Aliviomas

Aliviomas may be available in the countries listed below.

Ingredient matches for Aliviomas

Naproxen

Naproxen is reported as an ingredient of Aliviomas in the following countries:

• Spain

International Drug Name Search

Sparbact

Sparbact may be available in the countries listed below.

Ingredient matches for Sparbact

Sparfloxacin

Sparfloxacin is reported as an ingredient of Sparbact in the following countries:

• Russian Federation

International Drug Name Search

Julax

Julax may be available in the countries listed below.

Ingredient matches for Julax

Bisacodyl

Bisacodyl is reported as an ingredient of Julax in the following countries:

• India

International Drug Name Search

Jernadex

Jernadex may be available in the countries listed below.

In some countries, this medicine may only be approved for veterinary use.

Ingredient matches for Jernadex

Pyrantel

Pyrantel embonate (a derivative of Pyrantel) is reported as an ingredient of Jernadex in the following countries:

• Germany

International Drug Name Search

Noameba-DS

Noameba-DS may be available in the countries listed below.

Ingredient matches for Noameba-DS

Secnidazole

Secnidazole is reported as an ingredient of Noameba-DS in the following countries:

• India

International Drug Name Search

Cafcit Solution

Pronunciation: cah-FEEN
Generic Name: Caffeine
Brand Name: Cafcit

Cafcit Solution is used for:

Treating certain breathing problems in certain premature infants.

Cafcit Solution is a methylxanthine. It works by stimulating the breathing center of the brain and widening certain airways in the lungs, which helps to improve breathing.

Do NOT use Cafcit Solution if:

• you are allergic to any ingredient in Cafcit Solution


• you are taking theophylline

Contact your doctor or health care provider right away if any of these apply to you.

Before using Cafcit Solution:

Some medical conditions may interact with Cafcit Solution. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have stomach or intestinal problems, heart problems, kidney or liver problems, seizures, or diabetes

Some MEDICINES MAY INTERACT with Cafcit Solution. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Cimetidine, ketoconazole, or theophylline because side effects of Cafcit Solution may be increased


• Barbiturates (eg, phenobarbital) or hydantoins (eg, phenytoin) because effectiveness of Cafcit Solution may be decreased

This may not be a complete list of all interactions that may occur. Ask your health care provider if Cafcit Solution may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Cafcit Solution:

Use Cafcit Solution as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Cafcit Solution may be taken with or without food.


• Cafcit Solution comes with an additional patient leaflet. Read it carefully and reread it each time you get Cafcit Solution refilled.


• Cafcit Solution is usually administered as an injection at your doctor's office, hospital, or clinic. If you are using Cafcit Solution at home, carefully follow the injection procedures taught to you by your health care provider.


• If Cafcit Solution contains particles or is discolored, or if the vial is cracked or damaged in any way, do not use it.


• If you miss a dose of Cafcit Solution, use it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses at once.

Ask your health care provider any questions you may have about how to use Cafcit Solution.

Important safety information:

• If symptoms do not improve or if they become worse, check with your doctor. Do not use more of Cafcit Solution than prescribed without talking with your doctor.


• LAB TESTS, including lung function and blood glucose, may be performed to monitor your progress or to check for side effects. Be sure to keep all doctor and lab appointments.


• PREGNANCY and BREAST-FEEDING: If you become pregnant while taking Cafcit Solution, discuss with your doctor the benefits and risks of using Cafcit Solution during pregnancy. It is unknown if Cafcit Solution is excreted in breast milk. If you are or will be breast-feeding while you are using Cafcit Solution, check with your doctor or pharmacist to discuss the risks to your baby.

Possible side effects of Cafcit Solution:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Irritability; restlessness.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry stools; changes in the amount of urine; seizures; stomach pain or swelling; unusual tiredness (lethargy); vomiting.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Cafcit side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include fever; rapid breathing; seizures; spastic muscle movements; tremor; unusual jaw and lip movements; vomiting.

Proper storage of Cafcit Solution:

Cafcit Solution is usually handled and stored by a health care provider. If you are using Cafcit Solution at home, store Cafcit Solution as directed by your pharmacist or health care provider. Keep Cafcit Solution out of the reach of children and away from pets.

General information:

• If you have any questions about Cafcit Solution, please talk with your doctor, pharmacist, or other health care provider.


• Cafcit Solution is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Cafcit Solution. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Cafcit resources

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

Compare Cafcit with other medications

• Apnea of Prematurity
• Hypersomnia

Justum

Justum may be available in the countries listed below.

Ingredient matches for Justum

Dipotassium Clorazepate

Dipotassium Clorazepate is reported as an ingredient of Justum in the following countries:

• Argentina

International Drug Name Search

Joscina Butilbromuro FederFARMA

Joscina Butilbromuro FederFARMA may be available in the countries listed below.

Ingredient matches for Joscina Butilbromuro FederFARMA

Scopolamine

Scopolamine butylbromide (a derivative of Scopolamine) is reported as an ingredient of Joscina Butilbromuro FederFARMA in the following countries:

• Italy

International Drug Name Search

Regtin

Regtin may be available in the countries listed below.

Ingredient matches for Regtin

Sulfamethoxazole

Sulfamethoxazole is reported as an ingredient of Regtin in the following countries:

• Bangladesh

Trimethoprim

Trimethoprim is reported as an ingredient of Regtin in the following countries:

• Bangladesh

International Drug Name Search

Jodid

Jodid may be available in the countries listed below.

Ingredient matches for Jodid

Potassium Iodide

Potassium Iodide is reported as an ingredient of Jodid in the following countries:

• Czech Republic


• Georgia


• Germany


• Hungary


• Luxembourg


• Philippines


• Poland


• Romania


• Slovenia

International Drug Name Search

Justor

Justor may be available in the countries listed below.

Ingredient matches for Justor

Cilazapril

Cilazapril is reported as an ingredient of Justor in the following countries:

• Tunisia

Cilazapril monohydrate (a derivative of Cilazapril) is reported as an ingredient of Justor in the following countries:

• France

International Drug Name Search

Morphine Sulphate Injection 10 mg per ml (hameln)

1. Name Of The Medicinal Product

Morphine Sulphate Injection 10 mg per ml

2. Qualitative And Quantitative Composition

Each ml of sterile solution for injection contains 10 mg Morphine Sulphate

For excipients see 6.1

3. Pharmaceutical Form

Solution for injection

4. Clinical Particulars

4.1 Therapeutic Indications

Analgesic for severe and very severe pain.

4.2 Posology And Method Of Administration

Morphine injection may be administered subcutaneously, intramuscularly or intravenously. Dosage should be adjusted according to the severity of the pain and the response of the patient.

Appropriate starting doses are as follows:

Administration	Adults and adolescents over 12 years
Intravenously	2.5-10mg
Subcutaneously, intramuscularly	5 - 20 mg

Individuals might require considerably higher doses for sufficient relief of pain. In general, the minimum effective dose should be administered.

For intravenous administration it is important to inject morphine slowly over a period of 4 to 5 minutes with the patient in the recumbent position.

For continuous intravenous infusion of morphine, appropriate starting doses are 1-2 mg per hour in adults and adolescents over 12 years. Daily doses will not usually exceed 100 mg per day in adults and adolescents over 12 years, however, in cancer patients chronic administration of higher doses up to 4 g per day may occasionally be required.

Children under 12 years

This formulation is not recommended for use in children under 12 years.

In the Elderly

The dose of morphine should be reduced in elderly patients and titrated to provide optimal pain relief with minimal side effects. Morphine clearance decreases and half-life increase in older patients.

In patients with disturbed Renal Function

Caution should be exercised in the use of Morphine in patients with renal dysfunction i.e. renal failure, because such patients can show signs of overdose following conservative dosage regimens.

In patients with impaired Liver Function

Caution should be exercised in the use of Morphine in patients with impaired liver function e.g. cirrhosis as this condition is likely to affect elimination. The dose therefore should be carefully titrated to provide optimal pain relief.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients

Respiratory depression or insufficiency

Obstructive airways disease

Cerebral trauma

Increased intracranial pressure

Coma

Convulsive disorders

Acute alcoholism

Renal failure

Ureteral stenosis

Pancreatitis

Liver failure

Gall-bladder dysfunction

Ileus

Inflammatory bowel disease

Hypotension with hypovolaemia

Prostatic hypertrophy

Myxoedema

Pheochromocytoma

Concurrent administration of MAO inhibitors or within two weeks of discontinuation of their use.

4.4 Special Warnings And Precautions For Use

Drug dependence and tolerance

Morphine can produce drug dependence and therefore has the potential for being abused. Upon repeated administration of morphine, psychological and physical dependence may occur and tolerance may develop. However, when doses of morphine are carefully titrated against pain, clinically significant respiratory depression, addiction, rapid tolerance and euphoria rarely develop.

With regular administration of morphine at doses optimised for the individual patient drug dependence does not develop, and psychological dependence does not occur. A certain degree of physical dependence is possible, however. If patients no longer require morphine for relief of pain, doses should be gradually reduced in order to prevent withdrawal symptoms. Clinically significant tolerance to morphine is unusual in cancer patients with severe pain.

Hypotension, hypothyroidism, asthma (avoid during attack), and decreased respiratory reserve; pregnancy and breast-feeding; may precipitate coma in hepatic impairment (reduce dose but many such patients tolerate morphine well); reduce dose in renal impairment, elderly and debilitated (reduce dose); dependence (severe withdrawal symptoms if withdrawn abruptly).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

• CNS depressants: In patients concurrently receiving other central nervous system depressants (including sedatives, hypnotics, general anaesthetics, phenothiazines, other tranquillisers and alcohol) morphine should be used with caution and in reduced dosage because of the risk of respiratory depression, hypotension and profound sedation or coma.

• Muscle relaxants: Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants.

• Mixed agonist/ antagonist opioid analgesics: Mixed agonist/antagonist opioid analgesics (e.g. pentazocine, nalbuphine, and buprenorphine) can reduce the analgesic effect of morphine by competitive blocking of the receptor. Therefore these drugs should not be administered to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic.

• Monoamine oxidase inhibitors (MAOIs): MAOIs intensify the effect of morphine and other opioid drugs. Severe and even fatal events (e.g. anxiety, confusion and significant depression of respiration, sometimes leading to coma) have been observed with co-administration of both drugs. Morphine should not be given to patients taking MAOIs or within 14 days of stopping such treatment.

• Cimetidine: Higher plasma concentrations of morphine due to decreased metabolism of morphine have been observed with co-administration of cimetidine. Confusion and severe respiratory depression were reported after a haemodialysis patient had received both morphine and cimetidine.

• Diuretics: Morphine reduces the efficacy of diuretics by inducing the release of antidiuretic hormone. Morphine may also lead to acute retention of urine by causing spasm of the sphincter of the bladder, particularly in men with prostatism.

• Alcohol: enhanced sedative and hypotensive effect.

• Anti-Arrhythmtics: delayed absorption of mexiletine.

• Antidepressants: CNS excitation or depression (hypertension or hypotension) if pethidine and possibly other opioid analgesic are given to patients receiving MAOIs (including moclobemide).

• Anxiolytics and Hypnotics: enhanced sedative effect.

• Cisapride: possible antagonism of gastro-intestinal effect.

• Domperidone and metoclopramide: antagonism of gastro-intestinal effects.

• Dopaminerigcs: hyperpyrexia and CNS toxicity reported with selegiline.

4.6 Pregnancy And Lactation

Use in pregnancy

Animal reproduction studies have shown that morphine can cause foetal damage when administered throughout pregnancy. An association with increased frequency of inguinal hernias in Infants has been postulated in man. Pregnant patients should only be given morphine when the benefits clearly outweigh potential risks to the foetus.

Use in lactation

Morphine is excreted in human milk and breast-feeding is not recommended while a patient is receiving morphine. Withdrawal syndrome was observed in breast-fed infants after maternal administration of morphine sulphate had been stopped.

Use in labour/ delivery

Morphine may prolong labour by temporarily reducing the strength, duration and frequency of uterine contractions. Conversely, it may tend to shorten labour by increasing the rate of cervical dilatation. Infants born to mothers receiving opioid analgesics during labour should be observed closely for signs of respiratory depression. In such infants a specific opioid antagonist, naloxone hydrochloride, should be available for reversal of narcotic-induced respiratory depression. After chronic morphine use by the mother, new-borns may develop withdrawal symptoms.

4.7 Effects On Ability To Drive And Use Machines

Morphine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. Morphine in combination with other narcotic analgesics, phenothiazines, sedative-hypnotics, and alcohol have additive depressant effects.

Patients should not drive or operate machinery

4.8 Undesirable Effects

Common (> 10%):

Nausea, vomiting, respiratory depression, constipation, sedation, drowsiness, disorientation, itching, sweating, hallucinations, dysphoria, euphoria; with long-term treatment: tolerance and dependence.

Occasional (1 -9%):

Skin: Urticaria, skin rash, pain at injection site, contact dermatitis

CNS and nervous system: Headache, vertigo, agitation, convulsions, impairment of taste, mood changes, changes of cognitive and sensory abilities, insomnia, intracranial hypertension, tremor.

Musculoskeletal system: Muscle spasms.

Eye: Miosis, visual disturbances (blurred vision, nystagmus, diplopia)

Gastrointestinal system: Dryness of mouth, pylorospasm, singultus, diarrhoea, abdominal cramps, biliary colic.

Cardiovascular system: Flushing, chills, orthostatic hypotension, bradycardia, hypertension, tachycardia, heart failure, pulmonary oedema.

Respiratory system: Laryngeal spasm, bronchospasm, cough attenuation.

Urogenital system: Urinary retention or hesitancy, oliguria, loss of libido, impotence.

Endocrine: Inappropriate antidiuretic hormone (ADH) secretion characterised by hyponatraemia secondary to decreased free water excretion.

General: Oedema, hypothermia, hyperthermia, withdrawal syndrome.

Pulmonary oedema after overdose is a common cause of fatalities among opioid addicts.

Morphine and some other opioids have a dose-related histamine effect, which may be responsible in part for reactions such as urticaria and pruritis as well as hypotension and flushing. Contact dermatitis has been reported and pain and irritation may occur on injection. Anaphylactic reactions following intravenous injection have been reported rarely.

Rare (< 1 %):

Anaphylactic reaction after i.v. injection.

4.9 Overdose

Symptoms

Overdosage with morphine is characterised by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), pinpoint pupils, extreme somnolence progressing to stupor and coma, skeletal muscle flaccidity, cold and clammy skin and sometimes bradycardia and hypotension. In severe overdosage, apnoea, circulatory collapse, cardiac arrest and death may occur.

Treatment

Immediate attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Oxygen, intravenous fluid, vasopressors and other supportive measures should be employed as indicated.

The narcotic antagonist, naloxone, is a specific antidote for morphine. The recommended adult dose of naloxone is 0.4 to 2.0 mg IV every 2 to 3 minutes as necessary, simultaneously with assisted respiration. For children, the initial recommended dose is 0.01 mg/kg naloxone. A response should be seen after 2-3 doses. Note that the duration of action of naloxone is usually shorter than that of morphine and thus patients should be carefully monitored for signs of CNS depression returning.

If the response to naloxone is suboptimal or not sustained, additional naloxone may be administered as needed to maintain alertness and respiratory function. There is no additional information available about the cumulative dose of naloxone that may be safely administered.

To sustain opioid antagonism, an intravenous infusion of naloxone has been suggested. Naloxone (4 jig per ml) in sodium chloride injection (0.9 %) or glucose injection (5 %) may be infused at a rate titrated in accordance with the patient's response both to the infusion and previous bolus injections.

Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdosage. It should be administered cautiously to persons who are known or suspected to be physically dependant to morphine. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome. The severity of the withdrawal syndrome will depend on the degree of physical dependence and the dose of the antagonist administered. If it is necessary to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care and by titration with smaller than usual doses of the antagonist.

Morphine toxicity may be the result of overdosage but because of the large inter-individual variation in sensitivity to opioids it is difficult to assess the exact dose of any opioid that is toxic or lethal. The toxic effects of morphine tend to be overshadowed by the presence of pain or tolerance. Patients receiving chronic morphine therapy have been known to take in excess of 3000 mg/day with no apparent toxic effect.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Morphine is pharmacologically the most important alkaloid of opium. It is used primarily as an analgesic for severe pain.

The analgesic effect of morphine is primarily due to an interaction with the OP₃(u)-receptor, one of three major classes of opioid receptors that can be distinguished in the central nervous system. The metabolite morphine-6-glucuronide also acts as an agonist on opioid-receptors and contributes significantly to the pharmacological effects of chronic morphine treatment. Doses of 0.1 mg/kg body-weight of morphine and higher are effective in various animal analgesic tests.

Morphine causes respiratory depression by diminishing the response of the respiratory centres to CO₂. This effect is mediated by the action on OP₃-receptors and can be antagonised by naloxone.

Morphine stimulates the chemo-receptor trigger zone by action on dopamine- receptors and may cause nausea and vomiting.

Other effects: Morphine can induce euphoria and miosis. Hypotension may occur due to increased histamine release, especially in hypovolaemic patients.

5.2 Pharmacokinetic Properties

Approximately 35 % of morphine is bound to plasma proteins. Morphine is rapidly metabolized. Approximately 50 % is converted to the major metabolite, the pharmacologically inactive morphine-3-glucuronide and 10-15 % is converted to the active morphine-6-glucuronide. Further metabolites include a diglucuronide, normorphine and its glucuronides. Approximately 60% of morphine is excreted in the urine in 24 hours, of which less than 10% of the dose is excreted as unchanged drug.

5.3 Preclinical Safety Data

There are no preclinical safety data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium chloride, hydrochloric acid, water for injections, nitrogen.

6.2 Incompatibilities

Morphine sulphate is physically incompatible with aciclovir sodium, aminophylline, amobarbital sodium, cefepime hydrochloride, chlorothiazide sodium, floxacillin sodium, furosemide, gallium nitrate, heparin sodium, meperidine hydrochloride, meperidine sodium, methicillin sodium, minocycline hydrochloride, pentobarbital sodium, phenobarbital sodium, phenytoin sodium, sargramostim, sodium bicarbonate, thiopental sodium.

6.3 Shelf Life

Two years

6.4 Special Precautions For Storage

Do not store above 25°C. Keep the ampoule in the outer carton.

6.5 Nature And Contents Of Container

1 ml colourless glass DIN ampoules, glass type I Ph Eur, packed in cardboard cartons and containing 10 x 1 ml ampoules.

6.6 Special Precautions For Disposal And Other Handling

For Single Dose Use Only. Discard any unused solution immediately and safely after initial use.

7. Marketing Authorisation Holder

hameln Pharmaceuticals Ltd

Glevum Works

Upton Street

Gloucester

GL14LA

United Kingdom

8. Marketing Authorisation Number(S)

PL 01502/0063

9. Date Of First Authorisation/Renewal Of The Authorisation

10^th February 2005

10. Date Of Revision Of The Text

Julmentin

Julmentin may be available in the countries listed below.

Ingredient matches for Julmentin

Amoxicillin

Amoxicillin trihydrate (a derivative of Amoxicillin) is reported as an ingredient of Julmentin in the following countries:

• Bahrain


• Oman

Clavulanate

Clavulanic Acid potassium (a derivative of Clavulanic Acid) is reported as an ingredient of Julmentin in the following countries:

• Bahrain


• Oman

International Drug Name Search

Jodid-ratiopharm

Jodid-ratiopharm may be available in the countries listed below.

Ingredient matches for Jodid-ratiopharm

Potassium Iodide

Potassium Iodide is reported as an ingredient of Jodid-ratiopharm in the following countries:

• Germany

International Drug Name Search

Jasoprim

Jasoprim may be available in the countries listed below.

Ingredient matches for Jasoprim

Primaquine

Primaquine phosphate (a derivative of Primaquine) is reported as an ingredient of Jasoprim in the following countries:

• Bangladesh

International Drug Name Search

Estradiol-Hexal

Estradiol-Hexal may be available in the countries listed below.

Ingredient matches for Estradiol-Hexal

Estradiol

Estradiol is reported as an ingredient of Estradiol-Hexal in the following countries:

• Luxembourg

International Drug Name Search

Jumexal

Jumexal may be available in the countries listed below.

Ingredient matches for Jumexal

Selegiline

Selegiline hydrochloride (a derivative of Selegiline) is reported as an ingredient of Jumexal in the following countries:

• Switzerland

International Drug Name Search

Primaquine Phosphate

Primaquine Phosphate may be available in the countries listed below.

Ingredient matches for Primaquine Phosphate

Primaquine

Primaquine Phosphate (BANM, USAN) is known as Primaquine in the US.

International Drug Name Search

Glossary

BANM	British Approved Name (Modified)
USAN	United States Adopted Name

Click for further information on drug naming conventions and International Nonproprietary Names.

Fenoglide

In the US, Fenoglide (fenofibrate systemic) is a member of the drug class fibric acid derivatives and is used to treat Hyperlipoproteinemia, Hyperlipoproteinemia Type IIa - Elevated LDL, Hyperlipoproteinemia Type IIb - Elevated LDL VLDL, Hyperlipoproteinemia Type IV - Elevated VLDL, Hyperlipoproteinemia Type V - Elevated Chylomicrons VLDL and Hypertriglyceridemia.

