 nanomol/L), the appropriate diagnostic tests should be performed. Hypocalcaemia must be corrected before initiating therapy with alendronate sodium with colecalciferol (see Section 4.3 Contraindications). Other disturbances of mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients with these conditions, serum calcium and symptoms of hypocalcaemia should be monitored during therapy with alendronate sodium with colecalciferol. The content of vitamin D in alendronate sodium with colecalciferol (70 mg/70 microgram or 70 mg/140 microgram) is not suitable for correction of vitamin D deficiency.
Alendronate sodium with colecalciferol (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, Alendronate sodium with colecalciferol studies). Alendronate sodium with colecalciferol (70 mg/70 microgram or 70 mg/140 microgram) should not be used to treat osteomalacia. Vitamin D should be used to treat osteomalacia. Alendronate sodium with colecalciferol (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 alendronate sodium with colecalciferol and/or who fail to swallow it with the recommended amount of water, and/or who continue to take alendronate sodium with colecalciferol 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 alendronate sodium with colecalciferol 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 hypercalcemia 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), 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 (also known as insufficiency fractures), some of which occurred in the absence of apparent trauma. Some patients experienced prodromal pain in the affected area, often associated with imaging features of stress fracture, weeks to months before a complete fracture occurred. Approximately one third of these fractures were bilateral; therefore, the contralateral femur should be examined in patients who have sustained a femoral shaft stress fracture. The number of reported cases of this condition is very low (some 40 reported cases world-wide). 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), 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. The calcium content of BoneCal should be considered when these diets are prescribed.

Dosing instructions for patients.

Alendronate sodium with colecalciferol tablets.

To facilitate delivery to the stomach and thus reduce the potential for oesophageal irritation patients should be instructed to swallow each tablet of alendronate sodium with colecalciferol (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 alendronate sodium with colecalciferol (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 alendronate sodium with colecalciferol (70 mg/70 microgram or 70 mg/140 microgram) and consult their physician.
Patients should be instructed that if they miss a dose of alendronate sodium with colecalciferol (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.

Alendronate sodium with colecalciferol (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 alendronate sodium with colecalciferol (70 mg/70 microgram or 70 mg/140 microgram).

Paediatric use.

No data available. Alendronate sodium with colecalciferol (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 alendronate sodium with colecalciferol (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. cholestyramine, 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.

Alendronate sodium and colecalciferol combination.

No data available. 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.
 Alendronate sodium with colecalciferol (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 alendronate sodium with colecalciferol may affect some patients' ability to drive or operate machinery. Individual responses to alendronate sodium with colecalciferol may vary (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Treatment of osteoporosis.

Postmenopausal women.

Alendronate 70 mg 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 alendronate 10 mg daily in 146 men was generally similar to that seen in postmenopausal women.

Other studies in men and women.

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

Prevention of osteoporosis.

The safety of alendronate in postmenopausal women 40 - 60 years of age has been evaluated in three double-blind, placebo-controlled studies involving over 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.

Alendronate sodium with colecalciferol.

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.

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 Poison 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.

Alendronate sodium with colecalciferol 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.

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.
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 alendronate sodium with colecalciferol (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} alendronate sodium with colecalciferol 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 (alendronate sodium with colecalciferol 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 alendronate sodium with colecalciferol (70 mg/70 microgram) is similar to 70 microgram (2800 IU) vitamin D3 administered alone (using the AUC0-120 hrs and Cmax GMR values).
Following administration of alendronate sodium with colecalciferol 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} alendronate sodium with colecalciferol 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 (alendronate sodium with colecalciferol 70 mg/140 microgram/vitamin D3 only 0.94; 90% Cl: 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 alendronate sodium with colecalciferol 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

Microcrystalline cellulose, medium chain triglycerides, gelatin, croscarmellose sodium, sucrose, colloidal anhydrous silica, magnesium stearate, butylated hydroxytoluene, povidone.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C. Protect from light and moisture. Store in original container.

6.5 Nature and Contents of Container

Alendronate Plus D3 70 mg/70 microgram APOTEX once weekly tablet.

Available in blister packs (PA/Al/PVC/Al) of 1* and 4 tablets. (AUST R 308732).

Alendronate Plus D3 70 mg/140 microgram APOTEX once weekly tablet.

Available in blister packs (PA/Al/PVC/Al) of 1* and 4 tablets. (AUST R 308733).
* 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 is a white or almost white, crystalline powder. It is soluble in water, very slightly soluble in methanol, practically insoluble in methylene chloride.
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.
Chemical Name: (4-amino-1-hydroxybutylidene)bisphosphonic acid monosodium salt trihydrate.
Molecular Formula: C4H12NNaO7P2.3H2O. Molecular Weight: 325.12.

Colecalciferol.

Colecalciferol (vitamin D3) is a secosterol that is the natural precursor of the calcium-regulating hormone calcitriol (1,25-dihydroxyvitamin D3).
Colecalciferol is a white to almost white crystalline powder. Colecalciferol is practically insoluble in water, free soluble in alcohol, soluble in fatty oils.
Chemical Name: (5Z,7E)-9,10-secocholesta-5,7,10(19)-trien-3β-ol.
Molecular Formula: C27H44O.
Molecular Weight: 384.6.
Molecular Formula: C27H44O. Molecular Weight: 384.6.

Chemical structure.


CAS number.

Alendronate sodium.

121268-17-5.

Colecalciferol.

67-97-0.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes