Zyflo CR

Generic Name: zileuton (zye LOO ton)

Brand Names: Zyflo CR

What is Zyflo CR (zileuton)?

Zileuton is a leukotriene (loo-koe-TRY-een) inhibitor. Leukotrienes are chemicals your body releases when you breathe in an allergen (such as pollen). These chemicals cause swelling in your lungs and tightening of the muscles around your airways, which can result in asthma symptoms.

Zileuton is used to prevent asthma attacks in adults and children as young as 12 years old.

Zileuton may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about Zyflo CR (zileuton)?

Call your doctor at once if you have nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes). These may be early signs of liver problems. Do not use zileuton to treat an asthma attack that has already begun. It will not work fast enough to reverse your symptoms. Use only a fast-acting inhalation medication to treat an asthma attack. Talk with your doctor if any of your asthma medications do not seem to work as well in treating or preventing asthma attacks. It may take up to a few weeks of using this medicine before your symptoms improve. For best results, keep using zileuton as directed, even if you feel fine. Having no asthma symptoms is a sign that the medication is working.

Call your doctor right away if you feel that this medicine is not working as well as usual, or if it makes your condition worse. If it seems like you need to use more of any of your medications in a 24-hour period, talk with your doctor.

Avoid drinking alcohol while you are taking zileuton. Alcohol can increase your risk of liver damage. Call your doctor at once if you have any mood or behavior changes, anxiety, depression, or thoughts about suicide or hurting yourself.

What should I discuss with my healthcare provider before taking Zyflo CR (zileuton)?

Do not use this medication if you are allergic to zileuton, or if you have liver disease.

If you drink large amounts of alcohol or have a history of liver disease, you may need a dose adjustment or special tests to safely take zileuton

FDA pregnancy category C. It is not known whether zileuton is harmful to an unborn baby. Before taking this medication, tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether zileuton passes into breast milk or if it could harm a nursing baby. . Do not take zileuton without telling your doctor if you are breast-feeding a baby. Do not give this medication to a child without a doctor's advice.

How should I take Zyflo CR (zileuton)?

Take this medication exactly as it was prescribed for you. Do not take the medication in larger amounts, or take it for longer than recommended by your doctor. Follow the directions on your prescription label.

Take zileuton with a full glass of water. Zileuton tablets and extended-release tablets contain the same amount of the drug, but they are not taken in the same way. Follow your doctor's instructions.

Zileuton tablets are usually taken 4 times daily, with meals and at bedtime. Zileuton tablets may be swallowed whole or split in half to make swallowing easier.

Zileuton extended-release tablets are usually taken twice daily, within 1 hour after your morning and evening meals.

Do not crush, chew, or break an extended-release tablet. Swallow the pill whole. It is specially made to release medicine slowly in the body. Breaking the pill would cause too much of the drug to be released at one time. Do not use zileuton to treat an asthma attack that has already begun. It will not work fast enough to reverse your symptoms. Use only a fast-acting inhalation medication to treat an asthma attack. Talk with your doctor if any of your asthma medications do not seem to work as well in treating or preventing asthma attacks. It may take up to a few weeks of using this medicine before your symptoms improve. For best results, keep using zileuton as directed, even if you feel fine. Having no asthma symptoms is a sign that the medication is working.

Asthma is often treated with a combination of different drugs. To best treat your condition, use all of your medications as directed by your doctor. Be sure to read the medication guide or patient instructions provided with each of your medications. Do not change your doses or medication schedule without advice from your doctor, even if you have no asthma symptoms.

Call your doctor right away if you feel that this medicine is not working as well as usual, or if it makes your condition worse. If it seems like you need to use more of any of your medications in a 24-hour period, talk with your doctor.

To be sure this medication is not causing harmful effects, your blood will need to be tested on a regular basis. Your kidney or liver function may also need to be tested. Do not miss any scheduled visits to your doctor.

Store zileuton at room temperature away from moisture and heat.

What happens if I miss a dose?

Take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at your next regularly scheduled time. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

Symptoms of a zileuton overdose are not known.

What should I avoid while taking Zyflo CR (zileuton)?

Avoid situations or activities that may trigger an asthma attack.

Avoid drinking alcohol while taking zileuton. Alcohol may increase your risk of liver damage.

Zyflo CR (zileuton) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have any of these serious side effects:

• 
  

  nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

  
  


• 
  

  skin rash, bruising, severe tingling, numbness, pain, muscle weakness;

  
  


• 
  

  mood or behavior changes, anxiety, depression, or thoughts about suicide or hurting yourself; or

  
  


• 
  

  worsening asthma symptoms.

  
  

Less serious side effects may include:

• 
  

  cold symptoms such as stuffy nose, sinus pain, sneezing, sore throat;

  
  


• 
  

  headache;

  
  


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  diarrhea, upset stomach;

  
  


• 
  

  weakness; or

  
  


• 
  

  muscle pain.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Zyflo CR (zileuton)?

Before taking zileuton, tell your doctor if you are taking any of the following drugs:

• 
  

  a blood thinner such as warfarin (Coumadin);

  
  


• 
  

  theophylline (Theo-Dur, Theolair, Elixophyllin, Slo-Phyllin, others); or

  
  


• 
  

  propranolol (Inderal).

  
  

This list is not complete and there may be other drugs that can interact with zileuton. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

More Zyflo CR resources

• Zyflo CR Side Effects (in more detail)
• Zyflo CR Use in Pregnancy & Breastfeeding
• Zyflo CR Drug Interactions
• Zyflo CR Support Group
• 0 Reviews for Zyflo CR - Add your own review/rating

• Zyflo CR Prescribing Information (FDA)


• Zyflo CR Advanced Consumer (Micromedex) - Includes Dosage Information


• Zyflo CR Extended-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)


• Zileuton Professional Patient Advice (Wolters Kluwer)


• Zileuton Monograph (AHFS DI)


• Zileuton MedFacts Consumer Leaflet (Wolters Kluwer)


• Zyflo Prescribing Information (FDA)

Compare Zyflo CR with other medications

• Asthma, Maintenance

Where can I get more information?

• Your pharmacist can provide more information about zileuton.

See also: Zyflo CR side effects (in more detail)

Antepsin Tablets 1g

1. Name Of The Medicinal Product

Antepsin 1g Tablets

2. Qualitative And Quantitative Composition

Each tablet contains 1 gram of sucralfate.

For excipients, see section 6.1.

3. Pharmaceutical Form

Tablet

Biconvex, oblong, white tablets with a dividing score on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of duodenal ulcer, gastric ulcer, chronic gastritis.

4.2 Posology And Method Of Administration

For oral administration.

Duodenal ulcer, gastric ulcer, chronic gastritis:

Adults: The usual dose is 2 grams twice daily to be taken on rising and at bedtime, or 1 gram 4 times a day to be taken 1 hour before meals and at bedtime. Maximum daily dose: 8 grams. For ease of administration, Antepsin Tablets may be dispersed in 10-15 mL of water. Four to six weeks' treatment is usually needed for ulcer healing, but up to twelve weeks may be necessary in resistant cases.

Antacids may be used as required for relief of pain, but should not be taken half an hour before or after Antepsin.

Elderly: There are no special dosage requirements for elderly patients but, as with all medicines, the lowest effective dose should be used.

Children: Safety and effectiveness in children has not been established.

4.3 Contraindications

Contraindicated in individuals who are hypersensitive to any of the ingredients of Antepsin.

4.4 Special Warnings And Precautions For Use

The product should only be used with caution in patients with renal dysfunction, due to the possibility of increased aluminium absorption. In patients with severe renal impairment or on dialysis, Antepsin should be used with extreme caution and only for short-term treatment. The concomitant use of other aluminium containing medications is not recommended in view of the enhanced potential for aluminium absorption and toxicity.

Bezoars (an insoluble mass formed within the gastric lumen) have been reported occasionally in patients taking Antepsin Suspension. The majority of these patients had underlying conditions that may predispose to bezoar formation such as delayed gastric emptying, or were receiving concomitant enteral feeding (see under Interactions). Bezoars have been reported after administration of Antepsin Suspension to severely ill patients in ITU, especially in premature infants in whom the use of sucralfate is not recommended.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant administration of Antepsin may reduce the bioavailability of certain drugs including tetracycline, ciprofloxacin, norfloxacin, ketoconazole, digoxin, warfarin, phenytoin, theophylline, thyroxine, quinidine and H₂ antagonists. The bioavailability of these agents may be restored by separating the administration of these agents from Antepsin by two hours. This interaction appears to be non systemic in origin presumably resulting from these agents being bound by Antepsin in the gastrointestinal tract. Because of the potential of Antepsin to alter the absorption of some drugs from the gastrointestinal tract, the separate administration of Antepsin from that of other agents should be considered when alterations in bioavailability are felt to be critical for concomitantly administered drugs.

The administration of Antepsin Tablets 1 g and enteral feeds by nasogastric tube should be separated by one hour in patients receiving Antepsin Tablets 1 g for the prophylaxis of stress ulceration. In rare cases bezoar formation has been reported when Antepsin and enteral feeds have been given too closely together.

4.6 Pregnancy And Lactation

Pregnancy:

Teratogenicity studies in mice, rats and rabbits at doses up to 50 times the human dose have revealed no evidence of harm to the foetus. Safety in pregnant women has not been established and Antepsin should be used during pregnancy only if clearly needed.

Lactation:

It is not known whether this drug is excreted in human milk. Caution should be exercised when Antepsin is administered to breast-feeding women.

4.7 Effects On Ability To Drive And Use Machines

Do not drive if you feel dizzy or drowsy.

4.8 Undesirable Effects

Adverse reactions to Antepsin in clinical trials were minor and only rarely led to discontinuation of the drug. Adverse events seen during use of Antepsin have included constipation, diarrhoea, nausea, vomiting, gastric discomfort, indigestion, flatulence, dry mouth, rash, back pain, dizziness, headache, vertigo, drowsiness and hypersensitivity reactions including pruritus, oedema, urticaria and shortness of breath.

4.9 Overdose

There is no experience in humans with overdose. Acute oral toxicity studies in animals, however, using doses up to 12g/kg body weight, could not find a lethal dose. Risks associated with overdose, should, therefore, be minimal.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

The action of Antepsin is non-systemic as the drug is only minimally absorbed from the gastro-intestinal tract. The small amounts that are absorbed are excreted primarily in the urine. Antepsin exerts a generalised cytoprotective effect by preventing gastro-intestinal mucosal injury.

Studies in humans and animal models show that Antepsin forms an ulcer adherent complex with the proteinaceous exudate of the ulcer site. This property enables Antepsin to form a protective barrier over the ulcer lesion giving sustained protection against the penetration and action of gastric acid, pepsin and bile.

Studies both in humans and animals demonstrate that Antepsin protects the gastric mucosa against various irritants such as alcohol, acetylsalicyclic acid and sodium taurocholate.

Antepsin also directly inhibits pepsin activity and absorbs bile salts. It has only weak antacid activity. It does not alter gastric emptying time, nor normal digestive function. Antepsin has no demonstrated pharmacological effect on the cardiovascular or central nervous systems.

5.2 Pharmacokinetic Properties

Sucralfate is only minimally absorbed from the gastro-intestinal tract. The small amounts that are absorbed are excreted primarily in the urine. Absorption of aluminium from sucralfate may be increased in patients on dialysis or with renal dysfunction (see also “other special warnings and precautions”).

5.3 Preclinical Safety Data

There was no evidence of carcinogenesis in mice and rats receiving oral sucralfate in dosages of up to 1 g/kg daily (12 times the usual human dosage) for 2 years. In animal studies there was no effect evidence of impaired fertility. The effect of sucralfate on human fertility is not known.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Macrogol 6000

Microcrystalline cellulose

Calcium Carmellose

Magnesium stearate.

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Store below 25^oC.

6.5 Nature And Contents Of Container

Blister packs (pack size 50 tablets).

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Chugai Pharma UK Ltd.

Mulliner House

Flanders Road

Turnham Green

London

W4 1NN

U.K.

8. Marketing Authorisation Number(S)

PL 12185/0008

9. Date Of First Authorisation/Renewal Of The Authorisation

1 December 1998

10. Date Of Revision Of The Text

5 November 2007

Alphanate

1. Name Of The Medicinal Product

Alphanate^®, powder for injection.

2. Qualitative And Quantitative Composition

Alphanate^® is a high purity solvent detergent and heat treated preparation of human coagulation factor VIII, freeze-dried, Ph. Eur. Alphanate^® also contains human von Willebrand factor at pharmacologically effective levels.