US matches:

• Fenoglide

Ingredient matches for Fenoglide

Fenofibrate

Fenofibrate is reported as an ingredient of Fenoglide in the following countries:

• United States

International Drug Name Search

Xanax Tablets 250 micrograms & 500 micrograms

1. Name Of The Medicinal Product

Xanax® Tablets 250 and 500 micrograms

2. Qualitative And Quantitative Composition

Alprazolam 250 and 500 micrograms

3. Pharmaceutical Form

White, oval, biconvex tablets containing 250 microgram (0.25 mg) alprazolam, scored on one side and marked "Upjohn 29" on the other.

Pink, oval, biconvex tablets containing 500 microgram (0.5 mg) alprazolam, scored on one side and marked "Upjohn 55" on the other.

4. Clinical Particulars

4.1 Therapeutic Indications

Xanax is indicated for the short-term treatment of moderate or severe anxiety states and anxiety associated with depression. It is only indicated when the disorder is severe, disabling or subjecting the individual to extreme distress.

Xanax should not be used to treat short-term mild anxiety, such as anxiety or tension associated with the stress of everyday life. As the efficacy of Xanax in depression and in phobic or obsessional states has yet to be established, specific treatment may have to be considered.

4.2 Posology And Method Of Administration

Treatment should be as short as possible. It is recommended that the patient be reassessed at the end of no longer than 4 weeks' treatment and the need for continued treatment established, especially in case the patient is symptom free. The overall duration of treatment should not be more than 8-12 weeks, including a tapering off process.

In certain cases extension beyond the maximum treatment period may be necessary; if so, it should not take place without re-evaluation of the patient's status with special expertise. As with all benzodiazepines, physicians should be aware that long-term use might lead to dependence in certain patients.

The optimum dosage of Xanax should be based upon the severity of the symptoms and individual patient response. The lowest dose which can control symptoms should be used. Dosage should be reassessed at intervals of no more than 4 weeks. The usual dosage is stated below; in the few patients who require higher doses, the dosage should be increased cautiously to avoid adverse effects. When higher dosage is required, the evening dose should be increased before the daytime doses. In general, patients who have not previously received psychotropic medications will require lower doses than those so treated, or those with a history of chronic alcoholism.

Treatment should always be tapered off gradually. During discontinuation of alprazolam treatment, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of alprazolam be decreased by no more than 0.5 mg every three days. Some patients may require an even slower dosage reduction

There is a reduced clearance of the drug and, as with other benzodiazepines, an increased sensitivity to the drug in elderly patients.

Anxiety: 250 micrograms (0.25 mg) to 500 micrograms (0.5 mg) three times daily increasing if required to a total of 3 mg daily.

Geriatric patients or in the presence of debilitating disease: 250 micrograms (0.25 mg) two to three times daily to be gradually increased if needed and tolerated.

Children: Not recommended.

If side-effects occur, the dose should be lowered. It is advisable to review treatment regularly and to discontinue use as soon as possible. Should longer term treatment be necessary, then intermittent treatment may be considered to minimize the risk of dependence.

4.3 Contraindications

Myasthenia gravis Hypersensitivity to benzodiazepines or any of the other constituents of the tablet Severe respiratory insufficiency Sleep apnoea syndrome Severe hepatic insufficiency

4.4 Special Warnings And Precautions For Use

Tolerance

Some loss of efficacy to the hypnotic effects of benzodiazepines may develop after repeated use for a few weeks.

Dependence

Use of benzodiazepines may lead to the development of physical and psychic dependence upon these products. The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a history of alcohol and drug abuse.

Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. These may consist of headaches, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases the following symptoms may occur: derealization, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures.

Rebound insomnia and anxiety: a transient syndrome whereby the symptoms that led to treatment with a benzodiazepine recur in an enhanced form may occur on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and restlessness. Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage be decreased gradually by no more than 0.5 mg every three days. Some patients may require an even slower dose reduction.

Duration of treatment

The duration of treatment should bed as short as possible (see posology) depending on the indication, but should not exceed eight to twelve weeks including tapering off process. Extension beyond these periods should not take place without re-evaluation of the situation.

It may be useful to inform the patient when treatment is started that it will be of limited duration and to explain precisely how the dosage will be progressively decreased. Moreover it is important that the patient should be aware of the possibility of rebound phenomena, thereby minimising anxiety over such symptoms should they occur while the medicinal product is being discontinued.

There are indications, that in the case of benzodiazepines with a short duration of action, withdrawal phenomena can become manifest within the dosage interval, especially when the dosage is high. When benzodiazepines with a long duration of action are being used it is important to warn against changing to a benzodiazepine with a short duration of action, as withdrawal symptoms may develop.

Amnesia

Benzodiazepines may induce anterograde amnesia. The condition occurs most often several hours after ingesting the product and therefore to reduce the risk patients should ensure that they will be able to have uninterrupted sleep of 7-8 ours (see also undesirable effects).

Psychiatric and 'paradoxical' reactions

Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines. Should this occur, use of the drug should be discontinued.

They are more likely to occur in children and the elderly.

Specific patient groups

Benzodiazepines should not be given to children without careful assessment of the need to do so; the duration of treatment must be kept to a minimum. The elderly should be given a reduced dose (see posology). A lower dose is also recommended for patients with chronic respiratory insufficiency due to risk of respiratory depression.

Benzodiazepines are not indicated to treat patients with severe hepatic insufficiency as they may precipitate encephalopathy. Caution is recommended when treating patients with impaired renal or hepatic function.

Benzodiazepines are not recommended for the primary treatment of psychotic illness.

Benzodiazepines should not be used alone to treat depression of anxiety associated with depression (suicide may be precipitated in such patients). Administration to severely depressed or suicidal patients should be done with appropriate precautions and appropriate size of the prescription.

Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Not recommended: Concomitant intake with alcohol

The sedative effects may be enhanced when the product is used in combination with alcohol. This affects the ability to drive or use machines.

Take into account: Combination with CNS depressants

Enhancement of the central depressive effect may occur in cases of concomitant use with antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, anti-epileptic drugs, anaesthetics and sedative antihistamines.

Pharmacokinetic interactions can occur when alprazolam is administered along with drugs that interfere with its metabolism. Compounds that inhibit certain hepatic enzymes (particularly cytochrome P450 3A4) may increase the concentration of alprazolam and enhance it's activity. Data from clinical studies with alprazolam, in-vitro studies with alprazolam and clinical studies with drugs metabolised similarly to alprazolam provide evidence for varying degrees of interaction and possible interaction with alprazolam for a number of drugs. Based on the degree of interaction and the type of data available, the following recommendations are made:

The co-administration of alprazolam with ketoconazole, itraconazole, or other azole-type antifungals is not recommended.

Caution and consideration of dose reduction is recommended when alprazolam is co-administered with nefazodone, fluvoxamine and cimetidine.

Caution is recommended when alprazolam is co-administered with fluoxetine, propoxyphene, oral contraceptives, sertraline, diltiazem, or macrolide antibiotics such as erythromycin and troleandomycin.

