Mitoxantrone (Mitozantrone) 2 mg / ml Sterile Concentrate

1. Name Of The Medicinal Product

Mitoxantrone 2 mg/ml Concentrate for Solution for Infusion

2. Qualitative And Quantitative Composition

Each millilitre of concentrate contains 2 mg mitoxantrone (as hydrochloride). Each 10 ml vial contains 20 mg mitoxantrone (as hydrochloride).

This medicinal product contains 1.4 mmol sodium per 10 ml vial.

For full list of excipients, see section 6.1

3. Pharmaceutical Form

Concentrate for Solution for Infusion.

Clear, dark-blue aqueous solution with a pH of 3.0-4.5

4. Clinical Particulars

4.1 Therapeutic Indications

Mitoxantrone is indicated in the treatment of metastatic breast cancer, non-Hodgkin's lymphoma and adult acute non-lymphocytic leukaemia.

Mitoxantrone has also been used in the palliation of non-resectable primary hepatocellular carcinoma.

4.2 Posology And Method Of Administration

Posology

Metastatic breast cancer, Non-Hodgkin's lymphoma, Hepatoma:

Single Agent Dosage: The recommended initial dosage of mitoxantrone as a single agent is 14 mg/m² of body surface area, given as a single intravenous dose which may be repeated at 21-day intervals. A lower initial dosage (12 mg/m² or less) is recommended for patients with inadequate bone marrow reserves e.g. due to prior chemotherapy or poor general condition.

Dosage modification and the timing of subsequent doses should be determined by clinical judgement depending on the degree and duration of myelosuppression. For subsequent courses the prior dose can usually be repeated if white blood cell and platelet counts have returned to normal levels after 21 days. The following table is suggested as a guide to dosage adjustment in the treatment of metastatic breast cancer, non-Hodgkin's lymphoma and hepatoma according to haematological nadir (which usually occurs about 10 days after dosing).

Nadir after prior dose
WBC (per mm3 )		Platelets (per mm3 )	Time to recovery	Subsequent dose after adequate haematological recovery
>1,500	AND	>50,000		Repeat prior dose after recovery, or increase by 2 mg/m2 if myelosuppression is not considered adequate
>1,500	AND	>50,000	>21 days	Withhold until recovery then repeat prior dose
<1,500	OR	<50,000	Any duration	Decrease by 2 mg/m2 from prior dose after recovery
<1,000	OR	<25,000	Any duration	Decrease by 4 mg/m2 from prior dose after recovery

Combination Therapy: Mitoxantrone has been given as part of combination therapy. In metastatic breast cancer, combinations of mitoxantrone with other cytotoxic agents including cyclophosphamide and 5-fluorouracil, or methotrexate and mitomycin C, have been shown to be effective. Reference should be made to the published literature for information on dosage modifications and administration. Mitoxantrone has also been used in various combinations for non-Hodgkin's lymphoma, however data are presently limited and specific regimens cannot be recommended.

As a guide, when mitoxantrone is used in combination chemotherapy with another myelosuppressive agent, the initial dose of mitoxantrone should be reduced by 2-4 mg/m² below the doses recommended for single agent use. Subsequent doses, as outlined in the table above, depend on the degree and duration of myelosuppression.

Adult acute non-lymphocytic leukaemia:

Single Agent Dosage in Relapse: The recommended dosage for remission induction is 12 mg/m² of body surface area, given as a single intravenous dose daily for five consecutive days (total of 60 mg/m²). In clinical studies with a dosage of 12 mg/m² daily for 5 days, patients who achieved a complete remission did so as a result of the first induction course.

Combination Therapy: Mitoxantrone has been used in combination regimens for the treatment of acute non-lymphocytic leukaemia (ANLL). Most clinical experience has been with mitoxantrone combined with cytarabine. This combination has been used successfully for primary treatment of ANLL as well as in the treatment of relapse.

An effective regimen for induction in previously untreated patients has been mitoxantrone 10-12 mg/m² IV for 3 days combined with cytarabine 100 mg/m² IV for 7 days (by continuous infusion). This is followed by second induction and consolidation courses as thought appropriate by the treating clinician. In clinical studies, duration of therapy in induction and consolidation courses with mitoxantrone have been reduced to 2 days, and that of cytarabine to 5 days. However, modification to the above regimen should be carried out by the treating clinician depending on individual patient factors.

Efficacy has also been demonstrated with mitoxantrone in combination with etoposide in patients who had relapsed or who were refractory to primary conventional chemotherapy. The use of mitoxantrone in combination with etoposide, as with other cytotoxics, may result in greater myelosuppression than with mitoxantrone alone.

Reference should be made to the published literature for information on specific dosage regimens. Mitoxantrone should be used by clinicians experienced in the use of chemotherapy regimens. Dosage adjustments should be made by the treating clinician as appropriate, taking into account toxicity, response and individual patient characteristics. As with other cytotoxic drugs, mitoxantrone should be used with caution in combination therapy until wider experience is available.

Paediatrics: The safety and efficacy of mitoxantrone in paediatric patients have not been established.

Method of administration

FOR INTRAVENOUS USE ONLY.

Mitoxantrone should be given by intravenous infusion.

Syringes containing this product should be labelled 'MITOXANTRONE, FOR INTRAVENOUS USE ONLY.

Care should be taken to avoid contact of mitoxantrone with skin, mucous membranes or eyes; see section 6.6 Instructions for use and handling for further directions.

Dilute the required volume of Mitoxantrone Sterile Concentrate to at least 50 ml in either of the following infusion solutions: sodium chloride 0.9%, glucose 5%, or sodium chloride 0.18% and glucose 4%. Use Leur-lock fittings on all syringes and sets. Large bore needles are recommended to minimise pressure and the possible formation of aerosols. The latter may also be reduced by the use of a venting needle.

Administer the resulting solution over not less than 3 minutes via the tubing of a freely running intravenous infusion of the above fluids. Mitoxantrone should not be mixed with other drugs in the same infusion.

If extravasation occurs the administration should be stopped immediately and restarted in another vein. The non-vesicant properties of mitoxantrone minimise the risk of severe local reaction following extravasation.

4.3 Contraindications

FOR INTRAVENOUS USE ONLY.

Mitoxantrone Sterile Concentrate is contraindicated in patients who have demonstrated prior hypersensitivity to mitoxantrone hydrochloride, other anthracylines or any of its components. Use in patients with profound bone marrow suppression is a relative contraindication depending on the clinical circumstances.

Mitoxantrone Sterile Concentrate should not be used during pregnancy or lactation.

4.4 Special Warnings And Precautions For Use

Special warnings

There may be an increased risk of leukaemia when mitoxantrone is used as adjuvant treatment of non-metastatic breast cancer. In the absence of sufficient efficacy data, mitoxantrone must not be used as adjuvant treatment of non-metastatic breast cancer.

Mitoxantrone should be used with caution in patients with myelosuppression or poor general condition.

Cases of functional cardiac changes, including congestive heart failure and decreases in left ventricular ejection fraction have been reported during mitoxantrone therapy (see 4.8 Undesirable effects). These cardiac events have occurred most commonly in patients who have had prior treatment with anthracyclines, prior mediastinal/thoracic radiotherapy, or in patients with pre-existing heart disease. The concomitant administration of other cardiotoxic drugs may also increase the risk of cardiac toxicity. It is recommended that patients in these categories are treated with mitoxantrone at full cytotoxic dosage and schedule. However, added caution is required in these patients and careful regular cardiac examinations are recommended from the initiation of treatment.

Cardiac monitoring should also be performed in patients without identifiable risk factors during therapy exceeding 160 mg/m² of mitoxantrone, or during extended treatment.

Careful supervision is recommended when treating patients with hepatic insufficiency.

Topoisomerase II inhibitors, including mitoxantrone hydrochloride, when used concomitantly with other antineoplastic agents (particularly anthracyclines) and/or radiotherapy, have been associated with the development of Acute Myeloid Leukaemia (AML) or Myelodysplastic Syndrome (MDS). Treatment with mitoxantrone alone has also been associated with an increased risk of development of secondary acute myeloid leukaemia (see 4.8 Undesirable effects).

Sulphites can cause allergic-type reactions including anaphylactic symptoms and bronchospasm in susceptible people, especially those with a history of asthma or allergy.

Immunisation may be ineffective when given during mitoxantrone therapy. Immunisation with live virus vaccines are generally not recommended.

There is no experience with the administration of Mitoxantrone Sterile Concentrate other than by the intravenous route. Safety for intrathecal use has not been established.

Precautions for use

Mitoxantrone is an active cytotoxic drug which should be used by clinicians who are familiar with the use of antineoplastic agents and have the facilities for regular monitoring of clinical, haematological and biochemical parameters during and after treatment.

Full blood counts should be undertaken serially during a course of treatment. Dosage adjustments may be necessary based on these counts (see Dosage section).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Animal data suggest that if used in combination with other antineoplastic agents, additive myelosuppression may be expected. This has been supported by available clinical data on combination regimens. When used in combination regimens, the initial dose of Mitoxantrone Sterile Concentrate should be reduced by 2-4 mg/m² below the dose recommended for single agent usage. (see Posology and method of administration).

Combining mitoxantrone with potentially cardiotoxic drugs (anthracyclines) increases the risk of cardiac toxicity. The product must be used with caution in combination with immunosuppressive chemotherapy.

4.6 Pregnancy And Lactation

There are no adequate and well-controlled studies in pregnant women. Mitoxantrone should not normally be administered to patients who are pregnant. If the drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be advised of the potential hazard to the fetus. Women of childbearing potential and their partners should be advised to avoid becoming pregnant and use effective contraception during therapy and for at least six months after cessation of therapy.

Mitoxantrone is excreted in human milk and significant concentrations (18 ng/ml) have been reported for 28 days after the last administration. Because of the potential for serious adverse reactions in infants from mitoxantrone, breast-feeding should be discontinued before starting treatment.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

Serious or Life Threatening Reactions:

Blood and lymphatic system disorders: Some degree of leucopenia is to be expected following recommended doses of mitoxantrone. With the single dose every 21 days, suppression of WBC count below 1000/mm³ is infrequent. Leucopenia is usually transient reaching its nadir at about 10 days after dosing with recovery usually occurring by the 21^st day. Thrombocytopenia and anaemia occur less frequently. Myelosuppression may be more severe and prolonged in patients who have had extensive prior chemotherapy or radiotherapy or in debilitated patients.

When mitoxantrone is used as a single injection given every 21 days in the treatment of metastatic breast cancer and lymphomas, the most commonly encountered side effects are nausea and vomiting, although in the majority of cases these are mild and transient. Alopecia may occur, but is most frequently of minimal severity and reversible on cessation of therapy.

Cardiac disorders: Congestive heart failure may occur during therapy with mitoxantrone, or months to years after the end of treatment (see 4.4 Special Warnings and Special Precautions for Use). Some cases have been fatal. Treatment with digoxin and/or diuretics has been reported to be effective.

Other cardiovascular effects, which have been of clinical significance include decreased left ventricular ejection fraction, ECG changes and acute arrhythmia.

In patients with leukaemia an increase in the frequency of adverse cardiac events has been observed. The direct role of mitoxantrone in these cases is difficult to assess, since some patients had received prior therapy with anthracyclines and since the clinical course in leukaemic patients is frequently complicated by anaemia, fever, sepsis and intravenous fluid therapy. Cardiomyopathy has been reported in rare instances.

Other Undesirable Effects:

Hepato-biliary disorders: Mitoxantrone Sterile Concentrate may impart a blue-green colouration to the urine for 24 hours after administration, and patients should be advised to expect this during active therapy. Increased liver enzyme levels (with occasional reports of severe impairment of hepatic function in patients with leukaemia). Hyperuricaemia has also been reported. Elevated serum creatinine and blood urea nitrogen levels have been reported.

Skin and subcutaneous tissue disorders: Rash, onycholysis, blue discolouration of skin and nails and nail dystrophy has been reported occasionally.

Eye Disorders: Reversible blue colouration of the sclerae has been reported. Conjunctivitis.

Respiratory disorders: Dyspnoea.

Gastrointestinal Disorders: Diarrhoea, anorexia, constipation, gastrointestinal bleeding, abdominal pain, stomatitis, mucositis, altered taste.

Neoplasms: Secondary acute myeloid leukaemia (see 4.4 Special Warnings and Special Precautions for Use)

General disorders and administration site conditions: Allergic reaction, amenorrhoea, fever, fatigue and weakness, non-specific neurological side effects such as somnolence, confusion, anxiety and mild paraesthesia have been reported. Tumour lysis syndrome (characterised by hyperuricaemia, hyperkalaemia, hyperphosphataemia and hypocalcaemia) has been observed rarely during single-agent chemotherapy with mitoxantrone, as well as during combination chemotherapy.

In patients with leukaemia, the pattern of side-effects is generally similar, although there is an increase in both frequency and severity, particularly of stomatitis and mucositis. Nevertheless, overall, patients with leukaemia tolerate treatment with mitoxantrone well.

Extravasation at the infusion site has been reported, which may result in erythema, swelling, pain, burning and/or blue discolouration of the skin. Extravasation can result in tissue necrosis with resultant need for debridement and skin grafting. Phlebitis has also been reported at the site of infusion.

4.9 Overdose

There is no known specific antidote for Mitoxantrone Sterile Concentrate. Haemopoietic, gastrointestinal, hepatic or renal toxicity may be seen, depending on the dosage given and the physical condition of the patient. In cases of overdosage patients should be monitored closely and management should be symptomatic and supportive.

Fatalities have occurred on rare occasions as a result of severe leucopenia with infection in patients accidentally given single bolus injections of mitoxantrone at over ten times the recommended dosage. Mitoxantrone Sterile Concentrate is extensively tissue-bound and peritoneal dialysis or haemodialysis is unlikely to be effective in managing overdose.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC Code: L01D B07

Although its mechanism of action has not been determined, mitoxantrone is a DNA-reactive agent. It has a cytocidal effect on proliferating and non-proliferating cultured human cells, suggesting activity against rapidly proliferating and slow-growing neoplasms.

5.2 Pharmacokinetic Properties

Pharmacokinetic studies in patients following intravenous administration of mitoxantrone demonstrated a triphasic plasma clearance. Distribution to tissues is rapid and extensive. Elimination of the drug is slow with a mean half-life of 12 days (range 5-18) and persistent tissue concentrations. Similar estimates of half-life were obtained from patients receiving a single dose of mitoxantrone every 21 days and patients dosed on 5 consecutive days every 21 days.

Mitoxantrone is excreted via the renal and hepatobiliary systems. Only 20-32% of the administered dose was excreted within the first five days after dosing (urine 6-11%, faeces 13-25%). Of the material recovered in the urine 65% was unchanged mitoxantrone and the remaining 35% is primarily comprised of two inactive metabolites and their glucuronide conjugates. Approximately two thirds of the excretion occurred during the first day.

5.3 Preclinical Safety Data

Animal pharmacokinetic studies in rats, dogs and monkeys given radiolabelled mitoxantrone indicate rapid, extensive dose proportional distribution into most tissues.

Mitoxantrone does not cross the blood-brain barrier to any appreciable extent. Distribution into testes is relatively low. In pregnant rats the placenta is an effective barrier.

Plasma concentrations decrease rapidly during the first two hours and slowly thereafter. Animal data established biliary excretion as the major route of elimination. In rats, tissue elimination half-life of radioactivity ranged from 20 days to 25 days as compared with plasma half-life of 12 days. Mitoxantrone is not absorbed significantly in animals following oral administration.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Glacial acetic acid

Sodium acetate trihydrate

Sodium chloride

Sodium metabisulphite (E223)

Water for Injections

6.2 Incompatibilities

Mitoxantrone Sterile Concentrate must not be mixed in the same infusion as heparin since a precipitate may form.

It is recommended that Mitoxantrone Sterile Concentrate not be mixed in the same infusion with other drugs, as specific compatibility data are not available.

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Do not store above 25°C. Do not refrigerate or freeze.

Mitoxantrone Sterile Concentrate does not contain an antimicrobial preservative.

Chemical and physical stability of the diluted product has been demonstrated for 72 hours when stored at room temperature.

From a microbiological point of view, the diluted product should be used immediately. 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 to 8^oC, unless dilution has taken place in controlled and validated aseptic conditions.

6.5 Nature And Contents Of Container

20 mg/10 ml in a clear Type I glass vial (with or without Onco-Tain™ shrink wrapping) with rubber closure, presented in packs of single vials.

6.6 Special Precautions For Disposal And Other Handling

Single use only. Discard any unused contents. Any unused product or waste materials should be disposed of in accordance with local requirements.

Mitoxantrone, in common with other potentially hazardous cytotoxic drugs, should only be handled by adequately trained personnel. Pregnant staff should not be involved in the reconstitution or administration of mitoxantrone.

Care should be taken to avoid contact of mitoxantrone with the skin, mucous membranes, or eyes. The use of goggles, gloves and protective gowns is recommended during preparation, administration and disposal and the work surface should be covered with disposable plastic-backed absorbent paper.

Aerosol generation should be minimised. Mitoxantrone can cause staining. Skin accidentally exposed to mitoxantrone should be rinsed copiously with warm water and if the eyes are involved standard irrigation techniques should be used.

For instruction on dilution of Mitoxantrone Sterile Concentrate see Section 4.2 above.

Spillage disposal: The following clean-up procedure is recommended if Mitoxantrone Sterile Concentrate is spilled on equipment or environmental surfaces. Prepare a 50% solution of fresh concentrated bleach (any recognised proprietary brand containing either sodium or calcium hypochlorite) in water. Wet absorbent tissues in the bleach solution and apply the wetted tissues to the spillage. The spillage is deactivated when the blue colour has been fully discharged. Collect up the tissues with dry tissues. Wash the area with water and soak up the water with dry tissues. Appropriate protective equipment should be worn during the clean-up procedure. All mitoxantrone contaminated items (e.g. syringes, needles, tissues etc.) should be treated as toxic waste and disposed of accordingly. Incineration is recommended.

7. Marketing Authorisation Holder

Hospira UK Limited

Queensway

Royal Leamington Spa

Warwickshire CV31 3RW

United Kingdom

8. Marketing Authorisation Number(S)

PL 04515/0127

9. Date Of First Authorisation/Renewal Of The Authorisation

19^th September 2006

10. Date Of Revision Of The Text

26^th November 2007

topical emollients

Generic Name: topical emollients (TOP i kal ee MOL i ents)