Alphanate^® is presented as a powder and solvent for solution for injection containing nominally 500 I.U., 1000 I.U. or 1500 I.U. human coagulation factor VIII per container. Alphanate^® contains no less than 400 I.U. of von Willebrand factor activity per 1000 I.U. of factor VIII activity (i.e. VWF:RCo/FVIII:C ratio

Alphanate^® 500 I.U. contains approximately 100 I.U./ml human coagulation factor VIII and no less than approximately 40 I.U./ml human von Willebrand factor activity when reconstituted with 5 ml sterile Water for Injections, Ph. Eur.

Alphanate^® 1000 I.U. contains approximately 100 I.U./ml human coagulation factor VIII and no less than approximately 40 I.U./ml human von Willebrand factor activity when reconstituted with 10 ml sterile Water for Injections, Ph. Eur.

Alphanate^® 1500 I.U. contains approximately 150 I.U./ml human coagulation factor VIII and no less than approximately 60 I.U./ml human von Willebrand factor activity when reconstituted with 10 ml sterile Water for Injections, Ph. Eur.

Each container is labelled with the number of International Units of factor VIII and von Willebrand factor activity.

The factor VIII potency is determined using the Activated Partial Thromboplastin Time method, which gives results comparable to the European Pharmacopoeia chromogenic assay, and a reference standard calibrated against the WHO International Standard (FVIII:C I.U.).

The von Willebrand factor potency is determined by measuring the Ristocetin Cofactor Activity using a reference standard calibrated against the WHO International Standard (VWF:RCo I.U.).

The specific activity of Alphanate^®, prior to the addition of albumin, is greater than 100 I.U. factor VIII/mg protein and, as finished product, is greater than 5 I.U. factor VIII/mg protein.

For a full list of excipients see section 6.1.

3. Pharmaceutical Form

Powder for injection.

Solvent (Water for Injections).

Vial containing white or pale yellow powder and syringe with Water for Injections (solvent).

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency). This product may be used in the management of acquired factor VIII deficiency.

Prevention and treatment of haemorrhage or surgical bleeding in patients with von Willebrand disease (VWD), when desmopressin (DDAVP) treatment alone is ineffective or contra-indicated.

4.2 Posology And Method Of Administration

Treatment should be initiated under the supervision of a physician experienced in the treatment of haemostatic disorders.

Posology

Factor VIII deficiency

The dosage and duration of the substitution therapy depend on the severity of the factor VIII deficiency, on the location and extent of the bleeding and on the patient's clinical condition.

The number of units of factor VIII administered is expressed in International Units (I.U.), which are related to the current WHO standard for factor VIII products. Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to an International Standard for factor VIII in plasma).

One International Unit (I.U.) of factor VIII activity is equivalent to that quantity of factor VIII in one ml of normal human plasma. The calculation of the required dosage of factor VIII is based on the empirical finding that 1 International Unit (I.U.) factor VIII per kg body weight raises the plasma factor VIII activity by 1.5% to 2% of normal activity. The required dosage is determined using the following formula:

Required Units = Body weight (kg) x desired factor VIII rise (%) (I.U./dl) x 0.5

The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case.

In the case of the following haemorrhagic events, the factor VIII activity should not fall below the given plasma activity level (in % of normal or I.U./dl) in the corresponding period.

The following table can be used to guide dosing in bleeding episodes and surgery:

Degree of haemorrhage/Type of surgical procedure	Factor VIII level required as % of normal (I.U./dL)	Frequency of doses (hours)/Duration of therapy (days)
Haemorrhage Early haemarthrosis, muscle bleeding or oral bleeding   More extensive haemarthrosis, muscle bleeding or haematoma Life threatening haemorrhages	20 - 40   30 - 60 60 - 100	Repeat every 12 to 24 hours. At least 1 day, until the bleeding episode, as indicated by pain, is resolved or healing is achieved. Repeat infusion every 12 – 24 hours for 3 – 4 days or more until pain and disability are resolved. Repeat infusion every 8 – 24 hours until threat is resolved.
Surgery Minor, including tooth extraction Major	30 - 60 80 - 100 (pre- and post-operative)	Every 24 hours, at least 1 day, until healing is achieved. Repeat infusion every 8 - 24 hours until adequate wound healing, then therapy for at least another 7 days to maintain a FVIII activity of 30% to 60% (I.U./dL).

During the course of treatment, appropriate determination of factor VIII levels is advised to guide the dose to be administered and the frequency of repeated infusions. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor VIII activity) is indispensable. Individual patients may vary in their response to factor VIII, achieving different levels of in vivo recovery and demonstrating different half-lives.

For long term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are 20 to 40 I.U. of factor VIII per kg of body weight at intervals of 2 to 3 days. In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary.

Patients should be monitored for the development of factor VIII inhibitors. If the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, an assay should be performed to determine if a factor VIII inhibitor is present. In patients with high levels of inhibitor, factor VIII therapy may not be effective and other therapeutic options should be considered. Management of such patients should be directed by physicians with experience in the care of patients with haemophilia. See also section 4.4.

Von Willebrand disease

Generally, 1 I.U./kg VWF:RCo raises the circulating level of VWF:RCo by 2%. Levels of VWF:RCo of> 0.6 I.U./ml (60%) and of FVIII:C of> 0.4 I.U./ml (40%) should be achieved.

Usually 40 - 80 I.U./kg of von Willebrand factor (VWF:RCo) and 20 - 40 I.U./kg of FVIII:C are recommended to achieve haemostasis.

An initial dose of 80 I.U./kg of von Willebrand factor may be required, especially in patients with type 3 von Willebrand disease where maintenance of adequate levels may require greater doses than in other types of von Willebrand disease.

An appropriate dose should be re-administered every 12 - 24 hours. The dose and duration of the treatment depend on the clinical status of the patient, the type and severity of bleeding, and both VWF:RCo and FVIII:C levels.

When using a FVIII-containing von Willebrand factor product, the treating physician should be aware that continued treatment may cause an excessive rise in FVIII:C. After 24 - 48 hours of treatment, reduced doses and/or prolongation of the dose interval or the use of a VWF product containing a low level of FVIII should be considered.

There are insufficient data to recommend the use of Alphanate^® in children less than 6 years of age for the authorised indications.

Method of administration

Dissolve the preparation as described in section 6.6. The product should be administered via the intravenous route. The injection speed should not exceed 10 ml per minute.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings And Precautions For Use

As with any intravenous protein product, allergic-type hypersensitivity reactions are possible. The product contains traces of human proteins other than factor VIII. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. If these symptoms occur, they should be advised to discontinue use of the product immediately and contact their physician.