Interactions involving HIV protease inhibitors (e.g. ritonavir) and alprazolam are complex and time dependent. Low doses of ritonavir resulted in a large impairment of alprazolam clearance, prolonged its elimination half-life and enhanced clinical effects, however, upon extended exposure to ritonavir, CYP3A induction offset this inhibition. This interaction will require a dose-adjustment or discontinuation of alprazolam.

4.6 Pregnancy And Lactation

If the product is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuance of the product if she intends to become or suspects that she is pregnant. The data concerning teratogenicity and effects on postnatal development and behaviour following benzodiazepine treatment are inconsistent. There is evidence from some early studies with other members of the benzodiazepine class that in utero exposure may be associated with malformations. Later studies with the benzodiazepine class of drugs have provided no clear evidence of any type of defect.

If, for compelling medical reasons, the product is administered during the late phase of pregnancy or during labour, effects on the neonate such as hypothermia, hypotonia and moderate respiratory depression, can be expected, due to the pharmacological action of the compound.

Infants born to mothers who took benzodiazepines chronically during the latter stages of pregnancy may have developed physical dependence and may be at some risk of developing withdrawal symptoms in the postnatal period.

Since benzodiazepines are found in the breast milk, benzodiazepines should not be given to breast feeding mothers.

4.7 Effects On Ability To Drive And Use Machines

Sedation, amnesia, impaired concentration and impaired muscle function may adversely affect the ability to drive or use machines. If insufficient sleep occurs, the likelihood of impaired alertness may be increased (see also interactions).

These effects are potentiated by alcohol (see also interactions).

Patients should be cautioned about operating motor vehicles or engaging in other dangerous activities while taking Xanax.

4.8 Undesirable Effects

Sedation/drowsiness, light-headedness, numbed emotions, reduced alertness, confusion, fatigue, headache, dizziness, muscle weakness, ataxia, double or blurred vision, insomnia, nervousness/anxiety, tremor, change in weight. These phenomena occur predominantly at the start of therapy and usually disappear with repeated administration. Other side effects like gastrointestinal disturbances, changes in libido or skin reactions have been reported occasionally.

In addition, the following adverse events have been reported in association with the use of alprazolam: dystonia, anorexia, slurred speech, jaundice, musculoskeletal weakness, sexual dysfunction/changes in libido, menstrual irregularities, incontinence, urinary retention, abnormal liver function and hyperprolactinaemia. Increased intraocular pressure has been rarely reported.

Withdrawal symptoms have occurred following rapid decrease or abrupt discontinuance of benzodiazepines including alprazolam. These can range from mild dysphoria and insomnia to a major syndrome, which may include abdominal and muscle cramps, vomiting, sweating, tremor and convulsions. In addition, withdrawal seizures have occurred upon rapid decrease or abrupt discontinuation of therapy with alprazolam.

Amnesia

Anterograde amnesia may occur at therapeutic dosages, the risk increasing at higher dosages. Amnesic effects may be associated with inappropriate behaviour (see warnings and precautions).

Depression

Pre-existing depression may be unmasked during benzodiazepam use.

Psychiatric and 'paradoxical' reactions

Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines or benzodiazepine-like agents. They may be quite severe with this product. They are more likely to occur in children and the elderly.

In many of the spontaneous case reports of adverse behavioural effects, patients were receiving other CNS drugs concomitantly and/or were described as having underlying psychiatric conditions. Patients who have borderline personality disorder, a prior history of violent or aggressive behaviour, or alcohol or substance abuse may be at risk of such events. Instances of irritability, hostility and intrusive thoughts have been reported during discontinuance of alprazolam in patients with post-traumatic stress disorder.

Dependence

Use (even at therapeutic doses) may lead to the development of physical dependence: discontinuation of the therapy may result in withdrawal or rebound phenomena (see warnings and precautions). Psychic dependence may occur. Abuse of benzodiazepines have been reported.

4.9 Overdose

As with other benzodiazepines, overdose should not present a threat to life unless combined with other CNS depressants (including alcohol). In the management of overdose with any medicinal product, it should be borne in mind that multiple agents have been taken.

Following overdose with any medicinal product, vomiting may be induced (within 1 hour) if the patient is conscious or gastric lavage undertaken with the airway protected if the patient is unconscious. If there is no advantage in emptying the stomach, activated charcoal should be given to reduce absorption.

Special attention should be paid to respiratory and cardiovascular functions in intensive care.

Symptoms of overdose are extensions of its pharmacological activity and usually manifested by slurring of speech, motor incoordination and degrees of central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion and lethargy, in more serious cases, symptoms may include ataxia, hypotonia, hypotension, respiratory depression, rarely coma and very rarely death.

Flumazenil may be useful as an antidote.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Alprazolam, like other benzodiazepines, has a high affinity for the benzodiazepine binding site in the brain. It facilitates the inhibitory neurotransmitter action of gamma-aminobutyric acid, which mediates both pre- and post synaptic inhibition in the central nervous system (CNS).

5.2 Pharmacokinetic Properties

Alprazolam is readily absorbed. Following oral administration peak concentration in the plasma occurs after 1 - 2 hours.

The mean half-life is 12 - 15 hours. Repeated dosage may lead to accumulation and this should be borne in mind in elderly patients and those with impaired renal or hepatic function. Alprazolam and its metabolites are excreted primarily in the urine.

In vitro alprazolam is bound (80%) to human serum protein.

5.3 Preclinical Safety Data

None given

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose monohydrate, microcrystalline cellulose, colloidal anhydrous silica, maize starch, magnesium stearate and docusate sodium with sodium benzoate.

6.2 Incompatibilities

None known.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

Do not store above 25°C.

Blister pack: Keep container in the outer carton.

Bottle pack only: Store in the original container.

6.5 Nature And Contents Of Container

Clear PVC/aluminium foil blister strips of 10 tablets, packed 6 strips to a box. Glass bottle with metal screw cap or HDPE bottle with LDPE tamper evident cap containing 100 or 1000 tablets.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

Administrative Data

7. Marketing Authorisation Holder

Pharmacia Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

United Kingdom

8. Marketing Authorisation Number(S)

PL 00032/0092 and 0093

9. Date Of First Authorisation/Renewal Of The Authorisation

27 August 1982/23 January 2003

10. Date Of Revision Of The Text

June 2006

Legal category: POM

Ref: XX 2_0

Jetmonal

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Xgeva

1. Name Of The Medicinal Product

XGEVA^®

2. Qualitative And Quantitative Composition

Each vial contains 120 mg of denosumab in 1.7 ml of solution (70 mg/ml).

Denosumab is a human monoclonal IgG2 antibody produced in a mammalian cell line (CHO) by recombinant DNA technology.

Excipients with known effects:

Each 1.7 ml of solution contains 78 mg sorbitol (E420).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection (injection).

Clear, colourless to slightly yellow solution and may contain trace amounts of translucent to white proteinaceous particles.

4. Clinical Particulars

4.1 Therapeutic Indications

Prevention of skeletal related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with bone metastases from solid tumours.

4.2 Posology And Method Of Administration

Posology

The recommended dose of XGEVA is 120 mg administered as a single subcutaneous injection once every 4 weeks into the thigh, abdomen or upper arm.