Brand names: Aloe Vesta Cream, AlphaSoft, AmeriPhor, Aqua Glycolic, Aqua Lube, Aquaphor, Aveeno, Baby Lotion, Baby Oil, Bag Balm, Baza-Pro, Beta Care, Blistex Lip Balm, Carmex, CarraKlenz, CeraVe, CeraVe AM, Cetaphil Lotion, Chap Stick, Citraderm, CoolBottoms, Corn Huskers Lotion, Curel Moisture Lotion, Derma Soothe, Dr Scholl's Essentials Cracked Skin Repair, Eucerin, Herpecin-L, K-Y Jelly, Keri Lotion, Lamisilk Heel Balm, Lubri-Soft, Lubriderm, Mederma, Moisturel, Natural Ice, NeutrapHor, NeutrapHorus Rex, Neutrogena Cleansing, Neutrogena Lotion, Nivea, Nutraderm, Pacquin, Phisoderm, Pretty Feet & Hands, Proshield Skincare Kit, Remedy 4-in-1 Cleansing Lotion, Replens, Secura, Sensi-Care, Soft Sense, St. Ives, Theraplex Lotion, Vaseline Intensive Care, ...show all 401 brand names.Masse, Mammol, Formula 405 Lotion, Formula 405 Cream, Purpose Soap, Sayman Soap, Neutrogena Soap, Cetaphil Bar, Acne-Aid, Lowila, Complex-15, AcidMantle, DML Forte, DML Facial, Formula 405 Soap, Lubriderm Lotion, DML Moisture Lotion, Neutrogena Cream, Cetaphil Cream, Aquanil Lotion, Balneol, Ionax, Seba-Nil, Wibi Lotion, Kerodex-51, Kerodex-71, Tritles Lotion, Aquaderm, Dermasil Lotion, Vaseline Dermatology Formula, Uni Derm, Lubricating Lotion, Mother's Friend, Thames Lotion, Hydrocerin, Shepards, Therapeutic Bath, Oilatum Soap, Pen-Kera, Polysorb, Purpose Cream, Purpose Lotion, Hydrocream, Dermabase, Formula Finger Skin Cream, Panthoderm Cream, Ultra Derm, Unibase Ointment, Hydrophil Ointment, Absorbase, Hydrophor, Neutrogena Rainbath, Sarna Lotion, Thera Derm Bath, Sardo Bath, Petro-phylic Soap, Surgilube, Velvachol, Cetaklenz, Neutrogena Acne Formula, Neutrogena Cleansing Wash, Polybase, Hydrisinol, Sween Cream, Diab, Hydropel, Fattibase Ointment, Iamin Hydrating Gel, Aloe Vesta Protein Ointment, Cetaphil Cleanser, Aqua Lube Plus, Sproam Body Cleanser, Sea-Clens, Puri-Clens, Glycerin with Rose Water, Ocusoft, Phacid, Baby Soap, Lubricating Jelly, Natural Care Gel, CarraKlenz Wound Cleanser, Carrington, Green Soap, Peri-Wash, Sween Prep, SFC, Lantiseptic, Dermagran, Elta, Skin Care, Vanicream, Vanicream Lite, Robathol, Aquaphilic, Lubrex, Maxilube, Nu Soap, Moisturin, Hydrated Petrolatum, Constant Care Vaseline, Cam, Aqua Lacten, Cutemol, Carrington Foot and Body, Carrington Skin Balm, Elta Seal Skin Protectant, Ointment Base, Cream Base, Betamide, Lanaphilic, Nutraderm-30, Ostiderm, Dermalab Skin Cream, Dermalab Soap, Curel Ultra Pro, Epilyt, Phisoderm for Baby, Aloe Vesta 2 -n- 1, Oilatum-AD, Baza-Protect, RadiaCare, SBR-Lipocream, Carlesta, Clinac O.C., Aquaphor Healing, Lubri-Gel, Neoteric Diabetic, Theraplex Hydro Lotion, Neutrogena Toner, Elta Lite, Diabet-X Daily Prevention Therapy, Biafine RE, Diab Gel, Theraplex Clear, Dermalab Cleansing Bar, Dermalab Skin Cleanser, Dermalab Lotion, Dermalab Conditioning Shampoo, Secura EPC, Secura Protective, Nouriva Repair, Impruv, Moisturel Sensitive Skin, Secura Personal Cleanser, Dermal Therapy, Pretty Feet & Hands, Dermalube, Peri-Care, Chap Stick Tube, Lansinoh for Breast Feeding Mothers(obsolete), Lansinoh for Healthy Feet(obsolete), Atopiclair, CeraVe Hydrating Cleanser, MimyX, Elon Herbal Foot Cream, Elon Barrier Protectant, Biafine, Leader Finger Cream, DermaDaily, DermaCerin, DermaPhor, Proshield Foam & Spray Cleanser, Proshield Plus, Humatrix Microclysmic Treatment, Care-Creme, Loving Lotion, Skin Magic, Techni-Care, Loving Lather II, Concept, CC-500, Barri-Care, Satin Therapeutic, Ca-Rezz, Dermarest Rosacea, A-Mantle, Albolene Moisturizing Cleanser, Aquabase, Sensi-Care Perineal/Skin Cleanser, Aloe Vesta Body Wash & Shampoo, Aloe Vesta Perineal/Skin Cleanser, Aloe Vesta Skin Conditioner, Septi-Soft Concentrate, Vaseline Lip Therapy, Cherry, Vaseline Lip Therapy, Chap Stick, Cherry, Chap Stick Lip Moisturizer, Esoterica Dry Skin, Special Care, Baza Cleanse & Protect, Special Care Moisture Barrier, Mederma for Kids, Kinerase, Aloe Vesta Cleansing Foam, Amerigel Care, Durable Barr, Keri Original Therapy, Keri Advanced Therapy, Bedside-Care Perineal Wash, Eucerin Unscented, Avosil Scar Care, K-Y Warming, K-Y Sensual Mist, TheraSeal Hand Protection, Aqua Glycolic Facial Cleanser, Aqua Glycolic Toner, K-Y Silk-E Vaginal Moisturizer, OCEAN Ultra Moisturizing, Phisoderm Cleansing Bar, Phisoderm Deep Cleaning Cream Cleanser, Eucerin Gentle Hydrating Cleanser, basis sensitive skin bar, basis vitamin bar, Aveeno Daily Moisturizing, Eletone, Dermadrox, Aquaphor Healing for Baby, Thera-P, Spectro Jel Skin Cleanser, RepHresh, Lubriderm Daily Moisturizer, Cavilon Durable Barrier, Restore Skin Conditioning Creme, Restore Cleanser & Moisturizer, Secura Two Step Kit, Cavilon Foot Emollient, Cavilon Emollient, Secura Dimethicone Protectant, Secura Extra Protective, Secura Mosturizing, Normlshield, Medicine Shoppe Natural Cold Sore Cream, Resurfix, Carrington Moisture Guard, Blistex Lip Revitalizer, Proshield Plus Skin Protectant, Amerigel Barrier, Orabase Soothe-N-Seal, Orabase Paste Plain, Pacquin Plus, Triple Cream, BurnZone, DepthZone, ChafeZone, Sayman Salve, Aqua Glycolic Shampoo and Body Cleanser, Vagisil Intimate Lubricant, Moisture Magic, Chap Stick All Natural, Dermagran GP, Ceta-Klenz, Restore Hydrogel, Aveeno Moisturizing Bar, Restore Moisture Barrier, Eucerin Plus, Tetrix Cream, Hydrocerin Plus, Baby Oil Creamy, Remedy 4-in-1 Body Cleanser, Neosalus, EpiCeram Skin Barrier Emulsion, PruMyx, Normlgel, Plastibase 50W, Hylatopic Emollient, Hydrophylic GRX, Bodi Care, Bodi Line Almond Skin Cleanser, Bodi Line Antiseptic, Bodi Line Hair and Body Shampoo, Bodi Kleen Perineal Cleanser, Bodi Lotion, Bodi Whirl Bath, Geri-Lav Free, Promiseb, Impruv Deep Moisturizing, Impruv Natural Repair, Bodi Whirl Oil, Bodi Protect, DermaSoft with Aloe, SuperSoft, AmeriCerin, AmeriStore, GentleWash Body Wash / Shampoo, Soapreme, DermaFix, Chap Stick Fresh Effects, Chap Stick 100% Naturals, Dr. Smith's Rash-N-All, Gentle Cream, Geri-Soft, Bodi Bath & Shampoo, Nature's Wash Plus, PruVel, Balneol Cleansing, Zenieva, PeriScent Perineal Cleanser, Zenieva Cream and Cleanser, RadiaGel Hydrogel, CeraVe Facial Moisturizing, Carmex Click-Stick, Tropazone, Keri Sensitive Skin, Prutect, PruClair, Hydrolatum, Ultra-Klenz Wound Cleanser, Balneol for Her, Cetaphil Daily Advantage, Hydro-Lan Creme, GRx Rinse-Free, Carb-O-Lan10, Carb-O-Sal5 (obsolete), Carb-O-Lan20, Sensi-Care Moisturizing Body, Free & Clear, PR Cream, Vanicream Cleansing Bar, HylatopicPlus Emollient Foam, Nutraderm Advanced Formula, Lantiseptic Daily Cream, Lantiseptic Multi-Purpose, Cetaphil Restoraderm Wash, Cetaphil Restoraderm Moisturizer, PeriClean, Radiaderm System, Rash Relief Clear, Proshield Glove Skin Protectant, Isagel, Desitin Clear, Cara-Klenz Wound Cleanser, St. Ives Restoring, St. Ives Hydrating Vitamin E, St. Ives Cucumber, Melon and Vitamin E, Aveeno Active Naturals, Jergens, Gold Bond Ultimate Healing, Gold Bond Ultimate Softening, Gold Bond Ultimate Restoring, Lantiseptic Skin Protectant, Hylatopic Plus Aurstat, CetaKlenz Pump, Critic-Aid Clear, HylatopicPlus, Liqua-Gel, Lazer Creme, Lactinol HX (obsolete), TL-Cermide

What are topical emollients?

