Urokinase 100,000 I.U.

1. Name Of The Medicinal Product

Urokinase medac 100,000 I.U.

Powder for solution for injection or infusion

2. Qualitative And Quantitative Composition

Each vial contains 100,000 I.U. of human urokinase extracted from human urine.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder for solution for injection or infusion

4. Clinical Particulars

4.1 Therapeutic Indications

Intravascular lysis of blood clots in the following conditions:

• extensive acute proximal deep vein thrombosis

• acute massive pulmonary embolism

• acute occlusive peripheral arterial disease with limb threatening ischemia

• thrombosed arteriovenous haemodialysis shunts

• thrombosed central venous catheters

4.2 Posology And Method Of Administration

Urokinase medac should only be used by physicians experienced in the management of thrombotic diseases in hospitals where adequate diagnostic and monitoring techniques are available.

Depending on the indication, the route of administration of Urokinase medac is by systemic intravenous infusion, by local intra-arterial catheter-directed infusion during arteriography, or by local instillation.

It must not be given by subcutaneous or intramuscular injection.

For instructions regarding reconstitution and further dilution, see section 6.6.

Adults

The dosage may be adjusted individually depending on the clinical condition. The following dose regimens should be used as a guideline.

Deep vein thrombosis

Urokinase medac should be administered by intravenous infusion into a peripheral vein using an initial dose of 4,400 I.U./kg bodyweight infused over 10 – 20 min, followed by a maintenance dose of 100,000 I.U. per hour for 2 – 3 days.

Pulmonary embolism

Urokinase medac should be administered by intravenous infusion into a peripheral vein using an initial dose of 4,400 I.U./kg bodyweight infused over 10 – 20 min, followed by a maintenance dose of 4,400 I.U./kg bodyweight per hour for 12 hours.

Occlusive peripheral arterial disease

Urokinase medac should be administered by local intra-arterial catheter-directed graded infusion using an initial dose of 4,000 I.U./min (i.e. 240,000 I.U. per hour) for 2 – 4 hours or until restoration of antegrade flow, followed by a dose of 1,000 – 2,000 I.U./min until complete lysis or a maximum of 48 hours.

Thrombosed arteriovenous haemodialysis shunts

Urokinase medac should be administered by local forced periodic infusion (pulse spray) into both branches of the shunt at a concentration of 5,000 to 25,000 I.U./ml up to a total dose of 250,000 I.U. If necessary, the application can be repeated every 30 – 45 minutes up to a maximum of 2 hours.

Thrombosed central venous catheters

Urokinase medac should be dissolved in physiological saline at a concentration of 5,000 I.U./ml. A volume sufficient to completely fill the lumen of the occluded catheter should be instilled and either locked for a duration of 20 to 60 minutes or pushed with aliquots of saline before the lysate is aspirated. The procedure may be repeated if necessary.

Special populations

• Elderly patients: Available data are limited in patients over 65 years and it is not known whether they respond differently from younger subjects. Urokinase medac should be used with caution in elderly patients (see section 4.4).

• Patients with renal or hepatic impairment: A dose reduction may be required in patients with impaired renal and/or hepatic function. In these cases, the fibrinogen level should not fall below 100 mg/dl.

Paediatric patients

There is very limited experience with urokinase in children with thromboembolic occlusive vascular disease and urokinase should not be used in this indication.

Urokinase medac may be used in children of all ages for the treatment of thrombosed central venous catheters using the same lock procedure as in adults.

Therapeutic monitoring

Before starting thrombolytic therapy, haemostasis tests should be performed including haematocrit, platelet count, thrombin time (TT) and activated partial thromboplastin time (aPTT).

If heparin has been given, it should be discontinued and the aPTT should be less than twice the normal control value before urokinase therapy is initiated.

For systemic administration, a 3 to 5 fold prolongation of the TT measured 4 hours after initiation of therapy is generally considered sufficient. However, results of coagulation tests and fibrinolytic activity do not reliably predict either efficacy or risk of bleeding.

Follow-up treatment

In order to prevent recurrent thrombosis subsequent administration of anticoagulants should be instituted provided the aPTT is less than twice the normal control value.

4.3 Contraindications

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

• Active clinically relevant bleeding

• Aneurysm and arteriovenous malformation

• Intracranial neoplasm or other neoplasm with risk of haemorrhage

• Decreased blood coagulation (haemorrhagic diathesis, concomitant therapy with anticoagulants, spontaneous fibrinolysis) and severe thrombocytopenia

• Severe uncontrolled arterial hypertension (systolic > 200 mmHg, diastolic > 100 mmHg; grade III or IV hypertensive retinopathy)

• Acute pancreatitis, pericarditis, bacterial endocarditis, sepsis

• Recent cerebrovascular accident (e.g. within 2 months)

• Recent trauma including cardiopulmonary resuscitation, thoracic surgery or neurosurgery (e.g. within 2 months)

• Recent major surgery until primary wound healing, recent organ biopsy, lumbar puncture, translumbal aortography (e.g. within 10 days)

4.4 Special Warnings And Precautions For Use

In the following conditions, the risk of bleeding may be increased and should be weighed against the anticipated benefits:

• Recent severe gastrointestinal bleeding

• Recent surgery other than thoracic or neurosurgery, recent obstetrical delivery, puncture of non-compressible vessels

• Moderate coagulation defects including those due to severe hepatic or renal diseases

• Cavernous pulmonary diseases

• Genitourinary tract diseases with existing or potential sources of bleeding (e.g. implanted bladder catheter)

• High likelihood of a left heart thrombus (e.g. mitral stenosis with atrial fibrillation) with possible risk of cerebral embolism

• Known septic thrombotic disease

• Severe cerebrovascular disease

• Elderly patients (especially those over 75 years)

Concomitant administration of urokinase with other thrombolytic agents, anticoagulants, or agents inhibiting platelet function may further increase the risk of serious bleeding (see section 4.5).

When bleeding occurs in patients receiving urokinase, it may be difficult to control. Although urokinase is intended to produce sufficient amounts of plasmin to lyse intravascular deposits of fibrin, other fibrin deposits including those which provide haemostasis (at sites of needle puncture, catheter insertion, cut, etc.) are also subject to lysis, and bleeding from such sites may result. Oozing of blood from sites of percutaneous trauma occurs frequently.

The possibility of bruising or haematoma formation, especially after intramuscular injections, is high during urokinase therapy. Intramuscular injections and unnecessary handling of the patient should be avoided. Venipunctures and invasive venous procedures should be performed as infrequently as possible and with care to minimize bleeding. If bleeding from an invasive site is not serious, urokinase therapy may be continued while closely observing the patient; local measures such as application of pressure should be initiated immediately.

Arterial invasive procedures must be avoided before and during urokinase treatment to minimise bleeding. If an arterial puncture is absolutely essential, it should be performed by a physician experienced in the procedure, using a radial or brachial rather than a femoral artery. Direct pressure should be applied at the puncture site for at least 30 minutes, a pressure dressing applied, and the site checked frequently for evidence of bleeding.

If severe bleeding occurs following systemic treatment with urokinase, infusion should be stopped immediately and measures to manage the bleeding implemented. Plasma volume expanders other than dextrans may be used to replace blood volume deficits; if blood loss has been extensive, administration of packed red blood cells is preferred to whole blood. If very rapid reversal of the fibrinolytic state is required, administration of an antifibrinolytic agent such as epsilon-aminocaproic acid may be considered (see section 4.9).

Urokinase medac is a highly purified enzyme produced from human urine. It also contains human serum albumin. Products manufactured from human source materials have the potential to transmit infectious agents. Procedures to control such risks strongly reduce but cannot completely eliminate the risk of transmitting infectious agents.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Anticoagulants

Oral anticoagulants or heparin may increase the risk of haemorrhage and should not be used concomitantly with urokinase.

Active substances affecting platelet function

Due to increased risk of haemorrhage, concomitant use of urokinase and active substances that affect platelet function (e.g., acetylsalicylic acid, other non-steroidal anti-inflammatory agents, dipyridamole, dextrans) should be avoided.

Contrast agents

Contrast agents may delay fibrinolysis.

4.6 Pregnancy And Lactation

There are no adequate data from the use of urokinase in pregnant women. Animal studies are insufficient with respect to effects on pregnancy, embryonal/fetal development, parturition or postnatal development. The potential risk for humans is unknown. However, low-molecular urokinase fragments and active plasmin cross the placenta.

Urokinase should not be used during pregnancy or in the immediate post-partum period unless clearly necessary.

It is unknown whether urokinase is excreted into human breast milk. Breast feeding should be avoided during treatment with urokinase.

4.7 Effects On Ability To Drive And Use Machines

Not relevant.

4.8 Undesirable Effects

Haemorrhage

The most frequent and severe adverse effect of urokinase therapy is haemorrhage. The haemostatic status of the patient may be more profoundly altered with urokinase therapy than with heparin or coumarin-derivative anticoagulant therapy.

Severe spontaneous bleeding, including fatalities resulting from cerebral haemorrhage, has occurred during urokinase therapy. Less severe spontaneous bleeding has occurred approximately twice as frequently as that occurring during heparin therapy. Patients with pre-existing haemostatic defects have the greatest risk of spontaneous bleeding.

Moderate decreases in haematocrit not accompanied by clinically detectable bleeding have been reported in approximately 20 % of patients receiving urokinase.

Hypersensitivity reactions

In contrast to streptokinase, urokinase is reportedly non-antigenic. However, mild allergic reactions including bronchospasm and rash have been reported rarely. In addition, very rare cases of fatal anaphylaxis have been reported.

Infusion reactions

Fever and chills, including shaking chills (rigors), have been reported occasionally in patients receiving urokinase. Symptomatic treatment is usually sufficient to alleviate discomfort caused by urokinase-induced fever; however, acetylsalicylic acid should not be used.

Other infusion reactions reported with urokinase therapy include dyspnoea, cyanosis, hypoxemia, acidosis, back pain, and nausea and/or vomiting; these reactions generally occurred within one hour of beginning urokinase infusion.

The following frequency convention was used as a basis for the evaluation of undesirable effects:

Very common
Common:
Uncommon:
Rare:
Very rare	< 1/10,000

Immune system disorders

Rare	Hypersensitivity reactions including dyspnoea, hypotension, flushing, urticaria, rash
Very rare	Anaphylactic reactions

Vascular disorders

Very common	Haemorrhage from puncture sites, wounds
Haematoma
Epistaxis, gingival bleeding
Haematuria (microscopic)
Common	Intracranial haemorrhage
Gastrointestinal haemorrhage, retroperitoneal haemorrhage
Urogenital haemorrhage
Muscle haemorrhage
Embolism, including cholesterol embolism
Uncommon	Intrahepatic haemorrhage

General disorders and administration site conditions

Common

Fever, chills

Investigations

Very common

Decrease in haematocrit without clinically detectable haemorrhage Transient increase in transaminases

4.9 Overdose

Haemorrhage that occurs during treatment with urokinase may be controlled with local pressure and treatment continued. If severe bleeding occurs, treatment with urokinase must be stopped and inhibitors such as aprotinin, epsilon-aminocaproic acid, p-aminoethylbenzoic acid or tranexamic acid can be given. In serious cases, human fibrinogen, factor XII, packed red cells or whole blood should be given as appropriate. For correction of volume deficiency, dextrans should be avoided.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC code: B01A D04, antithrombotic agent.

Urokinase medac is a highly purified form of naturally occurring human urokinase extracted from urine. Urokinase exists in two distinct molecular entities, a high molecular weight (approximately 54,000 daltons) and a low molecular weight (approximately 33,000 daltons). Urokinase medac contains more than 85 % of the HMW form.

Urokinase is a thrombolytic agent which converts plasminogen into plasmin (fibrinolysin) a proteolytic enzyme that degrades fibrin as well as fibrinogen and other plasma proteins. The activity of urokinase leads to a dose-dependent decrease in plasminogen and fibrinogen levels and to increased presence of fibrin and fibrogen degradation products, which have an anticoagulant effect and potentiate the effect of heparin. These effects persist for 12 – 24 hours after the end of urokinase infusion.

5.2 Pharmacokinetic Properties

Urokinase is eliminated rapidly from the circulation by the liver with a half-life of 10 to 20 minutes. The inactive degradation products are excreted via the bile and primarily via the kidneys.

Elimination is delayed in patients with liver disease and impaired kidney function.

5.3 Preclinical Safety Data

There is no preclinical safety data of additional value to the prescribing physician.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Disodium phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate, human albumin.

6.2 Incompatibilities

No information is available regarding loss of activity in PVC containers or plastic bags/syringes.

6.3 Shelf Life

32 months

Use reconstituted material immediately.

After reconstitution and dilution, chemical and physical stability has been demonstrated for 72 hours at room temperature. From a microbiological point of view, the product should be used immediately after reconstitution and dilution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 °C to 8 °C.

6.4 Special Precautions For Storage

Do not store above 25 °C.

Keep the vial in the outer container to protect from light.

6.5 Nature And Contents Of Container

All presentations are contained in borosilicate clear type 1 glass vials closed with chlorobutyl rubber stoppers and sealed with an aluminium flip-off cap.

6.6 Special Precautions For Disposal And Other Handling

The powder for solution for infusion should be dissolved in water for injection and further diluted with 0.9 % sodium chloride solution or glucose 5 % or glucose 10 % solution.

The powder is to be reconstituted as follows:

For a 100,000 I.U. vial use 2 ml of water for injection.

After reconstitution the solution must be clear and colourless.