Supplementation of at least 500 mg calcium and 400 IU vitamin D is required in all patients, unless hypercalcaemia is present (see section 4.4).

Patients with renal impairment

No dose adjustment is required in patients with renal impairment (see section 5.2). Experience in patients on dialysis or with severe renal impairment (creatinine clearance < 30 ml/min) is limited.

Patients with hepatic impairment

The safety and efficacy of denosumab have not been studied in patients with hepatic impairment (see section 5.2).

Elderly patients (age

No dose adjustment is required in elderly patients (see section 5.2).

Paediatric population

XGEVA is not recommended in paediatric patients (age < 18) as the safety and efficacy of XGEVA in these patients have not been established. Inhibition of RANK/RANK ligand (RANKL) in animal studies has been coupled to inhibition of bone growth and lack of tooth eruption, and these changes were partially reversible upon cessation of RANKL inhibition (see section 5.3).

Method of administration

For subcutaneous use.

XGEVA should be administered under the responsibility of a healthcare professional.

The instructions for use, handling and disposal are given in section 6.6.

4.3 Contraindications

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

Severe, untreated hypocalcaemia (see section 4.4).

4.4 Special Warnings And Precautions For Use

Calcium and Vitamin D supplementation

Supplementation with calcium and vitamin D is required in all patients unless hypercalcaemia is present (see section 4.2).

Hypocalcaemia

Pre-existing hypocalcaemia must be corrected prior to initiating therapy with XGEVA.

Patients with severe renal impairment (creatinine clearance < 30 ml/min) or receiving dialysis are at greater risk of developing hypocalcaemia. Monitoring of calcium levels in these patients is recommended. If hypocalcaemia occurs while receiving XGEVA, additional short term calcium supplementation may be necessary.

Osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) was reported in patients treated with denosumab, predominantly in patients with advanced malignancies involving bone (see section 4.8).

Patients who developed ONJ in clinical studies generally had known risk factors for ONJ, including invasive dental procedures (e.g., tooth extraction, dental implants, oral surgery), poor oral hygiene or other pre-existing dental disease, advanced malignancies, infections, or concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors, radiotherapy to the head and neck). A dental examination with appropriate preventive dentistry should be considered prior to treatment with XGEVA in patients with active dental and jaw conditions (as listed above). While on treatment, patients should avoid invasive dental procedures if possible.

Good oral hygiene practices should be maintained during treatment with XGEVA. Patients who are suspected of having or who develop ONJ while on XGEVA therapy should receive care by a dentist or oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

An individual risk/benefit evaluation should be done for each patient before prescribing XGEVA in patients with unavoidable risk factors for ONJ; and in patients who have developed ONJ during treatment with XGEVA.

Skin infections leading to hospitalisation (predominantly cellulitis)

In clinical trials in patients with advanced malignancies involving bone, skin infections leading to hospitalisation (predominantly cellulitis) were reported (see section 4.8). Patients should be advised to seek prompt medical attention if they develop signs or symptoms of cellulitis.

Others

Patients being treated with XGEVA should not be treated concomitantly with other denosumab containing medicinal products (for osteoporosis indications).

Patients being treated with XGEVA should not be treated concomitantly with bisphosphonates.

Warnings for excipients

Patients with rare hereditary problems of fructose intolerance should not use XGEVA.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies have been performed.

In clinical trials, XGEVA has been administered in combination with standard anti-cancer treatment and in subjects previously receiving bisphosphonates. There were no clinically-relevant alterations in trough serum concentration and pharmacodynamics of denosumab (creatinine adjusted urinary N-telopeptide, uNTx/Cr) by concomitant chemotherapy and/or hormone therapy or by previous intravenous bisphosphonate exposure.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of XGEVA in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). In genetically engineered mice in which RANKL has been turned off by gene removal (a “knockout mouse”), studies suggest absence of RANKL (the target of denosumab – see section 5.1) could interfere with the development of lymph nodes in the foetus and could lead to postnatal impairment of dentition and bone growth (see section 5.3). XGEVA is not recommended for use in pregnant women and women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether denosumab is excreted in human milk. Knockout mouse studies suggest absence of RANKL during pregnancy may interfere with maturation of the mammary gland leading to impaired lactation post-partum (see section 5.3). A decision on whether to abstain from breast-feeding or to abstain from therapy with XGEVA should be made, taking into account the benefit of breast-feeding to the newborn/infant and the benefit of XGEVA therapy to the woman.

Fertility

No data are available on the effect of denosumab on human fertility. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

4.7 Effects On Ability To Drive And Use Machines

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

4.8 Undesirable Effects

Summary of the safety profile

The safety of XGEVA was evaluated in 5,931 patients with advanced malignancies involving bone and is derived from active-controlled, clinical trials examining the efficacy and safety of XGEVA versus zoledronic acid in preventing the occurrence of skeletal related events. The adverse reactions are presented in table 1.

Tabulated list of adverse reactions

The following convention has been used for the classification of the adverse reactions reported in three phase III and one phase II clinical studies (see table 1): very common (

Table 1 Adverse reactions reported in three phase III and one phase II active-controlled clinical studies in patients with advanced malignancies involving bone

MedDRA system organ class	Frequency category	Adverse reactions
Infections and infestations	Uncommon	Cellulitis1
Immune system disorder	Uncommon	Drug hypersensitivity
Metabolism and nutrition disorders	Common	Hypocalcaemia1
Common	Hypophosphataemia
Respiratory, thoracic and mediastinal disorders	Very common	Dyspnoea
Gastrointestinal disorders	Very common	Diarrhoea
Common	Tooth extraction
Skin and subcutaneous tissues disorders	Common	Hyperhidrosis
Musculoskeletal and connective tissue disorders	Common	Osteonecrosis of the jaw1

¹ See section Description of selected adverse reactions

Description of selected adverse reactions

Hypocalcaemia

In three phase III active-controlled clinical trials in patients with advanced malignancies involving bone, hypocalcaemia was reported in 9.6% of patients treated with XGEVA and 5.0% of patients treated with zoledronic acid.

A grade 3 decrease in serum calcium levels was experienced in 2.5% of patients treated with XGEVA and 1.2% of patients treated with zoledronic acid. A grade 4 decrease in serum calcium levels was experienced in 0.6% of patients treated with XGEVA and 0.2% of patients treated with zoledronic acid (see section 4.4).

Osteonecrosis of the jaw (ONJ)

In three phase III active-controlled clinical trials in patients with advanced malignancies involving bone, ONJ was confirmed in 1.8% of patients treated with XGEVA and 1.3% of patients treated with zoledronic acid. Clinical characteristics of these cases were similar between treatment groups. Among subjects with confirmed ONJ, most (81% in both treatment groups) had a history of tooth extraction, poor oral hygiene, and/or use of a dental appliance. In addition most subjects were receiving or had received chemotherapy (see section 4.4). Patients with certain identified risk factors for ONJ were excluded from participation in the pivotal studies (see section 5.1).