In case of shock, the current medical standards for shock treatment should be observed.

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV. The measures taken may be of limited value against non-enveloped viruses such as HAV and parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (foetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g. haemolytic anaemia).

Appropriate vaccination (hepatitis A and B) should be considered for patients in regular receipt of human plasma-derived factor VIII products.

The formation of neutralising antibodies, inhibitors, to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the factor VIII procoagulant activity, which are quantified in Bethesda units (BU) per ml of plasma using Nijmegen's modified assay. The risk of developing inhibitors is correlated to the exposure to antihaemophilic factor VIII, this risk being highest within the first 20 exposure days. Rarely, inhibitors may develop after the first 100 days. Patients treated with human coagulation factor VIII should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. See also section 4.8 Undesirable effects.

Reports in the literature suggest that patients with Type 3 (severe) von Willebrand Disease may occasionally develop alloantibodies to von Willebrand factor.

It is strongly recommended that every time that Alphanate^® is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interactions of human coagulation factor VIII or von Willebrand factor products with other medicinal products are known.

4.6 Pregnancy And Lactation

Animal reproduction studies have not been conducted with Alphanate^®.

Based on the rare occurrence of haemophilia A in women, experience regarding the use of human coagulation factor VIII during pregnancy and breast-feeding is not available.

There is no data from a clinical study regarding the use of von Willebrand factor in pregnant or lactating women.

Therefore, Alphanate^® should be used during pregnancy and lactation only if clearly indicated.

4.7 Effects On Ability To Drive And Use Machines

Alphanate has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed infrequently, and may in some cases progress to severe anaphylaxis (including shock).

On rare occasions, fever has been observed.

Patients with haemophilia A may develop neutralising antibodies (inhibitors) to factor VIII. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted. There is no data available regarding the development of inhibitors in previously untreated patients treated with Alphanate^®.

Patients with von Willebrand disease, especially type 3 patients, may very rarely develop neutralising antibodies (inhibitors) to von Willebrand factor. If such inhibitors occur, the condition will manifest itself as an inadequate clinical response. Such antibodies may occur in close association with anaphylactic reactions. Therefore, patients experiencing anaphylactic reaction should be evaluated for the presence of an inhibitor. In such cases, it is recommended that a specialised haemophilia centre be contacted.

When using this product for patients with von Willebrand disease, there is a risk of occurrence of thrombotic events, particularly in patients with known clinical or laboratory risk factors.

In patients receiving factor VIII-containing von Willebrand factor products sustained excessive FVIII:C levels may increase the risk of thrombotic events.

For information on transmissible agents safety, see section 4.4.

4.9 Overdose

No symptoms of overdose with human coagulation factor VIII and/or von Willebrand factor have been reported. Thromboembolic events may occur in case of major overdose.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic Group: Anti-haemorrhagics: blood coagulation factors, ATC code: B02BD06.

In Alphanate^®, factor VIII is presented as a complex with von Willebrand factor.

The factor VIII / von Willebrand factor complex consists of two molecules (factor VIII and von Willebrand factor) with different physiological functions.

Factor VIII deficiency

When infused into a haemophiliac patient, factor VIII binds to von Willebrand factor in the patient's circulation. Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

Von Willebrand disease

Alphanate^® behaves in the same way as endogenous von Willebrand factor.

Administration of von Willebrand factor allows correction of the haemostatic abnormalities exhibited by patients who suffer from von Willebrand factor deficiency (von Willebrand disease) at two levels:

- Von Willebrand factor re-establishes platelet adhesion to the vascular sub-endothelium at the site of vascular damage (as it binds both to the vascular sub-endothelium and to the platelet membrane), providing primary haemostasis as shown by the shortening of the bleeding time. This effect occurs immediately and is known to depend to a large extent on the level of polymerisation of the protein;

- Von Willebrand factor produces delayed correction of the associated factor VIII deficiency. Administered intravenously, von Willebrand factor binds to endogenous factor VIII (which is produced normally by the patient), and by stabilising this factor, avoids its rapid degradation.

Administration of a FVIII:C containing VWF preparation restores the FVIII:C level to normal immediately after the first infusion.

There are insufficient data from clinical trials in children less than 6 years of age for the authorised indications.

5.2 Pharmacokinetic Properties

Haemophilia A

In an open, randomised, crossover study, the pharmacokinetics of Alphanate^® were compared with the non heat-treated version of the same product. Haemophilia A patients (< 3 I.U. factor VIII/dL) were dosed to achieve peak plasma factor VIII levels of about 100 units/dL. Blood samples were withdrawn up to 28 hours post-infusion. The median half-life for Alphanate^® was 12.2 hours and the mean in vivo recovery was 86.5%. In these studies the mean AUC was 895 I.U. h/dL, the mean residence time was 9.9 hours and the clearance was 4.4 mL/h/kg.

Depending on the degree of bleeding, injury or tissue damage the biological half-life may decrease. This has to be taken into account when determining the dosage.

Von Willebrand Disease

A pharmacokinetic study of Alphanate^® was conducted in 18 non-bleeding subjects with von Willebrand Disease (3 Type 1, 3 Type 2A, and 12 Type 3). Subjects received a single intravenous dose of Alphanate^® at 60 VWF:RCo I.U./kg (75 VWF:RCo I.U./kg in subjects younger than 18 years of age). Blood samples were withdrawn up to 48 hours post-infusion. The mean plasma levels of VWF:RCo rose from 12.3 ± 4.8% at baseline to 206.0 ± 98.7% 15 minutes post-infusion, mean plasma levels of FVIII:C rose from 23.2 ± 31.2% to 215.4 ± 86.3%, and mean plasma levels of VWF:Ag rose from 13.0 ± 20.0% to 325.1 ± 133.9%. The mean skin bleeding time prior to infusion was 29.1 ± 3.9 minutes, which shortened to 10.4 ± 3.1 minutes 1 hour post-infusion. Similar results were observed in the subset of 12 subjects with Type 3 VWD.

The mean half-lives for VWF:RCo, FVIII:C, and VWF:Ag were 7.5 ± 3.2 hours, 21.5 ± 7.2 hours, and 13.0 ± 2.1 hours, respectively, and the mean incremental in vivo recoveries of VWF:RCo and FVIII:C were 3.1 ± 1.5% / VWF:RCo I.U./kg and 2.2 ± 0.6% / VWF:RCo I.U./kg, respectively.