Emollients are substances that moisten and soften your skin.

Topical (for the skin) emollients are used to treat or prevent dry skin. Topical emollients are sometimes contained in products that also treat acne, chapped lips, diaper rash, cold sores, or other minor skin irritation.

There are many brands and forms of topical emollients available and not all are listed on this leaflet.

Topical emollients may also be used for purposes not listed in this medication guide.

What is the most important information I should know about topical emollients?

You should not use a topical emollient if you are allergic to it. Topical emollients will not treat or prevent a skin infection.

Ask a doctor or pharmacist before using this medication if you have deep wounds or open sores, swelling, warmth, redness, oozing, bleeding, large areas of skin irritation, or any type of allergy.

What should I discuss with my healthcare provider before using topical emollients?

You should not use a topical emollient if you are allergic to it. Topical emollients will not treat or prevent a skin infection.

Ask a doctor or pharmacist if it is safe for you to use this medicine if you have:

• 
  

  deep wounds or open sores;

  
  


• 
  

  swelling, warmth, redness, oozing, or bleeding;

  
  


• 
  

  large areas of skin irritation;

  
  


• 
  

  any type of allergy; or

  
  


• if you are pregnant or breast-feeding.

How should I use topical emollients?

Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended.

Clean the skin where you will apply the topical emollient. It may help to apply this product when your skin is wet or damp. Follow directions on the product label.

Shake the product container if recommended on the label.

Apply a small amount of topical emollient to the affected area and rub in gently.

If you are using a stick, pad, or soap form of topical emollient, follow directions for use on the product label.

Do not use this product over large area of skin. Do not apply a topical emollient to a deep puncture wound or severe burn without medical advice.

If your skin appears white or gray and feels soggy, you may be applying too much topical emollient or using it too often.

Some forms of topical emollient may be flammable and should not be used near high heat or open flame, or applied while you are smoking.

Store as directed away from moisture, heat, and light. Keep the bottle, tube, or other container tightly closed when not in use.

What happens if I miss a dose?

Since this product is used as needed, it does not have a daily dosing schedule. Seek medical advice if your condition does not improve after using a topical emollient.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking topical emollients?

Avoid getting topical emollients in your eyes, nose, or mouth. If this does happen, rinse with water. Avoid exposure to sunlight or tanning beds. Some topical emollients can make your skin more sensitive to sunlight or UV rays.

Topical emollients side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Stop using the topical emollient and call your doctor if you have severe burning, stinging, redness, or irritation where the product was applied.

Less serious side effects are more likely, and you may have none at all.

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

What other drugs will affect topical emollients?

It is not likely that other drugs you take orally or inject will have an effect on topically applied products. But many drugs can interact with each other. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More topical emollients resources

• Topical emollients Use in Pregnancy & Breastfeeding
• Topical emollients Support Group
• 8 Reviews for Topical emollients - Add your own review/rating

Compare topical emollients with other medications

• Dry Skin

Where can I get more information?

• Your pharmacist can provide more information about topical emollients.

Olanzapine Sandoz 15 mg Film-coated Tablets

1. Name Of The Medicinal Product

Olanzapine Sandoz 15 mg Film-coated Tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 15 mg olanzapine.

Excipient: 169.31 mg lactose/film-coated tablet

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Film-coated tablet

Light blue, oval (12 mm length), with a breaking notch on both sides.

The tablet can be divided into equal halves.

4. Clinical Particulars

4.1 Therapeutic Indications

Adults

Olanzapine is indicated for the treatment of schizophrenia.

Olanzapine is effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response.

Olanzapine is indicated for the treatment of moderate to severe manic episode.

In patients whose manic episode has responded to olanzapine treatment, olanzapine is indicated for the prevention of recurrence in patients with bipolar disorder (see section 5.1).

4.2 Posology And Method Of Administration

Adults

Schizophrenia: The recommended starting dose for olanzapine is 10 mg/day.

Manic episode: The starting dose is 15 mg as a single daily dose in monotherapy or 10 mg daily in combination therapy (see section 5.1).

Preventing recurrence in bipolar disorder: The recommended starting dose is 10 mg/day. For patients who have been receiving olanzapine for treatment of manic episode, continue therapy for preventing recurrence at the same dose. If a new manic, mixed, or depressive episode occurs, olanzapine treatment should be continued (with dose optimisation as needed), with supplementary therapy to treat mood symptoms, as clinically indicated.

During treatment for schizophrenia, manic episode, and recurrence prevention in bipolar disorder, daily dosage may subsequently be adjusted on the basis of individual clinical status within the range 5-20 mg/day. An increase to a dose greater than the recommended starting dose is advised only after appropriate clinical reassessment and should generally occur at intervals of not less than 24 hours. Olanzapine can be given without regard for meals, as absorption is not affected by food. Gradual tapering of the dose should be considered when discontinuing olanzapine.

Paediatric population

Olanzapine is not recommended for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy. A greater magnitude of weight gain, lipid and prolactin alterations has been reported in short term studies of adolescent patients than in studies of adult patients (see sections 4.4, 4.8, 5.1 and 5.2).

Elderly

A lower starting dose (5 mg/day) is not routinely indicated but should be considered for those 65 and over when clinical factors warrant (see also section 4.4).

Renal and/or hepatic impairment

A lower starting dose (5 mg) should be considered for such patients. In cases of moderate hepatic insufficiency (cirrhosis, Child-Pugh class A or B), the starting dose should be 5 mg and only increased with caution.

Gender

The starting dose and dose range need not be routinely altered for female patients relative to male patients.

Smokers

The starting dose and dose range need not be routinely altered for non-smokers relative to smokers.

When more than one factor is present which might result in slower metabolism (female gender, geriatric age, non-smoking status), consideration should be given to decreasing the starting dose. Dose escalation, when indicated, should be conservative in such patients.

(See also section 4.5 and section 5.2.)

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients. Patients with known risk for narrow-angle glaucoma.

4.4 Special Warnings And Precautions For Use

During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored during this period.

Dementia-related psychoses and/or behavioural disturbances

Olanzapine is not approved for the treatment of dementia-related psychosis and/or behavioural disturbances, and is not recommended for use in this particular group of patients because of an increase in mortality and the risk of cerebrovascular accident. In placebo-controlled clinical trials (6-12 weeks duration) of elderly patients (mean age 78 years) with dementia-related psychosis and/or disturbed behaviours, there was a 2-fold increase in the incidence of death in olanzapine-treated patients compared to patients treated with placebo (3.5% versus 1.5%, respectively). The higher incidence of death was not associated with olanzapine dose (mean daily dose 4.4 mg) or duration of treatment. Risk factors that may predispose this patient population to increased mortality include age >65 years, dysphagia, sedation, malnutrition and dehydration, pulmonary conditions (e.g., pneumonia, with or without aspiration), or concomitant use of benzodiazepines. However, the incidence of death was higher in olanzapine-treated than in placebo-treated patients, independent of these risk factors.