Skin infections (predominantly cellulitis) leading to hospitalisation

In three phase III active-controlled clinical trials in patients with advanced malignancies involving bone, skin infections leading to hospitalisation (predominantly cellulitis) were reported more frequently in patients receiving XGEVA (0.9%) compared with zoledronic acid (0.7%).

In postmenopausal women with osteoporosis, skin infections leading to hospitalisation were reported for 0.4% women receiving Prolia^® (denosumab 60 mg every 6 months) and for 0.1% women receiving placebo (see section 4.4).

Other special populations

In a clinical study of patients without advanced cancer with severe renal impairment (creatinine clearance < 30 ml/min) or receiving dialysis, there was a greater risk of developing hypocalcaemia in the absence of calcium supplementation.

4.9 Overdose

There is no experience with overdose in clinical studies. XGEVA has been administered in clinical studies using doses up to 180 mg every 4 weeks and 120 mg weekly for 3 weeks.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Drugs for the treatment of bone diseases – other drugs affecting bone structure and mineralisation, ATC code: M05BX04

Mechanism of action

RANKL exists as a transmembrane or soluble protein. RANKL is essential for the formation, function and survival of osteoclasts, the sole cell type responsible for bone resorption. Increased osteoclast activity, stimulated by RANKL, is a key mediator of bone destruction in metastatic bone disease and multiple myeloma. Denosumab is a human monoclonal antibody (IgG2) that targets and binds with high affinity and specificity to RANKL, preventing the RANKL/RANK interaction from occurring and resulting in reduced osteoclast numbers and function, thereby decreasing bone resorption and cancer-induced bone destruction.

Pharmacodynamic effects

In phase II clinical studies of patients with advanced malignancies involving bone, subcutaneous (SC) dosing of XGEVA administered either every 4 weeks or every 12 weeks resulted in a rapid reduction in markers of bone resorption (uNTx/Cr, serum CTx), with median reductions of approximately 80% for uNTx/Cr occurring within 1 week regardless of prior bisphosphonate therapy or baseline uNTx/Cr level. In the phase III clinical trials, median reductions of approximately 80% were maintained in uNTx/Cr after 3 months of treatment in 2075 XGEVA-treated advanced cancer patients naïve to IV-bisphosphonate.

Immunogenicity

In clinical studies, neutralising antibodies have not been observed for XGEVA. Using a sensitive immunoassay < 1% of patients treated with denosumab for up to 3 years tested positive for non neutralising binding antibodies with no evidence of altered pharmacokinetics, toxicity, or clinical response.

Clinical efficacy in patients with bone metastases from solid tumours

Efficacy and safety of 120 mg XGEVA SC every 4 weeks or 4 mg zoledronic acid (dose-adjusted for reduced renal function) IV every 4 weeks were compared in three randomised, double blind, active controlled studies, in IV-bisphosphonate naïve patients with advanced malignancies involving bone: adults with breast cancer (study 1), other solid tumours or multiple myeloma (study 2), and castrate-resistant prostate cancer (study 3). Patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure, were not eligible for inclusion in these studies. The primary and secondary endpoints evaluated the occurrence of one or more skeletal related events (SREs).

XGEVA reduced the risk of developing a SRE, and developing multiple SREs (first and subsequent) in patients with bone metastases from solid tumours (see table 2).

Table 2: Efficacy results in patients with advanced malignancies involving bone

	Study 1 breast cancer	Study 2 other solid tumours** or multiple myeloma	Study 3 prostate cancer	Combined advanced cancer
	XGEVA	zoledronic acid	XGEVA	zoledronic acid	XGEVA	zoledronic acid	XGEVA	zoledronic acid
N	1026	1020	886	890	950	951	2862	2861
First SRE
Median time (months)	NR	26.4	20.6	16.3	20.7	17.1	27.6	19.4
Difference in median time (months)	NA	4.2	3.5	8.2
HR (95% CI) / RRR (%)	0.82 (0.71, 0.95) / 18	0.84 (0.71, 0.98) / 16	0.82 (0.71, 0.95) / 18	0.83 (0.76, 0.90) / 17
Non-inferiority / Superiority p-values	< 0.0001†/ 0.0101†	0.0007† / 0.0619†	0.0002† / 0.0085†	< 0.0001 / < 0.0001
Proportion of subjects (%)	30.7	36.5	31.4	36.3	35.9	40.6	32.6	37.8
First and subsequent SRE*
Mean number/patient	0.46	0.60	0.44	0.49	0.52	0.61	0.48	0.57
Rate ratio (95% CI) / RRR (%)	0.77 (0.66, 0.89) / 23	0.90 (0.77, 1.04) / 10	0.82 (0.71, 0.94) / 18	0.82 (0.75, 0.89) / 18
Superiority p-value	0.0012†	0.1447†	0.0085†	< 0.0001
SMR per Year	0.45	0.58	0.86	1.04	0.79	0.83	0.69	0.81
First SRE or HCM
Median time (months)	NR	25.2	19.0	14.4	20.3	17.1	26.6	19.4
HR (95% CI) / RRR (%)	0.82 (0.70, 0.95) / 18	0.83 (0.71, 0.97) / 17	0.83 (0.72, 0.96) / 17	0.83 (0.76, 0.90) / 17
Superiority p-value	0.0074	0.0215	0.0134	< 0.0001
First radiation to bone
Median time (months)	NR	NR	NR	NR	NR	28.6	NR	33.2
HR (95% CI) / RRR (%)	0.74 (0.59, 0.94) / 26	0.78 (0.63, 0.97) / 22	0.78 (0.66, 0.94) / 22	0.77 (0.69, 0.87) / 23
Superiority p-value	0.0121	0.0256	0.0071	< 0.0001

NR = not reached; NA = not available; HCM = hypercalcaemia of malignancy; SMR = skeletal morbidity rate; HR = Hazard Ratio; RRR = Relative Risk Reduction †Adjusted p-values are presented for Studies 1, 2 and 3 (first SRE and first and subsequent SRE endpoints); *Accounts for all skeletal events over time; only events occurring

** Including NSCLC, renal cell cancer, colorectal cancer, small cell lung cancer, bladder cancer, head and neck cancer, GI/genitourinary cancer and others, excluding breast and prostate cancer

Figure 1. Kaplan-Meier plots of time to first on-study SRE

Disease progression and overall survival

Disease progression was similar between XGEVA and zoledronic acid in all three studies and in the pre-specified analysis of all three-studies combined.

In all three studies overall survival was balanced between XGEVA and zoledronic acid in patients with advanced malignancies involving bone: patients with breast cancer (hazard ratio and 95% CI was 0.95 [0.81, 1.11]), patients with prostate cancer (hazard ratio and 95% CI was 1.03 [0.91, 1.17]), and patients with other solid tumours or multiple myeloma (hazard ratio and 95% CI was 0.95 [0.83, 1.08]). A post-hoc analysis in study 2 (patients with other solid tumours or multiple myeloma) examined overall survival for the 3 tumour types used for stratification (non-small cell lung cancer, multiple myeloma, and other). Overall survival was longer for XGEVA in non-small cell lung cancer (hazard ratio [95% CI] of 0.79 [0.65, 0.95]; n = 702) and longer for zoledronic acid in multiple myeloma (hazard ratio [95% CI] of 2.26 [1.13, 4.50]; n = 180) and similar between XGEVA and zoledronic acid in other tumour types (hazard ratio [95% CI] of 1.08 (0.90, 1.30); n = 894). This study did not control for prognostic factors and anti-neoplastic treatments. In a combined pre-specified analysis from studies 1, 2 and 3, overall survival was similar between XGEVA and zoledronic acid (hazard ratio and 95% CI 0.99 [0.91, 1.07]) (see section 4.4).