7. Marketing Authorisation Holder

medac

Gesellschaft für klinische

Spezialpräparate mbH

Fehlandtstr. 3

20354 Hamburg

Germay

Phone: +49 (0)4103 8006-0

Fax: +49 (0)4103 8006-100

8. Marketing Authorisation Number(S)

PL 11587/0067

9. Date Of First Authorisation/Renewal Of The Authorisation

17/03/2010

10. Date Of Revision Of The Text

22/09/2010

Ultrabase Cream

INTENDIS

Ultrabase
Cream

Read all of this leaflet carefully because it contains important information for you.

This medicine is available without prescription. However, you still need to use Ultrabase carefully to get the best results from it.

• Keep this leaflet. You may need to read it again.


• Ask your pharmacist if you need more information or advice.


• You must contact a doctor if your symptoms worsen or do not improve.


• If you experience any side effect and this becomes serious, tell your doctor or pharmacist.

In this leaflet:

• 
  1. What Ultrabase is and what it is used for
  


• 
  2. Before you use Ultrabase
  


• 
  3. How to use Ultrabase
  


• 
  4. Possible side effects
  


• 
  5. How to store Ultrabase
  


• 
  6. Further information
  

What Ultrabase is and what it is used for

Ultrabase is a moisturiser that can be used to dilute skin preparations and is also used as a base for other medicines. It may be used as an alternative to topical corticosteroids (medicines put on the skin to reduce the redness and itchiness of certain skin problems) when they are being stopped. It may also be used alone after the topical corticosteroid is no longer used.

Before you use Ultrabase

Do not use Ultrabase

if you are allergic (hypersensitive) to any of the ingredients of Ultrabase as listed in section 6 “Further Information”.

Important information about some of the ingredients of Ultrabase

Ultrabase contains stearyl alcohol which may cause local skin reactions e.g. inflammation of the skin (contact dermatitis).

Ultrabase contains methyl parahydroxybenzoate (methyl paraben) [E218] and propyl parahydroxybenzoate (propyl paraben) [E216]. These ingredients may cause allergic reactions (possibly delayed).

How to use Ultrabase

The cream should be smoothed into the skin as often as it is needed.

If you use more Ultrabase than you should or accidentally swallow the cream

If you accidentally swallow Ultrabase it is unlikely to be dangerous but contact your doctor or pharmacist if you are worried.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Ultrabase Cream Side Effects

There have been no reports of side effects with Ultrabase. You should ask your doctor or pharmacist if you notice any change in your health or general sense of well-being while using Ultrabase.

How to store Ultrabase

• 
  Store Ultrabase out of the reach and sight of children.
  


• Do not use Ultrabase after the expiry date which is printed on the pack.

Further information

What Ultrabase contains

• Ultrabase has no active substance.


• Ultrabase contains the inactive ingredients: polyoxyl 40 stearate [E431], white soft paraffin, liquid paraffin, stearyl alcohol, carbomer, sodium hydroxide, methyl parahydroxybenzoate (methyl paraben) [E218], propyl parahydroxybenzoate (propyl paraben) [E216], disodium edetate [E463], purified water, citrus-rose perfume oil.

What Ultrabase looks like and contents of the pack

Ultrabase is a white cream.

This product is supplied in the following presentations:

• aluminium tubes containing 10 g or 50 g of Ultrabase


• plastic jars containing 500 g of Ultrabase


• plastic pump dispensers containing 500 g of Ultrabase

Marketing Authorisation Holder

Intendis GmbH

Max-Dohrn-Strasse 10

D-10589

Berlin

Germany

Manufacturer

Intendis Manufacturing, S.p.A.

Milan

Italy

Distributor in the UK

Meda Pharmaceuticals Ltd

Skyway House

Parsonage Road

Takeley

Bishop Stortford

CM22 6PU

UK

This leaflet was last approved in July 2009

Ultrabase is a registered trademark of Intendis GmbH.

81920606

Ultravist 370

1. Name Of The Medicinal Product

Ultravist® 370

2. Qualitative And Quantitative Composition

1ml contains 769mg of iopromide (equivalent to 370mg iodine).

3. Pharmaceutical Form

Aqueous solution for injection.

4. Clinical Particulars

4.1 Therapeutic Indications

X-ray contrast medium for computerised tomography, digital subtraction angiography, intravenous urography, venography (phlebography), arteriography, arthrography, hysterosalpingography and fistulography.

4.2 Posology And Method Of Administration

• General information

Experience shows that contrast medium is tolerated better if it is warmed to body temperature.

Intravenous urography

Adults: The minimum dose is 0.8ml/kg body weight Ultravist 370, (1ml/kg Ultravist 300 or 1.3ml/kg Ultravist 240). These doses should provide adequate filling of the ureters. It may be necessary to increase the dose in individual cases.

Children: The poor concentrating ability of the immature nephron of infantile kidneys necessitates the use of relatively high doses of contrast medium, i.e. for Ultravist 300:

Neonates:	4.0 ml/kg body weight
Babies:	3.0 ml/kg body weight
Small children:	1.5 ml/kg body weight

Computerised tomography

Cranial CT: The following dosages are recommended for cranial CT:

Ultravist 240:	1.5-2.5ml/kg body weight
Ultravist 300:	1-2ml/kg body weight
Ultravist 370:	1-1.5ml/kg body weight

Whole-body CT: For whole-body computerised tomography, the doses of contrast medium and the rates of administration depend on the organs under investigation, the diagnostic problem and, in particular, the different scan and image-reconstruction times of the scanners in use.

Angiography: The dosage depends on the age, weight, cardiac output and general condition of the patient, the clinical problem, examination technique and the nature and volume of the vascular region to be investigated.

The following dosages may serve as a guide:

Cerebral angiography

Aortic arch angiography	50-80 ml Ultravist 300/inj.
Selective angiography	6-15 ml Ultravist 300/inj.
Retrograde carotid angiography	30-40 ml Ultravist 300/inj.
Thoracic aortography:	50-80 ml Ultravist 300/inj.
Abdominal aortography:	40-60 ml Ultravist 300/inj.
Bifemoral arteriography: Peripheral angiography:	40-60 ml Ultravist 300/inj.

Upper extremities:

Arteriography	8-12 ml Ultravist 300/inj.
Venography	50-60 ml Ultravist 240/inj. 15-30 ml Ultravist 300/inj.

Lower extremities:

Arteriography	20-30 ml Ultravist 300/inj.
Venography	50-80 ml Ultravist 240/inj. 30-60 ml Ultravist 300/inj.

Angiocardiography:

Cardiac-ventriculography	40-60 ml Ultravist 370/inj.
Coronary angiography:	5-8 ml Ultravist 370/inj.