In the same clinical trials, cerebrovascular adverse events (CVAE, e.g. stroke, transient ischaemic attack), including fatalities, were reported. There was a 3-fold increase in CVAE in patients treated with olanzapine compared to patients treated with placebo (1.3% versus 0.4%, respectively). All olanzapine- and placebo-treated patients who experienced a cerebrovascular event had pre-existing risk factors. Age >75 years and vascular/mixed type dementia were identified as risk factors for CVAE in association with olanzapine treatment. The efficacy of olanzapine was not established in these trials.

Parkinson's disease

The use of olanzapine in the treatment of dopamine agonist associated psychosis in patients with Parkinson's disease is not recommended. In clinical trials, worsening of Parkinsonian symptomatology and hallucinations were reported very commonly and more frequently than with placebo (see section 4.8), and olanzapine was not more effective than placebo in the treatment of psychotic symptoms. In these trials, patients were initially required to be stable on the lowest effective dose of anti-Parkinsonian medicinal products (dopamine agonist) and to remain on the same anti-Parkinsonian medicinal products and dosages throughout the study. Olanzapine was started at 2.5 mg/day and titrated to a maximum of 15 mg/day based on investigator judgement.

Neuroleptic Malignant Syndrome (NMS)

NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. Rare cases reported as NMS have also been received in association with olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicinal products, including olanzapine, must be discontinued.

Hyperglycaemia and diabetes

Hyperglycaemia and/or development or exacerbation of diabetes, occasionally associated with ketoacidosis or coma, has been reported rarely, including some fatal cases (see section 4.8). In some cases, a prior increase in body weight has been reported, which may be a predisposing factor. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines. Patients treated with any antipsychotic medicinal products, including olanzapine, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control. Weight should be monitored regularly.

Lipid alterations

Undesirable alterations in lipids have been observed in olanzapine-treated patients in placebo-controlled clinical trials (see section 4.8). Lipid alterations should be managed as clinically appropriate, particularly in dyslipidemic patients and in patients with risk factors for the development of lipid disorders. Patients treated with any antipsychotic medicinal products, including olanzapine, should be monitored regularly for lipids in accordance with utilised antipsychotic guidelines.

Anticholinergic activity

While olanzapine demonstrated anticholinergic activity in vitro, experience during the clinical trials revealed a low incidence of related events. However, as clinical experience with olanzapine in patients with concomitant illness is limited, caution is advised when prescribing for patients with prostatic hypertrophy, or paralytic ileus and related conditions.

Hepatic function

Transient, asymptomatic elevations of hepatic aminotransferases, alanine transferase (ALT), aspartate transferase (AST), have been seen commonly, especially in early treatment. Caution should be exercised and follow-up organized in patients with elevated ALT and/or AST, in patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic medicinal products. In cases where hepatitis (including hepatocellular, cholestatic, or mixed liver injury) has been diagnosed, olanzapine treatment should be discontinued.

Neutropenia

Caution should be exercised in patients with low leucocyte and/or neutrophil counts for any reason, in patients receiving medicinal products known to cause neutropenia, in patients with a history of drug-induced bone marrow depression/toxicity, in patients with bone marrow depression caused by concomitant illness, radiation therapy or chemotherapy, and in patients with hypereosinophilic conditions or with myeloproliferative disease. Neutropenia has been reported commonly when olanzapine and valproate are used concomitantly (see section 4.8).

Discontinuation of treatment

Acute symptoms, such as sweating, insomnia, tremor, anxiety, nausea, or vomiting, have been reported very rarely (<0.01%) when olanzapine is stopped abruptly.

QT interval

In clinical trials, clinically meaningful QTc prolongations (Fridericia QT correction [QTcF]

Thromboembolism

Temporal association of olanzapine treatment and venous thromboembolism has very rarely (<0.01%) been reported. A causal relationship between the occurrence of venous thromboembolism and treatment with olanzapine has not been established. However, since patients with schizophrenia often present with acquired risk factors for venous thromboembolism, all possible risk factors of VTE, e.g., immobilisation of patients, should be identified and preventive measures undertaken.

General CNS activity

Given the primary CNS effects of olanzapine, caution should be used when it is taken in combination with other centrally acting medicinal products and alcohol. As it exhibits in vitro dopamine antagonism, olanzapine may antagonise the effects of direct and indirect dopamine agonists.

Seizures

Olanzapine should be used cautiously in patients who have a history of seizures or are subject to factors which may lower the seizure threshold. Seizures have been reported to occur rarely in patients when treated with olanzapine. In most of these cases, a history of seizures or risk factors for seizures were reported.

Tardive dyskinesia

In comparator studies of one year or less duration, olanzapine was associated with a statistically significant lower incidence of treatment emergent dyskinesia. However, the risk of tardive dyskinesia increases with long-term exposure, and therefore if signs or symptoms of tardive dyskinesia appear in a patient on olanzapine, a dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or even arise after discontinuation of treatment.

Postural hypotension

Postural hypotension was infrequently observed in the elderly in olanzapine clinical trials. As with other antipsychotics, it is recommended that blood pressure is measured periodically in patients over 65 years.

Sudden cardiac death

In postmarketing reports with olanzapine, the event of sudden cardiac death has been reported in patients with olanzapine. In a retrospective observational cohort study, the risk of presumed sudden cardiac death in patients treated with olanzapine was approximately twice the risk in patients not using antipsychotics. In the study, the risk of olanzapine was comparable to the risk of atypical antipsychotics included in a pooled analysis.

Paediatric population

Olanzapine is not indicated for use in the treatment of children and adolescents. Studies in patients aged 13-17 years showed various adverse reactions, including weight gain, changes in metabolic parameters and increases in prolactin levels. Long-term outcomes associated with these events have not been studied and remain unknown (see sections 4.8 and 5.1).

Lactose

Olanzapine film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Paediatric population

Interaction studies have only been performed in adults.

Potential interactions affecting olanzapine

Since olanzapine is metabolised by CYP1A2, substances that can specifically induce or inhibit this isoenzyme may affect the pharmacokinetics of olanzapine.

Induction of CYP1A2

The metabolism of olanzapine may be induced by smoking and carbamazepine, which may lead to reduced olanzapine concentrations. Only slight to moderate increase in olanzapine clearance has been observed. The clinical consequences are likely to be limited, but clinical monitoring is recommended and an increase of olanzapine dose may be considered if necessary (see section 4.2).

Inhibition of CYP1A2

Fluvoxamine, a specific CYP1A2 inhibitor, has been shown to significantly inhibit the metabolism of olanzapine. The mean increase in olanzapine C_max following fluvoxamine was 54% in female non-smokers and 77% in male smokers. The mean increase in olanzapine AUC was 52% and 108%, respectively. A lower starting dose of olanzapine should be considered in patients who are using fluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin. A decrease in the dose of olanzapine should be considered if treatment with an inhibitor of CYP1A2 is initiated.