Effect on pain

The time to pain improvement (i.e.,

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with XGEVA in one or more subsets of the paediatric population in bone metastases (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic Properties

Following SC administration, bioavailability was 62% and denosumab displayed non-linear pharmacokinetics with dose over a wide dose range, but approximately dose-proportional increases in exposure for doses of 60 mg (or 1 mg/kg) and higher. The non-linearity is likely due to a saturable target-mediated elimination pathway of importance at low concentrations.

With multiple doses of 120 mg every 4 weeks an approximate 2-fold accumulation in serum denosumab concentrations was observed and steady-state was achieved by 6 months, consistent with time-independent pharmacokinetics. In subjects who discontinued 120 mg every 4 weeks, the mean half-life was 28 days (range 14 to 55 days).

A population pharmacokinetic analysis did not indicate clinically significant changes in the systemic exposure of denosumab at steady state with respect to age (18 to 87 years), race/ethnicity (Blacks, Hispanics, Asians and Caucasians explored), gender or solid tumour types. Increasing body weight was associated with decreases in systemic exposure, and vice versa. The alterations were not considered clinically relevant, since pharmacodynamic effects based on bone turnover markers were consistent across a wide range of body weight.

Denosumab is composed solely of amino acids and carbohydrates as native immunoglobulin and is unlikely to be eliminated via hepatic metabolic mechanisms. Its metabolism and elimination are expected to follow the immunoglobulin clearance pathways, resulting in degradation to small peptides and individual amino acids.

Special populations

No overall differences in safety or efficacy were observed between geriatric patients and younger patients. Controlled clinical studies of XGEVA in patients with advanced malignancies involving bone over age 65 revealed similar efficacy and safety in older and younger patients. No dose adjustment is required in elderly patients.

In a study of 55 patients without advanced cancer but with varying degrees of renal function, including patients on dialysis, the degree of renal impairment had no effect on the pharmacokinetics of denosumab. There is no need for renal monitoring when receiving XGEVA.

No specific study in patients with hepatic impairment was performed. In general, monoclonal antibodies are not eliminated via hepatic metabolic mechanisms. The pharmacokinetics of denosumab is not expected to be affected by hepatic impairment.

The pharmacokinetic profile in paediatric populations has not been assessed.

5.3 Preclinical Safety Data

Since the biological activity of denosumab in animals is specific to nonhuman primates, evaluation of genetically engineered (knockout) mice or use of other biological inhibitors of the RANK/RANKL pathway, such as OPG-Fc and RANK-Fc, were used to evaluate the pharmacodynamic properties of denosumab in rodent models.

In mouse bone metastasis models of oestrogen receptor positive and negative human breast cancer, prostate cancer and non small cell lung cancer, OPG-Fc reduced osteolytic, osteoblastic, and osteolytic/osteoblastic lesions, delayed formation of de novo bone metastases, and reduced skeletal tumour growth. When OPG-Fc was combined with hormonal therapy (tamoxifen) or chemotherapy (docetaxel) in these models, there was additive inhibition of skeletal tumour growth in breast, and prostate or lung cancer respectively. In a mouse model of mammary tumour induction, RANK-Fc reduced hormone-induced proliferation in mammary epithelium and delayed tumour formation.

Standard tests to investigate the genotoxicity potential of denosumab have not been evaluated, since such tests are not relevant for this molecule. However, due to its character it is unlikely that denosumab has any potential for genotoxicity.

The carcinogenic potential of denosumab has not been evaluated in long-term animal studies.

In single and repeated dose toxicity studies in cynomolgus monkeys, denosumab doses resulting in 2.7 to 15 times greater systemic exposure than the recommended human dose had no impact on cardiovascular physiology, male or female fertility, or produced specific target organ toxicity. In an embryofoetal developmental study in cynomolgus monkeys, denosumab doses resulting in 9 times greater systemic exposure than the recommended human dose did not induce maternal toxicity or foetal harm during a period equivalent to the first trimester, although foetal lymph nodes were not examined (see section 4.6). During the second and third trimesters, when denosumab is expected to cross the placenta, potential maternal and foetal toxicity have not been assessed.

In preclinical bone quality studies in monkeys on long-term denosumab treatment, decreases in bone turnover were associated with improvement in bone strength and normal bone histology.

In male mice genetically engineered to express huRANKL (knock-in mice), which were subjected to a transcortical fracture, denosumab delayed the removal of cartilage and remodelling of the fracture callus compared to control, but biomechanical strength was not adversely affected.

In preclinical studies knockout mice lacking RANK or RANKL had an absence of lactation due to inhibition of mammary gland maturation (lobulo-alveolar gland development during pregnancy) and exhibited impairment of lymph node formation. Neonatal RANK/RANKL knockout mice exhibited decreased body weight, reduced bone growth, altered growth plates and lack of tooth eruption. Reduced bone growth, altered growth plates and impaired tooth eruption were also seen in studies of neonatal rats administered RANKL inhibitors, and these changes were partially reversible when dosing of RANKL inhibitor was discontinued. Adolescent primates dosed with denosumab at 2.7 and 15 times (10 and 50 mg/kg dose) the clinical exposure had abnormal growth plates. Therefore, treatment with denosumab may impair bone growth in children with open growth plates and may inhibit eruption of dentition.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Acetic acid, glacial*

Sodium hydroxide (for pH adjustment)*

Sorbitol (E420)

Water for injections

* Acetate buffer is formed by mixing acetic acid with sodium hydroxide

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

3 years.

XGEVA may be stored at room temperature (up to 25°C) for up to 30 days in the original container. Once removed from the refrigerator, XGEVA must be used within this 30 day period.

6.4 Special Precautions For Storage

Store in a refrigerator (2°C – 8°C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

6.5 Nature And Contents Of Container

1.7 ml solution in a single use vial (type I glass) with stopper (fluoropolymer coated elastomeric) and seal (aluminium) with flip-off cap.

Pack size of one or four.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Before administration, the XGEVA solution should be inspected visually. The solution may contain trace amounts of translucent to white proteinaceous particles. Do not inject the solution if it is cloudy or discoloured. Do not shake excessively. To avoid discomfort at the site of injection, allow the vial to reach room temperature (up to 25ºC) before injecting and inject slowly. Inject the entire contents of the vial. A 27 gauge needle is recommended for the administration of denosumab. Do not re-enter the vial.

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

7. Marketing Authorisation Holder

Amgen Europe B.V.

Minervum 7061

NL-4817 ZK Breda

The Netherlands

8. Marketing Authorisation Number(S)

EU/1/11/703/001

EU/1/11/703/002

9. Date Of First Authorisation/Renewal Of The Authorisation

13 July 2011

10. Date Of Revision Of The Text

XGEVA is a registered trademark of Amgen Inc.

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.