Digital subtraction angiography (DSA): I.V. injection of 30-60 ml Ultravist 300 or 370 as a bolus (flow-rate: 8-12 ml/second into the cubital vein; 10-20 ml/second into the vena cava) is recommended for high-contrast demonstrations of the great vessels, of the pulmonary arteries and of the arteries of the neck, head, kidneys and extremities.

Intra-arterial digital subtraction angiography requires smaller volumes and lower iodine concentrations than the intravenous technique.

4.3 Contraindications

Uncontrolled thyrotoxicosis (see section 4.4).

4.4 Special Warnings And Precautions For Use

• Hypersensitivity reactions

As Ultravist can be associated with anaphylactoid/hypersensitivity or other idiosyncratic reactions with cardiovascular, respiratory and/or cutaneous effects, appropriate emergency drugs and equipment should be available for immediate use. It is also advisable to use a flexible indwelling cannula for intravenous contrast medium administration.

Due to an increased risk of hypersensitivity reactions, particularly careful risk/benefit judgment is required in patients:

- with known hypersensitivity to Ultravist or any excipient of Ultravist

- with a previous hypersensitivity reaction to any other iodinated contrast medium

- history of bronchial asthma or other allergic disorders.

If pre-medication is given, a corticosteroid regimen is recommended.

Allergy-like reactions range from mild to severe (including shock – see section 4.8). Most reactions occur within one hour of administration. However, as with other contrast agents, delayed reaction (after hours to days) may occur.

In order to minimise risk if a severe reaction should occur, patients:

- should lie down during Ultravist administration

- must be kept under close observation for 15 minutes following the last injection as the majority of severe reactions occur at this time

- should remain in the hospital environment (but not necessarily the radiology department) for one hour after the last injection, and should be advised to return to the radiology department immediately if any symptoms develop.

If the administration does not take place on the X-ray table, any patient with a labile circulation should be brought to the X-ray machine sitting or lying down.

If hypersensitivity reactions occur, administration of the contrast medium must be stopped at once and – if necessary – specific therapy instituted intravenously. Patients who experience hypersensitivity reactions while taking beta-blockers may be resistant to treatment effects of beta agonists (see section 4.5). In the event of a severe hypersensitivity reaction, patients with cardiovascular disease are more susceptible to serious or even fatal outcomes.

• Thyroid dysfunction

Particularly careful risk/benefit judgement is required in patients with known or suspected hyperthyroidism or goitre, as iodinated contrast media may induce hyperthyroidism and thyrotoxic crisis in these patients. Testing of thyroid function prior to Ultravist administration and/or preventive thyrostatic medication may be considered in patients with known or suspected hyperthyroidism.

• Cerebral arteriosclerosis, pulmonary emphysema or poor general health

For patients with cerebral arteriosclerosis, pulmonary emphysema or poor general health, the need for examination with X-ray contrast media merits careful consideration.

• Renal impairment

Contrast media-induced nephrotoxicity, presenting as a transient impairment of renal function, may occur after intravascular administration of iodinated contrast media.

Acute renal failure may occur in rare cases.

Risk factors include, for example:

- pre-existing renal insufficiency

- dehydration

- diabetes mellitus

- multiple myeloma / paraproteinaemia

- repetitive and / or large doses of iodinated contrast media.

• Hydration

Adequate hydration should be ensured in all patients who receive Ultravist administration. This applies especially to patients with multiple myeloma, diabetes mellitus, polyuria, oliguria or gout and in babies, small children and patients in a very poor state of health. Existing disturbances of the balance of water and electrolytes must be corrected before the administration of Ultravist.

• Cardiovascular disease

There is an increased risk of clinically relevant haemodynamic changes and arrhythmia in patients with significant cardiac disease or severe coronary artery disease. In the event of a severe hypersensitivity reaction, patients with cardiovascular disease are more susceptible to serious or even fatal outcomes.

• CNS disorders

Patients with seizure history or other CNS disorders may be at increased risk of seizures and neurological complications with administration of iodinated contrast media. Neurological complications are more frequent in cerebral angiography and related procedures.

• Thromboembolic events

Non-ionic contrast media have less anticoagulant activity in-vitro than ionic media. Meticulous attention should therefore be paid to angiographic technique. Non-ionic media should not be allowed to remain in contact with blood in a syringe, and intravascular catheters should be flushed frequently with physiological saline solution (if necessary with heparin added) to minimise the risk of clotting, which has rarely led to serious thromboembolic complications of the procedure.

• Phaeochromocytoma

Premedication with an alpha-blocker is recommended in patients with phaeochromocytoma because of the risk of blood pressure crises.

• Anxiety

Experience shows that pronounced states of excitement, anxiety and pain can be the cause of side effects or intensify contrast medium-related reactions. They can be counteracted by calm management of the patient and the use of suitable drugs.

• Myelography

Ultravist should not be used in myelography.

• Hysterosalpingography

Hysterosalpingography must not be carried out during pregnancy or in patients with acute inflammatory conditions in the pelvic cavity.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Biguanides (metformin): Diabetic nephropathy may predispose to renal impairment following intravascular contrast medium administration. This may precipitate lactic acidosis in patients who are taking biguanides. As a precaution, biguanides should be stopped 48 hours prior to the contrast medium examination and reinstated only after control of renal function has been regained.

Beta-blockers: Patients who experience hypersensitivity reactions while taking beta-blockers may be resistant to treatment effects of beta agonists (see section 4.4).

Interleukin: The prevalence of delayed reactions (e.g. fever, rash, flu-like symptoms, joint pain and pruritus) to contrast media is higher in patients who have received interleukin.

Radioisotopes: If iodine isotopes are to be administered for the diagnosis of thyroid disease, it should be borne in mind that after the administration of iodinated contrast media which are excreted via the kidneys, the capacity of the thyroid tissue to take up iodine will be reduced for 2 weeks and sometimes up to 6 weeks.

4.6 Pregnancy And Lactation

X-ray examinations should, if possible, be avoided during pregnancy. It has not yet been proved beyond question that Ultravist may be used without hesitation in pregnant patients. Therefore, an examination with a contrast medium during pregnancy should be carried out only if considered absolutely necessary by the physician.

It is not known whether Ultravist enters the breast milk.

4.7 Effects On Ability To Drive And Use Machines

There is no known effect on the ability to drive or operate machines. However, because of the risk of reactions, driving or operating machinery is not advisable for one hour after the last injection (see Section 4.4).

4.8 Undesirable Effects

Undesirable effects in association with the use of iodinated contrast media are usually mild to moderate and transient in nature. However, severe and life-threatening reactions as well as deaths have been reported. Nausea, headache, a sensation of pain and a general feeling of warmth are the most frequently recorded reactions.