Decreased bioavailability

Activated charcoal reduces the bioavailability of oral olanzapine by 50 to 60% and should be taken at least 2 hours before or after olanzapine.

Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine have not been found to significantly affect the pharmacokinetics of olanzapine.

Potential for olanzapine to affect other medicinal products

Olanzapine may antagonise the effects of direct and indirect dopamine agonists.

Olanzapine does not inhibit the main CYP450 isoenzymes in vitro (e.g. 1A2, 2D6, 2C9, 2C19, 3A4). Thus, no particular interaction is expected, as verified through in vivo studies, where no inhibition of metabolism of the following active substances was found: tricyclic antidepressant (representing mostly CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2), or diazepam (CYP3A4 and 2C19).

Olanzapine showed no interaction when co-administered with lithium or biperiden.

Therapeutic monitoring of valproate plasma levels did not indicate that valproate dosage adjustment is required after the introduction of concomitant olanzapine.

General CNS activity

Caution should be exercised in patients who consume alcohol or receive medicinal products that can cause central nervous system depression.

The concomitant use of olanzapine with anti-Parkinsonian medicinal products in patients with Parkinson's disease and dementia is not recommended (see section 4.4).

QTc interval

Caution should be used if olanzapine is being administered concomitantly with medicinal products known to increase QTc interval (see section 4.4).

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with olanzapine. Nevertheless, because human experience is limited, olanzapine should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus.

Spontaneous reports have been very rarely received on tremor, hypertonia, lethargy, and sleepiness, in infants born to mothers who had used olanzapine during the 3^rd trimester.

Breast feeding

In a study in breast-feeding, healthy women, olanzapine was excreted in breast milk. Mean infant exposure (mg/kg) at steady-state was estimated to be 1.8% of the maternal olanzapine dose (mg/kg). Patients should be advised not to breast-feed an infant if they are taking olanzapine.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Because olanzapine may cause somnolence and dizziness, patients should be cautioned about operating machinery, including motor vehicles.

4.8 Undesirable Effects

Adults

The most frequently (seen in

The following table lists the adverse reactions and laboratory investigations observed from spontaneous reporting and in clinical trials. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency terms listed are defined as follows:

Very common (

Common (1/100 to <1/10)

Uncommon (1/1,000 to <1/100)

Rare (1/10,000 to <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

Very common	Common	Uncommon	Not known
Blood and the lymphatic system disorders
	Eosinophilia	Leukopenia Neutropenia	Thrombocytopenia
Immune system disorders
			Allergic reaction
Metabolism and nutrition disorders
Weight gain1	Elevated cholesterol levels2,3 Elevated glucose levels4 Elevated triglyceride levels2,5 Glucosuria Increased appetite		Development or exacerbation of diabetes occasionally associated with ketoacidosis or coma, including some fatal cases (see section 4.4) Hypothermia
Nervous system disorders
Somnolence	Dizziness Akathisia6 Parkinsonism6 Dyskinesia6		Seizures where in most cases a history of seizures or risk factors for seizures were reported Neuroleptic malignant syndrome (see section 4.4)
			Dystonia (including oculogyration) Tardive dyskinesia Discontinuation symptoms7
Cardiac disorders
		Bradycardia QTc prolongation (see section 4.4)	Ventricular tachycardia/fibrillation, sudden death (see section 4.4)
Vascular disorders
	Orthostatic hypotension		Thromboembolism (including pulmonary embolism and deep vein thrombosis)
Gastrointestinal disorders
	Mild, transient anticholinergic effects including constipation and dry mouth		Pancreatitis
Hepato-biliary disorders
	Transient, asymptomatic elevations of hepatic aminotransferases (ALT, AST), especially in early treatment (see section 4.4)		Hepatitis (including hepatocellular, cholestatic or mixed liver injury)
Skin and subcutaneous tissue disorders
	Rash	Photosensitivity reaction Alopecia
Musculoskeletal and connective tissue disorders
			Rhabdomyolysis
Renal and urinary disorders
		Urinary incontinence	Urinary hesitation
Reproductive system and breast disorders
			Priapism
General disorders and administration site conditions
	Asthenia Fatigue Oedema
Investigations
Elevated plasma prolactin levels8		High creatine phosphokinase Increased total bilirubin	Increased alkaline phosphatase

¹ Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Following short term treatment (median duration 47 days), weight gain

² Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline.

³ Observed for fasting normal levels at baseline (< 5.17 mmol/l) which increased to high (

⁴ Observed for fasting normal levels at baseline (< 5.56 mmol/l) which increased to high (

⁵ Observed for fasting normal levels at baseline (< 1.69 mmol/l) which increased to high (

⁶ In clinical trials, the incidence of parkinsonism and dystonia in olanzapine-treated patients was numerically higher, but not statistically significantly different from placebo. Olanzapine-treated patients had a lower incidence of parkinsonism, akathisia and dystonia compared with titrated doses of haloperidol. In the absence of detailed information on the pre-existing history of individual acute and tardive extrapyramidal movement disorders, it can not be concluded at present that olanzapine produces less tardive dyskinesia and/or other tardive extrapyramidal syndromes.

⁷ Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea and vomiting have been reported when olanzapine is stopped abruptly.

⁸ In clinical trials of up to 12 weeks, plasma prolactin concentrations exceeded the upper limit of normal range in approximately 30% of olanzapine treated patients with normal baseline prolactin value. In the majority of these patients the elevations were generally mild, and remained below two times the upper limit of normal range. Generally in olanzapine-treated patients potentially associated breast- and menstrual related clinical manifestations (e.g. amenorrhoea, breast enlargement, galactorrhea in females, and gynaecomastia/breast enlargement in males) were uncommon. Potentially associated sexual function-related adverse reactions (e.g. erectile dysfunction in males and decreased libido in both genders) were commonly observed.

Long-term exposure (at least 48 weeks)

The proportion of patients who had adverse, clinically significant changes in weight gain, glucose, total/LDL/HDL cholesterol or triglycerides increased over time. In adult patients who completed 9-12 months of therapy, the rate of increase in mean blood glucose slowed after approximately 6 months.

Additional information on special populations

In clinical trials in elderly patients with dementia, olanzapine treatment was associated with a higher incidence of death and cerebrovascular adverse reactions compared to placebo (see also section 4.4). Very common adverse reactions associated with the use of olanzapine in this patient group were abnormal gait and falls. Pneumonia, increased body temperature, lethargy, erythema, visual hallucinations and urinary incontinence were observed commonly.

In clinical trials in patients with drug-induced (dopamine agonist) psychosis associated with Parkinson's disease, worsening of Parkinsonian symptomatology and hallucinations were reported very commonly and more frequently than with placebo.

In one clinical trial in patients with bipolar mania, valproate combination therapy with olanzapine resulted in an incidence of neutropenia of 4.1%; a potential contributing factor could be high plasma valproate levels. Olanzapine administered with lithium or valproate resulted in increased levels (

Paediatric population

Olanzapine is not indicated for the treatment of children and adolescent patients below 18 years. Although no clinical studies designed to compare adolescents to adults have been conducted, data from the adolescent trials were compared to those of the adult trials.