For VWF:RCo, FVIII:C and VWF:Ag, mean AUC was 1737, 5022 and 4891%*hr respectively; mean residence time was 10.7, 31.6 and 18.7 hours, respectively; and clearance was 0.05, 0.01 and 0.01 (I.U./kg) / (%*hr) respectively.

Following infusion of Alphanate^® there was a predictable increase in the size of von Willebrand factor multimers, which persisted for at least 24 hours. The shortening of the bleeding time was transient, generally lasting less than 6 hours following treatment.

5.3 Preclinical Safety Data

Human plasma coagulation factor VIII and von Willebrand factor (active ingredients for Alphanate^®) are normal constituents of human plasma and act like the corresponding endogenous proteins.

Single dose toxicity testing is of no relevance since higher doses result in overloading.

Repeated dose toxicity testing in animals is impracticable due to interference with developing antibodies to heterologous protein.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Albumin

Histidine

Arginine

Water for Injections Ph. Eur. (Solvent)

6.2 Incompatibilities

Alphanate^® should not be mixed with other medicinal products.

Only the provided infusion set should be used because treatment failure can occur as a consequence of FVIII/VWF complex adsorption to the internal surfaces of some infusion equipment.

6.3 Shelf Life

Lyophilised Alphanate^® has a shelf life of 24 months at 2 °C – 8 °C.

Storage at no more than 30 °C for 6 months within this period is acceptable.

Reconstituted Alphanate^® has a shelf life of 3 hours at 25 °C.

6.4 Special Precautions For Storage

Lyophilised Alphanate^® should be stored in a refrigerator (2 °C – 8 °C), protected from light. Do not freeze.

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature And Contents Of Container

Alphanate^® is a white to slightly yellow freeze dried powder containing 500, 1000 or 1500 I.U. of factor VIII (nominal) and no less than 400 I.U. of von Willebrand factor activity per 1000 I.U. of factor VIII activity. The glass containers are made of Type I glass and closed with grey butyl rubber stoppers, aluminium crimp seal (bearing the lot number) and plastic “flip-off” dust cover.

Each vial of Alphanate^® is supplied with a Type I glass syringe containing 5 ml (for the presentation of 500 I.U. factor VIII) or 10 ml (for the presentations of 1000 and 1500 I.U. factor VIII) of Water for Injections Ph. Eur. (PL 4447/0016).

The accessories supplied with Alphanate^® for reconstitution and administration of the product are: vial adaptor, filter, butterfly needle and two alcohol swabs.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Do not use after the expiry date shown on the vial label.

Use aseptic technique during reconstitution and administration.

Left-over product must never be stored for later use, nor stored in a refrigerator.

To prepare the solution:

1. Warm the vial and syringe but not above 30 °C

2. Attach plunger to syringe containing solvent.

3. Remove filter from packaging. Remove cap from syringe tip and attach syringe to filter.

4. Remove vial adaptor from packaging and attach to syringe and filter.

5. Remove cap from vial and wipe stopper with swabs provided.

6. Pierce vial stopper with adaptor needle.

7. Transfer all solvent from syringe to vial.

8. Gently shake vial until all product is dissolved. As with other parenteral solutions, do not use if product is not properly dissolved or particles are visible.

9. Briefly separate the syringe/filter from vial/adaptor to release the vacuum.

10. Turn the vial upside down and draw the solution into the syringe.

11. Prepare injection site, separate syringe and inject product using the butterfly needle provided. Injection rate should be 3 ml/min into a vein and never more than 10 ml/min to avoid vasomotor reactions.

After reconstitution with the Water for Injections solvent provided, the product should be used immediately.

Do not re-use the administration sets.

Any unused product or waste material should be disposed of in accordance with local requirements.

The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have deposits. Reconstituted product should be inspected visually for particulate matter and discoloration prior to administration.

7. Marketing Authorisation Holder

Instituto Grifols, S. A. Can Guasch, 2 – Parets del Vallès 08150 Barcelona – SPAIN

8. Marketing Authorisation Number(S)

PL 12930/0015

9. Date Of First Authorisation/Renewal Of The Authorisation

10 December 2003

10. Date Of Revision Of The Text

03/2009

Bondronat 2mg and 6mg Concentrate for solution for infusion

1. Name Of The Medicinal Product

Bondronat 2 mg

Bondronat 6 mg

Concentrate for solution for infusion

2. Qualitative And Quantitative Composition

Bondronat 2 mg

One vial with 2 ml concentrate for solution for infusion contains 2 mg ibandronic acid (as 2.25 mg ibandronic acid, monosodium salt, monohydrate).

Bondronat 6 mg

One vial with 6 ml concentrate for solution for infusion contains 6 mg ibandronic acid (as 6.75 mg ibandronic acid, monosodium salt, monohydrate).

Excipients: Sodium (less than 1 mmol per dose).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Concentrate for solution for infusion.

Clear, colourless solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Bondronat is indicated in adults for

- Prevention of skeletal events (pathological fractures, bone complications requiring radiotherapy or surgery) in patients with breast cancer and bone metastases.

- Treatment of tumour-induced hypercalcaemia with or without metastases.

4.2 Posology And Method Of Administration

Bondronat therapy should only be initiated by physicians experienced in the treatment of cancer.

Posology

Prevention of skeletal events in patients with breast cancer and bone metastases

The recommended dose for prevention of skeletal events in patients with breast cancer and bone metastases is 6 mg intravenous injection given every 3-4 weeks. The dose should be infused over at least 15 minutes. For infusion, the contents of the vials(s) should only be added to 100 ml isotonic sodium chloride solution or 100 ml 5% glucose solution.

A shorter (i.e. 15 min) infusion time should only be used for patients with normal renal function or mild renal impairment. There are no data available characterizing the use of a shorter infusion time in patients with creatinine clearance below 50 ml/min. Prescribers should consult the section Patients with Renal Impairment (see section 4.2) for recommendations on dosing and administration in this patient group.

Treatment of tumour-induced hypercalcaemia

Prior to treatment with Bondronat the patient should be adequately rehydrated with 9 mg/ml (0.9%) sodium chloride. Consideration should be given to the severity of the hypercalcaemia as well as the tumour type. In general patients with osteolytic bone metastases require lower doses than patients with the humoral type of hypercalcaemia. In most patients with severe hypercalcaemia (albumin-corrected serum calcium*

* Note albumin-corrected serum calcium concentrations are calculated as follows:

Albumin-corrected Serum calcium (mmol/l)	=	serum calcium (mmol/l) - [0.02 x albumin (g/l)] + 0.8
Or
Albumin-corrected Serum calcium (mg/dl)	=	serum calcium (mg/dl) + 0.8 x [4 - albumin (g/dl)]
To convert the albumin-corrected serum calcium in mmol/l value to mg/dl, multiply by 4.