System organ class	Common (	Uncommon (	Rare (< 1/1,000)
Immunological		Anaphylactoid reactions / hypersensitivity	Anaphylactoid shock (including fatal cases)
Endocrine			Alteration in thyroid function, thyrotoxic crisis
Nervous, Psychiatric		Dizziness, restlessness	Paraesthesia / hypoaesthesia, confusion, anxiety, agitation, amnesia, speech disorders, somnolence, unconciousness, coma, tremor, convulsion, paresis / paralysis, cerebral ischaemia / infarction, stroke. Transient cortical blindnessa
Eye		Blurred / disturbed vision	Conjunctivitis, lacrimation.
Ear			Hearing disorders.
Cardiac		Arrhythmia	Palpitations, chest pain / tightness, bradycardia, tachycardia, cardiac arrest, heart failure, myocardial ischaemia/infarction, cyanosis.
Vascular		Vasodilatation	Hypotension, hypertension, shock. Vasospasm,a thromboembolic eventsa
Respiratory		Sneezing, coughing	Rhinitis, dyspnoea, mucosal swelling, asthma, hoarseness, laryngeal / pharyngeal / tongue / face oedema, bronchospasm, laryngeal/pharyngeal spasm, pulmonary oedema, respiratory insufficiency, respiratory arrest.
Gastrointestinal	Nausea	Vomiting, taste disturbance	Throat irritation , dysphagia, swelling of salivary glands, abdominal pain, diarrhoea
Skin and subcutaneous tissue		Urticaria, pruritus, rash, erythema	Angioedema, mucocutaneous syndrome (e.g. Stevens-Johnson's or Lyell's syndrome)
Renal and urinary		Renal impairmenta	Acute renal failurea
General disorders and administration site conditions	Heat or pain sensations, headache	Malaise, chills, sweating, vasovagal reactions	Pallor, body temperature alterations, oedema Local pain, mild warmth and oedema, inflammation and tissue injury in case of extravasation

^a intravascular use only

Frequency estimates are based on data obtained in pre-marketing studies in more than 3900 patients and post-marketing studies in more than 74000 patients, as well as data from spontaneous reporting and literature. (Frequency estimations are based predominantly on intravascular use.).

4.9 Overdose

Symptoms may include fluid and electrolyte imbalance, renal failure, cardiovascular and pulmonary complications.

Monitor fluids, electrolytes and renal function. Treatment of overdose should be directed towards the support of vital functions.

Ultravist is dialysable.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Ultravist (iopromide) is a non-ionic contrast medium for intravascular radiological examinations and has only minimal pharmacological activity within the body.

The rate of protein binding is low and iopromide is a weak liberator of histamine. Cardiovascular and renal tolerance are good.

Ultravist has low osmolality.

The physico-chemical characteristics of the Ultravist range are listed below:

Iodine concentration (mg/ml)	150	240	300	370
Osmolality (osm/kg H2O) at 37 °C	0.33	0.48	0.59	0.77
Viscosity (mPa·s) at 20 °C at 37 °C	2.3 1.5	4.9 2.8	8.9 4.7	22.0 10.0
Density (g/ml) at 20 °C at 37 °C	1.164 1.158	1.263 1.255	1.328 1.322	1.409 1.399

5.2 Pharmacokinetic Properties

Following intravascular administration, iopromide is very rapidly distributed in the extracellular space. Plasma protein binding with a concentration of 1.2mg I/ml plasma is 0.9±0.2%. 5 minutes after intravenous bolus injection (within 1-5 min) of Ultravist 300, 28 ±6% of the dose was found in the total plasma volume, irrespective of the size of the dose. The contrast medium is first of all rapidly distributed, the half-life being 3 minutes, while the elimination half-life in patients with normal kidney function is approximately 2 hours, irrespective of the size of the dose. Under the doses recommended for diagnostic purposes, filtration of iopromide is exclusively glomerular. Renal excretion is approximately 18% of the dose within 30 minutes, approximately 60% within 3 hours and 92% within 24 hours. No metabolites were demonstrable in man following administration of the clinically relevant doses of iopromide.

5.3 Preclinical Safety Data

There are no pre-clinical safety data which could be of relevance to the prescriber and which are not already included in other relevant sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium calcium edetate, trometamol,hydrochloric acid (diluted 10%), water for injection.

6.2 Incompatibilities

Some radiologists give an antihistamine or a corticosteroid prophylactically to patients with a history of allergy.

Because of possible precipitation, X-ray contrast media and prophylactic agents must not be injected as mixed solutions.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Store below 30°C. Protect from light and X-rays.

6.5 Nature And Contents Of Container

Colourless glass infusion bottles of 50, 75, 100 and 200 ml. Colourless glass ampoules of 30 ml. Packs of 10 x 50 or 75 ml bottles and 1 x 100 or 200ml bottles.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Contrast media should be visually inspected prior to use and must not be used, if discoloured, nor in the presence of particulate matter (including crystals) or defective containers. As Ultravist is a highly concentrated solution, crystallization (milky-cloudy appearance and/or sediment at the bottom, or floating crystals) may occur very rarely.

The contrast medium solution should not be drawn up into the syringe of the infusion bottle attached to the infusion set until immediately before the examination.

Vials containing contrast medium are not intended for the withdrawal of multiple doses. The rubber stopper should never be pierced more than once.

Contrast medium solution not used in one examination session must be discarded.

7. Marketing Authorisation Holder

Bayer plc

Bayer House

Strawberry Hill

Newbury

Berkshire RG14 1JA

United Kingdom

Trading as Bayer plc, Bayer Schering Pharma

8. Marketing Authorisation Number(S)

PL 00010/0567

9. Date Of First Authorisation/Renewal Of The Authorisation

1 May 2008

10. Date Of Revision Of The Text

25 September 2009

Unguentum M (Almirall Limited )

1. Name Of The Medicinal Product

Unguentum M

2. Qualitative And Quantitative Composition

There is no specific active ingredient.

3. Pharmaceutical Form

Cream

4. Clinical Particulars

4.1 Therapeutic Indications

Unguentum M has emollient properties and is recommended for the symptomatic treatment of dermatitis, nappy rash, ichthyosis, eczema, protection of raw and abraded skin areas, pruritus and related skin conditions where dry scaly skin is a problem, and as a pre-bathing emollient for dry/eczematous skin, to alleviate drying effects.

Unguentum M is to be used as a diluent for various topical corticosteriod formulations in those instances where a lower strength preparation is considered desirable by the physician and as a general base for extemporaneous dispensing.

4.2 Posology And Method Of Administration

A thin application of the cream should be gently massaged into the skin three times daily or at appropriate intervals.

When used as a protective cream Unguentum M should be applied sparingly to the affected areas of the skin before, or immediately after, exposure to a potentially harmful factor.

4.3 Contraindications

Unguentum M should not be used:

- if hypersensitivity to any of the ingredients is known.

- near the eyes and on mucous membranes.

4.4 Special Warnings And Precautions For Use

Sorbic acid and Cetostearyl alcohol may cause local skin reactions, (e.g. contact dermatitis)

Propylenglycol may cause skin reactions.