In most cases a raised serum calcium level can be reduced to the normal range within 7 days. The median time to relapse (return of albumin-corrected serum calcium to levels above 3 mmol/l) was 18 - 19 days for the 2 mg and 4 mg doses. The median time to relapse was 26 days with a dose of 6 mg.

A limited number of patients (50 patients) have received a second infusion for hypercalcaemia. Repeated treatment may be considered in case of recurrent hypercalcaemia or insufficient efficacy.

Patients with hepatic impairment

No dosage adjustment is required (see section 5.2).

Patients with renal impairment

For patients with mild renal impairment (CLcr

Creatinine Clearance (ml/min)	Dosage / Infusion time 1	Infusion Volume 2
	6 mg / 15 minutes	100 ml
	4 mg / 1 hour	500 ml
<30	2 mg / 1 hour	500 ml

¹ Administration every 3 to 4 week

² 0.9% sodium chloride solution or 5% glucose solution

A 15 minute infusion time has not been studied in cancer patients with CLCr <50 mL/min.

Elderly

No dose adjustment is required.

Paediatric population

The safety and efficacy of Bondronat in children and adolescents below age 18 years have not been established. No data are available.

Method of administration

For intravenous administration.

For single use only. Only clear solution without particles should be used.

Bondronat concentrate for solution for infusion should be administered as an intravenous infusion. For this purpose, the contents of the vials are to be added to 500 ml isotonic sodium chloride solution (or 500 ml 5% dextrose solution) and infused over two hours.

As the inadvertent intra-arterial administration of preparations not expressly recommended for this purpose as well as paravenous administration can lead to tissue damage, care must be taken to ensure that Bondronat concentrate for solution for infusion is administered intravenously.

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients.

- Caution is to be taken in patients with known hypersensitivity to other bisphosphonates.

- Hypocalcaemia

4.4 Special Warnings And Precautions For Use

Patients with disturbances of bone and mineral metabolism

Hypocalcaemia and other disturbances of bone and mineral metabolism should be effectively treated before starting Bondronat therapy for metastatic bone disease.

Adequate intake of calcium and vitamin D is important in all patients. Patients should receive supplemental calcium and/or vitamin D if dietary intake is inadequate

Osteonecrosis of the jaw (ONJ)

Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).

While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment.

During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.

Patients with renal impairment

Clinical studies have not shown any evidence of deterioration in renal function with long term Bondronat therapy. Nevertheless, according to clinical assessment of the individual patient, it is recommended that renal function, serum calcium, phosphate and magnesium should be monitored in patients treated with Bondronat.

Patients with hepatic impairment

As no clinical data are available, dosage recommendations cannot be given for patients with severe hepatic insufficiency.

Patients with cardiac impairment

Overhydration should be avoided in patients at risk of cardiac failure.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction studies have only been performed in adults.

No interaction was observed when co-administered with melphalan/prednisolone in patients with multiple myeloma.

Other interaction studies in postmenopausal women have demonstrated the absence of any interaction potential with tamoxifen or hormone replacement therapy (oestrogen).

In relation to disposition, no drug interactions of clinical significance are likely. Ibandronic acid is eliminated by renal secretion only and does not undergo any biotransformation. The secretory pathway does not appear to include known acidic or basic transport systems involved in the excretion of other active substances. In addition, ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and does not induce the hepatic cytochrome P450 system in rats. Plasma protein binding is low at therapeutic concentrations and ibandronic acid is therefore unlikely to displace other active substances.

Caution is advised when bisphosphonates are administered with aminoglycosides, since both substances can lower serum calcium levels for prolonged periods. Attention should also be paid to the possible existence of simultaneous hypomagnesaemia.

In clinical studies, Bondronat has been administered concomitantly with commonly used antineoplastics, diuretics, antibiotics and analgesics without clinically apparent interactions occurring.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of ibandronic acid in pregnant women. Studies in rats have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Therefore, Bondronat should not be used during pregnancy.

Breast-feeding

It is not known whether ibandronic acid is excreted in human milk. Studies in lactating rats have demonstrated the presence of low levels of ibandronic acid in the milk following intravenous administration. Bondronat should not be used during lactation.

Fertility

There are no data on the effects of ibandronic acid from humans. In reproductive studies in rats by the oral route, ibandronic acid decreased fertility. In studies in rats using the intravenous route, ibandronic acid decreased fertility at high daily doses (see section 5.3).

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.

4.8 Undesirable Effects

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common (

Treatment of tumour induced hypercalcaemia

The safety profile for Bondronat in tumour-induced hypercalcaemia is derived from controlled clinical trials in this indication and after the intravenous administration of Bondronat at the recommended doses. Treatment was most commonly associated with a rise in body temperature. Occasionally, a flu-like syndrome consisting of fever, chills, bone and/or muscle ache-like pain was reported. In most cases no specific treatment was required and the symptoms subsided after a couple of hours/days.

Table 1 Adverse Events in Controlled Clinical Trials in Tumour-Induced Hypercalcaemia after Treatment with Bondronat

System Organ Class	Very common	Common	Uncommon	Rare	Very rare
Immune system disorders					Hypersensitivity
Metabolism and nutritional disorders		Hypocalcaemia**
Respiratory, thoracic, and mediastinal disorders					Bronchospasm
Skin and subcutaneous tissue disorders					Angioneurotic oedema
Musculoskeletal and connective tissue disorders		Bone pain	Myalgia
General disorders and administration site conditions	Pyrexia		Influenza-like illness**, rigors

Note: Data for both the 2 mg and 4 mg doses of ibandronic acid are pooled.

**See further information below

Hypocalcaemia

Decreased renal calcium excretion may be accompanied by a fall in serum phosphate levels not requiring therapeutic measures. The serum calcium level may fall to hypocalcaemic values.

Influenza-like illness

A flu-like syndrome consisting of fever, chills, bone and/or muscle ache-like pain has occurred. In most cases no specific treatment was required and the symptoms subsided after a couple of hours/days.

Prevention of skeletal events in patients with breast cancer and bone metastases

The safety profile of intravenous Bondronat in patients with breast cancer and bone metastases is derived from a controlled clinical trial in this indication and after the intravenous administration of Bondronat at the recommended dose.

Table 2 lists adverse drug reactions from the pivotal phase III study (152 patients treated with Bondronat 6 mg), i.e. adverse events with a remote, possible, or probable relationship to study medication, and from postmarketing experience.

Table 2 Adverse Drug Reactions Occurring in Patients with Metastatic Bone Disease due to Breast Cancer Treated with Bondronat 6 mg administered intravenously

System Organ Class	Very common	Common	Uncommon	Rare	Very rare
Infections and infestations		Infection	Cystitis, vaginitis, oral candidiasis
Neoplasms benign, malignant, and unspecified			Benign skin neoplasm
Blood and lymphatic system disorders			Anaemia, blood dyscrasia
Endocrine disorders		Parathyroid disorder
Metabolism and nutrition disorders			Hypophosphataemia
Psychiatric disorders			Sleep disorder, anxiety, affection lability
Nervous system disorders		Headache, dizziness, dysgeusia (taste perversion)	Cerbrovascular disorder, nerve root lesion , amnesia, migraine, neuralgia, hypertonia, hyperaestesia, paraesthesia circumoral, parosmia
Eye disorders		Cataract		Ocular inflammation†**
Ear and labyrinth disorders			Deafness
Cardiac disorders		Bundle branch block	Myocardial ischaemia, cardiovascular disorder, palpitations
Respiratory, thoracic, and mediastinal disorders		Pharyngitis	Lung oedema, stridor
Gastrointestinal disorders		Diarrhoea, vomiting, dyspepsia, gastrointestinal pain, tooth disorder	Gastroenteritis, gastritis, mouth ulceration, dysphagia, cheilitis
Hepatobiliary disorders			Cholelithiasis
Skin and subcutatneous tissue disorders		Skin disorder, ecchymosis	Rash, alopecia
Musculoskeletal and connective tissue disorders		Osteoarthritis, myalgia, arthralgia, joint disorder		Atypical subtrochanteric and diaphyseal femoral fractures† (bisphosphonate class adverse reaction)	Osteonecrosis of jaw†**
Renal and urinary disorders			Urinary retention, renal cyst
Reproductive system and breast disorders			Pelvic pain
General disorders and administration site conditions		Influenza-like illness, oedema peripheral, asthenia, thirst	Hypothermia
Investigations		Gamma-GT increased, creatinine increased	Blood alkaline phosphatase increase, weight decrease
Injury, poisoning and procedural complications			Injury, injection site pain

**See further information below.

†Identified in postmarketing experience.

Osteonecrosis of jaw

Osteonecrosis of the jaw has been reported in patients treated by bisphosphonates. The majority of the reports refer to cancer patients, but such cases have also been reported in patients treated for osteoporosis. Osteonecrosis of the jaw is generally associated with tooth extraction and / or local infection (including osteomyelitis). Diagnosis of cancer, chemotherapy, radiotherapy, corticosteroids and poor oral hygiene are also deemed as risk factors (see section 4.4).

Ocular inflammation

Ocular inflammation events such as uveitis, episcleritis and scleritis have been reported with ibandronic acid. In some cases, these events did not resolve until the ibandronic acid was discontinued.

4.9 Overdose

Up to now there is no experience of acute poisoning with Bondronat concentrate for solution for infusion. Since both the kidney and the liver were found to be target organs for toxicity in preclinical studies with high doses, kidney and liver function should be monitored. Clinically relevant hypocalcaemia should be corrected by intravenous administration of calcium gluconate.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmaco-therapeutic group: Drugs for treatment of bone diseases, bisphosphonate, ATC Code: M05BA06

Ibandronic acid belongs to the bisphosphonate group of compounds which act specifically on bone. Their selective action on bone tissue is based on the high affinity of bisphosphonates for bone mineral. Bisphosphonates act by inhibiting osteoclast activity, although the precise mechanism is still not clear.

In vivo, ibandronic acid prevents experimentally-induced bone destruction caused by cessation of gonadal function, retinoids, tumours or tumour extracts. The inhibition of endogenous bone resorption has also been documented by ⁴⁵Ca kinetic studies and by the release of radioactive tetracycline previously incorporated into the skeleton.

At doses that were considerably higher than the pharmacologically effective doses, ibandronic acid did not have any effect on bone mineralisation.

Bone resorption due to malignant disease is characterized by excessive bone resorption that is not balanced with appropriate bone formation. Ibandronic acid selectively inhibits osteoclast activity, reducing bone resorption and thereby reducing skeletal complications of the malignant disease.

Clinical studies in the treatment of tumour-induced hypercalcaemia

Clinical studies in hypercalcaemia of malignancy demonstrated that the inhibitory effect of ibandronic acid on tumour-induced osteolysis, and specifically on tumour-induced hypercalcaemia, is characterised by a decrease in serum calcium and urinary calcium excretion.

In the dose range recommended for treatment, the following response rates with the respective confidence intervals have been shown in clinical trials for patients with baseline albumin-corrected serum calcium

For these patients and dosages, the median time to achieve normocalcaemia was 4 to 7 days. The median time to relapse (return of albumin-corrected serum calcium above 3.0 mmol/l) was 18 to 26 days.

Clinical studies in the prevention of skeletal events in patients with breast cancer and bone metastases

Clinical studies in patients with breast cancer and bone metastases have shown that there is a dose dependent inhibitory effect on bone osteolysis, expressed by markers of bone resorption, and a dose dependent effect on skeletal events.

Prevention of skeletal events in patients with breast cancer and bone metastases with Bondronat 6 mg administered intravenously was assessed in one randomized placebo controlled phase III trial with duration of 96 weeks. Female patients with breast cancer and radiologically confirmed bone metastases were randomised to receive placebo (158 patients) or 6 mg Bondronat (154 patients). The results from this trial are summarised below.

Primary efficacy endpoints

The primary endpoint of the trial was the skeletal morbidity period rate (SMPR). This was a composite endpoint which had the following skeletal related events (SREs) as sub-components:

- radiotherapy to bone for treatment of fractures/impending fractures

- surgery to bone for treatment of fractures

- vertebral fractures

- non-vertebral fractures.

The analysis of the SMPR was time-adjusted and considered that one or more events occurring in a single 12 week period could be potentially related. Multiple events were therefore counted only once for the purposes of the analysis. Data from this study demonstrated a significant advantage for intravenous Bondronat 6 mg over placebo in the reduction in SREs measured by the time-adjusted SMPR (p=0.004). The number of SREs was also significantly reduced with Bondronat 6 mg and there was a 40% reduction in the risk of a SRE over placebo (relative risk 0.6, p = 0.003). Efficacy results are summarised in Table 3.