Ingestion of Unguentum M should be avoided.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None.

4.6 Pregnancy And Lactation

No evidence of any harmful effect on the use of Unguentum M in pregnancy and lactation.

4.7 Effects On Ability To Drive And Use Machines

None.

4.8 Undesirable Effects

Rarely (1 in 10 out of 10,000 persons treated) skin irritation such as burning sensations and reddening or allergic contact dermatitis may occur.

4.9 Overdose

None.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Unguentum M is an ambiphilic topical preparation with emollient properties which maintains the high lipid content of an ointment but also has the water miscible characteristics of a cream. The high lipid content reduces water loss from the skin and therefore has a hydrating effect which permits the recovery from dermatitis, eczema, and dry or scaly skin conditions. Unguentum M also contains sorbic acid which has an antibacterial effect.

5.2 Pharmacokinetic Properties

Unguentum M is for topical use only and contains no specific active ingredient. There are no phamacokinetic data for this product.

5.3 Preclinical Safety Data

--

6. Pharmaceutical Particulars

6.1 List Of Excipients

Purified water, white soft paraffin, cetostearyl alcohol, polysorbate 40, propylene glycol, glycerol monostearate 40 – 50, liquid paraffin, medium-chain triglycerides, sorbic acid, colloidal anhydrous silica, sodium hydroxide.

6.2 Incompatibilities

None.

6.3 Shelf Life

Aluminium tubes: 5 years

Plastic containers: 3 years

6.4 Special Precautions For Storage

None.

6.5 Nature And Contents Of Container

Aluminium tubes. Content: 10g, 15g, 30g, 50g, 60g, 80g and 100g.

Plastic jars. Content: 100g, 500g and 900g.

Plastic tubs. Content: 8kg, l0kg and 50kg.

Plastic bag in metal tins. Content: 5kg, l0kg and 25kg.

Plastic pump dispensers. Content: 75ml and 200ml.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Almirall Hermal GmbH

Scholtzstrasse 3

D-21465 Reinbek

Germany

8. Marketing Authorisation Number(S)

PL 33016/0014

9. Date Of First Authorisation/Renewal Of The Authorisation

12/09/2005

10. Date Of Revision Of The Text

19^th October 2010

Ucerax Tablets 25 mg

1. Name Of The Medicinal Product

Ucerax Tablets 25 mg.

2. Qualitative And Quantitative Composition

Hydroxyzine hydrochloride 25 mg.

For excipients, see 6.1.

3. Pharmaceutical Form

Film-coated tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

Ucerax is indicated to assist in the management of anxiety.

Ucerax is indicated to assist in the management of pruritus associated with acute and chronic urticaria, including cholinergic and physical types, and in atopic and contact dermatosis in adults and children.

4.2 Posology And Method Of Administration

Adults:

Anxiety.

50 mg/day in 3 separate administrations of 12.5-12.5-25mg. In more severe cases, doses up to 300mg/day can be used.

Pruritus.

Starting dose of 25 mg at night, increasing as necessary to 25 mg three or four times daily.

The maximum single dose in adults should not exceed 200mg whereas the maximum daily doses should not exceed 300mg.

Children:

Children aged from 12 months to 6 years: 1mg/kg/day up to 2.5mg/kg/day in divided doses.

Children aged over 6 years:1mg/kg/day up to 2mg/kg/day in divided doses.

The dosage should be adjusted according to the patient's response to therapy.

In the elderly, it is advised to start with half the recommended dose due to the prolonged action.

In patients with hepatic dysfunction, it is recommended to reduce the daily dose by 33%.

Dosage should be reduced in patients with moderate or severe renal impairment due to decreased excretion of its metabolite cetirizine.

4.3 Contraindications

Ucerax is contra-indicated in patients with a history of hypersensitivity to any of its constituents, to cetirizine, to other piperazine derivatives, to aminophylline, or to ethylenediamine.

Ucerax is contra-indicated during pregnancy and lactation.

Ucerax is contra-indicated in patients with porphyria.

Ucerax film-coated tablets 25 mg tablets contain lactose. Patients with rare hereditiary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose mal-absorption should not take this medicine.

4.4 Special Warnings And Precautions For Use

Ucerax should be administered cautiously in patients with increased potential for convulsions.

Young children are more susceptible to develop adverse events related to the central nervous system (see section 4.8). In children, convulsions have been more frequently reported than in adults.

Because of its potential anticholinergic effects, Ucerax should be used cautiously in patients suffering from glaucoma, bladder outflow obstruction, decreased gastro-intestinal motility, myasthenia gravis, or dementia.

Dosage adjustments may be required if Ucerax is used simultaneously with other central nervous system depressant drugs or with drugs having anticholinergic properties (see section 4.5).

The concomitant use of alcohol and Ucerax should be avoided (see section 4.5).

Caution is needed in patients who have a known predisposing factor to cardiac arrhythmia, or who are concomitantly treated with a potentially arrhythmogenic drug.

In patients with pre-existing prolonged QT intervals, use of alternative treatments is to be considered.

In the elderly, it is advised to start with half the recommended dose due to a prolonged action.

Ucerax dosage should be reduced in patients with hepatic dysfunction and in patients with moderate or severe renal impairment (see section 4.2).

The treatment should be stopped at least 5 days before allergy testing or methacholine bronchial challenge, to avoid effects on the test results.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Patients should be informed that Ucerax may potentiate the effects of barbiturates, other CNS depressants or drugs having anticholinergic properties.

Alcohol also potentiates the effects of Ucerax.

Ucerax antagonizes the effects of betahistine, and of anticholinesterase drugs.

The treatment should be stopped at least 5 days before allergy testing or methacholine bronchial challenge, to avoid effects on the test results.

Simultaneous administration of Ucerax with monoamine oxidase inhibitors should be avoided.

Ucerax counteracts the epinephrine pressor action.

In rats, hydroxyzine antagonised the anticonvulsant action of phenytoin.

Cimetidine 600 mg bid has been shown to increase the serum concentrations of hydroxyzine by 36% and to decrease peak concentrations of the metabolite cetirizine by 20%.

Ucerax is an inhibitor of cytochrome P450 2D6 (Ki: 3.9 µM ; 1.7 µg/ml) and may cause at high doses drug-drug interactions with CYP2D6 substrates.

Ucerax has no inhibitory effect at 100 µM on UDP-glucuronyl transferase isoforms 1A1 and 1A6 in human liver microsomes. It inhibits cytochrome P₄₅₀ 2C9/C10, 2C19 and 3A4 isoforms at concentrations (IC₅₀ : 19 to 140 µM ; 7 to 52 µg/ml) well above peak plasma concentrations. The metabolite cetirizine at 100 µM has no inhibitory effect on human liver cytochrome P₄₅₀ (1A2, 2A6, 2C9/C10, 2C19, 2D6, 2E1 and 3A4) and UDP-glucuronyl transferase isoforms. Therefore, Ucerax is unlikely to impair the metabolism of drugs which are substrates for these enzymes.

As hydroxyzine is metabolized in the liver, an increase in hydroxyzine blood concentrations may be expected when hydroxyzine is co-administered with other drugs known to be potent inhibitors of liver enzymes.

4.6 Pregnancy And Lactation

Animal studies have shown reproductive toxicity.

Hydroxyzine crosses the placental barrier leading to higher fetal than maternal concentrations.

To date, no relevant epidemiological data are available relating to exposure to Ucerax during pregnancy.

In neonates whose mothers received Ucerax during late pregnancy and/or labour, the following events were observed immediately or only a few hours after birth : hypotonia, movement disorders including extrapyramidal disorders, clonic movements, CNS depression, neonatal hypoxic conditions, or urinary retention.

Therefore, Ucerax should not be used during pregnancy.

Ucerax is contra-indicated during lactation. Breast-feeding should be stopped if Ucerax therapy is needed.

4.7 Effects On Ability To Drive And Use Machines

Alertness or reaction time may be impaired by Ucerax therefore patients' driving capacity or ability to use machines may be reduced. Concomitant use of Ucerax with alcohol or other sedative drugs should be avoided as it aggravates these effects.

4.8 Undesirable Effects

Undesirable effects are mainly related to CNS depressant or paradoxical CNS stimulation effects, to anticholinergic activity, or to hypersensitivity reactions.

A Clinical trials

The following table list the relevant undesirable effects reported in placebo-controlled clinical trials for hydroxyzine and including 735 subjects exposed to hydroxyzine up to 50 mg daily. The frequency has been estimated using the following definitions: very common (

System Organ Class	Adverse event preferred term	Frequency
Nervous system disorders	Somnolence	Very common
Headache	Common
Dizziness	Uncommon
Insomnia	Uncommon
Disturbance in attention	Uncommon
Gastrointestinal disorders	Dry mouth	Common
Constipation	Uncommon
Nausea	Uncommon
General disorders and administration site conditions	Fatigue	Common
Asthenia	Uncommon

B Post-marketing experience

The following table lists, per body system, the additional undesirable adverse reactions reported during marketed use of the drug. No frequency can be estimated from post-marketing reporting of events.

Immune system disorders :

Hypersensitivity, anaphylactic shock

Psychiatric disorders :

Agitation, confusion, disorientation, hallucination

Nervous system disorders :

Sedation, tremor, convulsions, dyskinesia

Eye disorders :

Accommodation disorder, vision blurred

Cardiac disorders :

Tachycardia

Vascular disorders :

Hypotension

Respiratory, thoracic and mediastinal disorders :

Bronchospasm

Gastrointestinal disorders :

Vomiting

Skin and subcutaneous tissue disorders :

Pruritus, erythematous rash, maculo-papular rash, urticaria, dermatitis, angioneurotic oedema, sweating increased, fixed drug eruption

Renal and urinary disorders :

Urinary retention

General disorders and administration site conditions :

Malaise, pyrexia

Investigations :

Liver function tests abnormal

4.9 Overdose

Symptoms observed after an important overdose are mainly associated with excessive anticholinergic load, CNS depression or CNS paradoxical stimulation. They include nausea, vomiting, tachycardia, pyrexia, somnolence, impaired pupillary reflex, tremor, confusion, or hallucination. This may be followed by depressed level of consciousness, respiratory depression, convulsions, hypotension, or cardiac arrhythmia. Deepening coma and cardiorespiratory collapse may ensue.

Airway, breathing and circulatory status must be closely monitored with continuous ECG recording and an adequate oxygen supply should be available. Cardiac and blood pressure monitoring should be maintained until the patient is free of symptoms for 24 hours. Patients with altered mental status should be checked for simultaneous intake of other drugs or alcohol and should be given oxygen, naloxone, glucose, and thiamine if deemed necessary.

Norepinephrine or metaraminol should be used if vasopressor is needed. Epinephrine should not be used.

Syrup of ipecac should not be administered in symptomatic patients or those who could rapidly become obtunded, comatose or convulsing, as this could lead to aspiration pneumonitis. Gastric lavage with prior endotracheal intubation may be performed if a clinically significant ingestion has occurred. Activated charcoal may be left in the stomach but there are scant data to support its efficacy.

It is doubtful that hemodialysis or hemoperfusion would be of any value.

There is no specific antidote.

Literature data indicate that, in the presence of severe, life-threatening, intractable anticholinergic effects unresponsive to other agents, a therapeutic trial dose of physostigmine may be useful. Physostigmine should not be used just to keep the patient awake. If cyclic antidepressants have been coingested, use of physostigmine may precipitate seizures and intractable cardiac arrest. Also avoid physostigmine in patients with cardiac conduction defects.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Hydroxyzine is a psycholeptic and anxiolytic agent (ataractic).

ATC code is N05B B01

The active substance, hydroxyzine dihydrochloride, is a diphnylmethane derivative, chemically unrelated to the phenothiazines, reserpine, meprobamate or benzodiazepines.

Mechanism of action

Hydroxyzine is a first generation antihistamine that crosses extensively the blood/brain barrier and has a high affinity for histaminic receptors into the brain, thereby producing sedative-anxiolytic effects.

Pharmacodynamic effects

Antihistaminic and bronchodilatator activities have been demonstrated experimentally and confirmed clinically. An antiemetic effect, both by the apomorphine test and the veriloid test, has been demonstrated. Pharmacological and clinical studies indicate that hydroxyzine at therapeutic dosage does not increase gastric secretion or acidity and in most cases has mild antisecretory activity. Wheal and flare reduction have been demonstrated in adult healthy volunteers and in children after intradermal injections of histamine or antigens. Hydroxyzine has also revealed its efficacy in relieving pruritus in various forms of urticaria, eczema and dermatitis.

Hydroxyzine was studied in eight patients with primary biliary cirrhosis. All had abnormal liver biochemistry tests, all had biopsies compatible with primary cirrhosis, and seven of eight had positive tests for antimitochodrial antibodies. The patients received a single dose of hydroxyzine (0.7mg/kg – mean does 43.9 ± 6.6 mg).

In these subjects with hepatic dysfunction secondary to primary cirrhosis, total body clearance was approximately 66% that of normal subjects (8.65 ± 7.46 ml/min/kg versus 10 ml/min/kg for normal subjects). The half-life was increased to 37 hours and the serum concentrations of the carboxylic metabolite, cetirizine (500.4 ± 302.0 mg/ml), were higher than in young patients with a normal liver function. As hydroxyzine elimination is impaired in patients with hepatic dysfunction, daily dose or dose frequency should be reduced in patients with impaired liver function.