Table 3 Efficacy Results (Breast Cancer Patients with Metastatic Bone Disease)

	All Skeletal Related Events (SREs)
Placebo n=158	Bondronat 6 mg n=154	p-value
SMPR (per patient year)	1.48	1.19	p=0.004
Number of events (per patient)	3.64	2.65	p=0.025
SRE relative risk	-	0.60	p=0.003

Secondary efficacy endpoints

A statistically significant improvement in bone pain score was shown for intravenous Bondronat 6 mg compared to placebo. The pain reduction was consistently below baseline throughout the entire study and accompanied by a significantly reduced use of analgesics. The deterioration in Quality of Life was significantly less in Bondronat treated patients compared with placebo. A tabular summary of these secondary efficacy results is presented in Table 4.

Table 4 Secondary Efficacy Results (Breast cancer Patients with Metastatic Bone Disease)

	Placebo n=158	Bondronat 6 mg n=154	p-value
Bone pain *	0.21	-0.28	p<0.001
Analgesic use *	0.90	0.51	p=0.083
Quality of Life *	-45.4	-10.3	p=0.004

* Mean change from baseline to last assessment.

There was a marked depression of urinary markers of bone resorption (pyridinoline and deoxypyridinoline) in patients treated with Bondronat that was statistically significant compared to placebo.

In a study in 130 patients with metastatic breast cancer the safety of Bondronat infused over 1 hour or 15 minutes was compared. No difference was observed in the indicators of renal function. The overall adverse event profile of ibandronic acid following the 15 minute infusion was consistent with the known safety profile over longer infusion times and no new safety concerns were identified relating to the use of a 15 minute infusion time.

A 15 minute infusion time has not been studied in cancer patients with a creatinine clearance of <50ml/min.

Paediatric population

The safety and efficacy of Bondronat in children and adolescents below age 18 years have not been established. No data are available.

5.2 Pharmacokinetic Properties

After a 2 hour infusion of 2, 4 and 6 mg ibandronic acid pharmacokinetic parameters are dose proportional.

Distribution

After initial systemic exposure, ibandronic acid rapidly binds to bone or is excreted into urine. In humans, the apparent terminal volume of distribution is at least 90 l and the amount of dose reaching the bone is estimated to be 40-50% of the circulating dose. Protein binding in human plasma is approximately 87% at therapeutic concentrations, and thus drug-drug interaction due to displacement is unlikely.

Biotransformation

There is no evidence that ibandronic acid is metabolized in animals or humans.

Elimination

The range of observed apparent half-lives is broad and dependent on dose and assay sensitivity, but the apparent terminal half-life is generally in the range of 10-60 hours. However, early plasma levels fall quickly, reaching 10% of peak values within 3 and 8 hours after intravenous or oral administration respectively. No systemic accumulation was observed when ibandronic acid was administered intravenously once every 4 weeks for 48 weeks to patients with metastatic bone disease.

Total clearance of ibandronic acid is low with average values in the range 84-160 ml/min. Renal clearance (about 60 ml/min in healthy postmenopausal females) accounts for 50-60% of total clearance and is related to creatinine clearance. The difference between the apparent total and renal clearances is considered to reflect the uptake by bone.

Pharmacokinetics in special populations

Gender

Bioavailability and pharmacokinetics of ibandronic acid are similar in both men and women.

Race

There is no evidence for clinically relevant interethnic differences between Asians and Caucasians in ibandronic acid disposition. There are only very few data available on patients with African origin.

Patients with renal impairment

Exposure to ibandronic acid in patients with various degrees of renal impairment is related to creatinine clearance (CLcr). In subjects with severe renal impairment (mean estimated CLcr = 21.2 mL/min), dose-adjusted mean AUC_0-24h was increased by 110% compared to healthy volunteers. In clinical pharmacology trial WP18551, after a single dose intravenous administration of 6 mg (15 minutes infusion), mean AUC_0-24 increased by 14% and 86%, respectively, in subjects with mild (mean estimated CLcr=68.1 mL/min) and moderate (mean estimated CLcr=41.2 mL/min) renal impairment compared to healthy volunteers (mean estimated CLcr=120 mL/min). Mean C_max was not increased in patients with mild renal impairment and increased by 12% in patients with moderate renal impairment. For patients with mild renal impairment (CLcr

Patients with hepatic impairment

There are no pharmacokinetic data for ibandronic acid in patients who have hepatic impairment. The liver has no significant role in the clearance of ibandronic acid since it is not metabolized but is cleared by renal excretion and by uptake into bone. Therefore dosage adjustment is not necessary in patients with hepatic impairment. Further, as protein binding of ibandronic acid is approximately 87% at therapeutic concentrations, hypoproteinaemia in severe liver disease is unlikely to lead to clinically significant increases in free plasma concentration.

Elderly

In a multivariate analysis, age was not found to be an independent factor of any of the pharmacokinetic parameters studied. As renal function decreases with age, this is the only factor that should be considered (see renal impairment section).

Paediatric population

There are no data on the use of Bondronat in patients less than 18 years old.

5.3 Preclinical Safety Data

Effects in non-clinical studies were observed only at exposures sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. As with other bisphosphonates, the kidney was identified to be the primary target organ of systemic toxicity.

Mutagenicity/Carcinogenicity:

No indication of carcinogenic potential was observed. Tests for genotoxicity revealed no evidence of effects on genetic activity for ibandronic acid.

Reproductive toxicity:

No evidence of direct foetal toxicity or teratogenic effects were observed for ibandronic acid in intravenously treated rats and rabbits. In reproductive studies in rats by the oral route effects on fertility consisted of increased preimplantation losses at dose levels of 1 mg/kg/day and higher. In reproductive studies in rats by the intravenous route, ibandronic acid decreased sperm counts at doses of 0.3 and 1 mg/kg/day and decreased fertility in males at 1 mg/kg/day and in females at 1.2 mg/kg/day. Adverse effects of ibandronic acid in reproductive toxicity studies in the rat were those expected for this class of drug (bisphosphonates). They include a decreased number of implantation sites, interference with natural delivery (dystocia), an increase in visceral variations (renal pelvis ureter syndrome) and teeth abnormalities in F1 offspring in rats.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium chloride

Acetic acid (99%)

Sodium acetate