EEG recordings in healthy volunteers show an anxiolytic-sedative profile. Anxiolytic effect was confirmed in patients by the use of various classical psychometric tests. Polysomnographic recordings in anxious and insomniac patients have evidenced an increase in total sleep time, a reduction of total time of night awakenings and a reduction of sleep latency either after single or repeated daily doses of 50 mg. A reduction of the muscular tension was demonstrated in anxious patients at a daily dose of 3 x 50 mg. No memory deficiency has been observed. No withdrawal signs or symptoms have appeared after 4-week treatment in anxious patients.

Onset of action

The antihistaminic effect begins approximately after 1 hour with oral pharmaceutical forms. The sedative effect starts after 5-10 minutes with oral liquid and after 30-45 minutes with tablets.

Hydroxyzine has a weak affinity for muscarinic receptors.

5.2 Pharmacokinetic Properties

Absorption

Hydroxyzine is rapidly absorbed from the gastro-intestinal tract. The peak plasma level (C_max) is reached approximately two hours after oral intake. After single oral doses of 25 mg and 50 mg in adults, C_max concentrations are typically 30 and 70 ng/ml, respectively. The rate and extent of exposure to hydroxyzine is very similar when given as tablet or as a syrup. Following repeat administration once a day, concentrations are increased by 30%. The oral bioavailability of hydroxyzine with respect to intramuscular (IM) administration is about 80%. After a single 50 mg IM dose, C_max concentrations are typically 65 ng/ml.

Distribution

Hydroxyzine is widely distributed in the body and generally more concentrated in the tissues than in plasma. The apparent volume of distribution is 7 to 16 l/kg in adults. Hydroxyzine enters the skin following oral administration. Skin concentrations of hydroxyzine are higher than serum concentrations, following both single and multiple administration. Hydroxyzine crosses the blood-brain and placental barriers leading to higher fetal than maternal concentrations.

Biotransformation

Hydroxyzine is extensively metabolized. The formation of the major metabolite cetirizine, a carboxylic acid metabolite (approximately 45% of the oral dose), is mediated by alcohol dehydrogenase. This metabolite has significant peripheral H1-antagonist properties. An elimination half-life for cetirizine of about 20 hours has been reported. The other metabolites identified include a N-dealkylated metabolite, and an O-dealkylated metabolite with a plasma half-life of 59 hours. These pathways are mediated principally by CYP3A4/5.

Elimination

Across studies, the half life (t½) of hydroxyzine in adults is 12 ± 5 hrs (range 7 – 20 hrs). Across studies the apparent plasma clearance (CL/F) of hydroxyzine is 14 ± 4 ml/min/kg (range 9.4-17.5 ml/min/kg).

The apparent total body clearance calculated across studies is 13 ml/min/kg. Only 0.8% of the dose is excreted unchanged in urine. The major metabolite cetirizine is excreted mainly unchanged in urine (25% and 16 % of the hydroxyzine oral and IM dose, respectively).

After a single dose of 50 mg hydroxyzine, the C_max of cetirizine (261 ng/ml) was comparable to that after a single dose of 10 mg cetirizine (282 ng/ml) but the AUC was similar to that after a single dose of 20 mg cetirizine.

Special population

Elderly patients

The pharmacokinetics of hydroxyzine was investigated in 9 healthy elderly subjects (69.5 ± 3.7 years) following a single 0.7 mg/kg oral dose. The elimination half-life of hydroxyzine was prolonged to 29± 10 hrs (range 20-53 hrs) and the apparent volume of distribution was increased to 22 ± 6 l/kg (range 13 -31 l/kg). In view of the longer t½ and of the prolonged Pharmacodynamic effect (suppression of the wheal and flare response to histamine), it is advised to start with half the recommended dose (see section 4.2).

Paediatric patients

The pharmacokinetics of hydroxyzine was evaluated in 12 paediatric patients aged 1 to 14 years (mean 6.1 ± 4.6 yrs) with severe atopic dermatitis. A 0.7 mg/kg single dose of hydroxyzine was administered orally. The mean peak serum concentration was 47 ± 17 ng/ml and occurred at a mean time of 2.0 ± 0.9h after the dose. The mean plasma clearance was higher than in adults (32 ± 11 ml/min/kg). The half-life was shorter than in adults and increased with age from 4 hrs at 1 year of age to 11 hrs at 14 years of age. No data was available regarding the metabolite cetirizine.

Like in adults, the antipruritic effect lasted longer than anticipated for the half-life as pruritus was significantly suppressed from 1 to 24 hrs post-dose with>85% suppression from 2 to 12 hrs.

Dosage should be adjusted in paediatric population (see section 4.2).

Hepatic impairment

Hydroxyzine was studied in eight patients with primary biliary cirrhosis. All had abnormal liver biochemistry tests, all had biopsies compatible with primary cirrhosis, and seven of eight had positive tests for antimitochodrial antibodies. The patients received a single dose of hydroxyzine (0.7mg/kg – mean does 43.9 ± 6.6 mg).

In these subjects with hepatic dysfunction secondary to primary cirrhosis, total body clearance was approximately 66% that of normal subjects (8.65 ± 7.46 ml/min/kg versus 10 ml/min/kg for normal subjects). The half-life was increased to 37 hours and the serum concentrations of the carboxylic metabolite, cetirizine (500.4 ± 302.0 mg/ml), were higher than in young patients with a normal liver function. As hydroxyzine elimination is impaired in patients with hepatic dysfunction, daily dose or dose frequency should be reduced in patients with impaired liver function (see section 4.2).

Renal impairment

The pharmacokinetics of hydroxyzine was studied in 8 severe renally impaired subjects (Creatinine clearance: 24 ± 7 ml/min). The extent of exposure (AUC) to hydroxyzine was not altered in a relevant manner while that to the carboxylic metabolite, cetirizine, was increased. This metabolite is not removed efficiently by hemodialysis. In order to avoid any important accumulation of the cetirizine metabolite following multiple doses of hydroxyzine, the daily dose of hydroxyzine should be reduced in subjects with impaired renal function (see section 4.2).

5.3 Preclinical Safety Data

There is no pre-clinical data of relevance to the subscriber additional to that noted in other sections of this SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose monohydrate.

Microcrystalline cellulose

Magnesium stearate

Anhydrous colloidal silica

Purified water

Opadry® Y-1-7000 containing:

Titanium dioxide

Hydroxypropylmethylcellulose 2910 5cP

Macrogol 400.

6.2 Incompatibilities

None.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

Keep container in the outer pack.

6.5 Nature And Contents Of Container

Aluminium foil / PVC blister packs containing 25, 30, 50 or 60 tablets.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

UCB Pharma Limited

208 Bath Road

Slough

Berkshire

SL1 3WE

8. Marketing Authorisation Number(S)

PL 00039/0538

9. Date Of First Authorisation/Renewal Of The Authorisation

16 August 2001

10. Date Of Revision Of The Text

August 2010