The following table summarises the adverse reactions reported with a greater frequency in adolescent patients (aged 13-17 years) than in adult patients or adverse reactions only identified during short-term clinical trials in adolescent patients. Clinically significant weight gain (

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency terms listed are defined as follows:

Very common (

Common (

Metabolism and nutrition disorders Very common: Weight gain9, elevated triglyceride levels10, increased appetite. Common: Elevated cholesterol levels11

Nervous system disorders Very common: Sedation (including: hypersomnia, lethargy, somnolence).

Gastrointestinal disorders Common: Dry mouth

Hepato-biliary disorders Very common: Elevations of hepatic aminotransferases (ALT/AST; see section 4.4).

Investigations Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels12.

⁹ Following short term treatment (median duration 22 days), weight gain

¹⁰ Observed for fasting normal levels at baseline (< 1.016 mmol/l) which increased to high (

¹¹ Changes in total fasting cholesterol levels from normal at baseline (< 4.39 mmol/l) to high (

¹² Elevated plasma prolactin levels were reported in 47.4% of adolescent patients.

4.9 Overdose

Signs and symptoms

Very common symptoms in overdose (>10% incidence) include tachycardia, agitation/aggressiveness, dysarthria, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma.

Other medically significant sequelae of overdose include delirium, convulsion, coma, possible Neuroleptic Malignant Syndrome, respiratory depression, aspiration, hypertension or hypotension, cardiac arrhythmias (<2% of overdose cases), and cardiopulmonary arrest. Fatal outcomes have been reported for acute overdoses as low as 450 mg, but survival has also been reported following acute overdose of approximately 2 g of oral olanzapine.

Management of overdose

There is no specific antidote for olanzapine. Induction of emesis is not recommended. Standard procedures for management of overdose may be indicated (i.e. gastric lavage, administration of activated charcoal). The concomitant administration of activated charcoal was shown to reduce the oral bioavailability of olanzapine by 50 to 60%.

Symptomatic treatment and monitoring of vital organ function should be instituted according to clinical presentation, including treatment of hypotension and circulatory collapse and support of respiratory function. Do not use epinephrine, dopamine, or other sympathomimetic agents with beta-agonist activity, since beta stimulation may worsen hypotension. Cardiovascular monitoring is necessary to detect possible arrhythmias. Close medical supervision and monitoring should continue until the patient recovers.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antipsychotics: diazepines, oxazepines and thiazepines

ATC code: N05A H03

Olanzapine is an antipsychotic, antimanic, and mood stabilising agent that demonstrates a broad pharmacologic profile across a number of receptor systems.

In preclinical studies, olanzapine exhibited a range of receptor affinities (Ki; <100 nM) for serotonin 5HT_2A/2C, 5HT₃, 5HT₆; dopamine D₁, D₂, D₃, D₄, D₅; cholinergic muscarinic receptors m₁-m₅; alpha₁ adrenergic; and histamine H₁ receptors. Animal behavioural studies with olanzapine indicated 5HT, dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine demonstrated a greater in vitro affinity for serotonin 5HT₂ than dopamine D₂ receptors and greater 5HT₂ than D₂ activity in in vivo models. Electrophysiological studies demonstrated that olanzapine selectively reduced the firing of mesolimbic (A10) dopaminergic neurons, while having little effect on the striatal (A9) pathways involved in motor function. Olanzapine reduced a conditioned avoidance response, a test indicative of antipsychotic activity, at doses below those producing catalepsy, an effect indicative of motor side-effects. Unlike some other antipsychotic agents, olanzapine increases responding in an 'anxiolytic' test.

In a single oral dose (10 mg) Positron Emission Tomography (PET) study in healthy volunteers, olanzapine produced a higher 5HT_2A than dopamine D₂ receptor occupancy. In addition, a Single Photon Emission Computed Tomography (SPECT) imaging study in schizophrenic patients revealed that olanzapine-responsive patients had lower striatal D₂ occupancy than some other antipsychotic- and risperidone-responsive patients, while being comparable to clozapine-responsive patients.

In two of two placebo- and two of three comparator-controlled trials with over 2,900 schizophrenic patients presenting with both positive and negative symptoms, olanzapine was associated with statistically significantly greater improvements in negative as well as positive symptoms.

In a multinational, double-blind, comparative study of schizophrenia, schizoaffective and related disorders, which included 1,481 patients with varying degrees of associated depressive symptoms (baseline mean of 16.6 on the Montgomery-Asberg Depression Rating Scale), a prospective secondary analysis of baseline to endpoint mood score change demonstrated a statistically significant improvement (P = 0.001) favouring olanzapine (-6.0) versus haloperidol. (-3.1).

In patients with a manic or mixed episode of bipolar disorder, olanzapine demonstrated superior efficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks. Olanzapine also demonstrated comparable efficacy results to haloperidol in terms of the proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks. In a co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the addition of olanzapine 10 mg (co-therapy with lithium or valproate) resulted in a greater reduction in symptoms of mania than lithium or valproate monotherapy after 6 weeks.

In a 12-month recurrence prevention study in manic episode patients who achieved remission on olanzapine and were then randomised to olanzapine or placebo, olanzapine demonstrated statistically significant superiority over placebo on the primary endpoint of bipolar recurrence. Olanzapine also showed a statistically significant advantage over placebo in terms of preventing either recurrence into mania or recurrence into depression.

In a second 12-month recurrence prevention study in manic episode patients who achieved remission with a combination of olanzapine and lithium and were then randomised to olanzapine or lithium alone, olanzapine was statistically non-inferior to lithium on the primary endpoint of bipolar recurrence (olanzapine 30.0%, lithium 38.3%; P = 0.055).

In an 18-month co-therapy study in manic or mixed episode patients stabilised with olanzapine plus a mood stabiliser (lithium or valproate), long-term olanzapine co-therapy with lithium or valproate was not statistically significantly superior to lithium or valproate alone in delaying bipolar recurrence, defined according to syndromic (diagnostic) criteria.

Paediatric population

The experience in adolescents (ages 13 to 17 years) is limited to short term efficacy data in schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving less than 200 adolescents. Olanzapine was used as a flexible dose starting with 2.5 and ranging up to 20 mg/day. During treatment with olanzapine, adolescents gained significantly more weight compared with adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, and prolactin (see sections 4.4 and 4.8) were greater in adolescents than in adults. There are no data on maintenance of effect and limited data on long term safety (see sections 4.4 and 4.8).

5.2 Pharmacokinetic Properties

Olanzapine is well absorbed after oral administration, reaching peak plasma concentrations within 5 to 8 hours. The absorption is not affected by food. Absolute oral bioavailability relative to intravenous administration has not been determined.

Olanzapine is metabolised in the liver by conjugative and oxidative pathways. The major circulating metabolite is the 10-N-glucuronide, which does not pass the blood brain barrier. Cytochromes P450-CYP1A2 and P450-CYP2D6 contribute to the formation of the N-desmethyl and 2-hydroxymethyl metabolites; both exhibited significantly less in vivo pharmacological activity than olanzapine in animal studies. The predominant pharmacologic activity is from the parent, olanzapine. After oral administration, the mean terminal elimination half-life of olanzapine in healthy subjects varied on the basis of age and gender.

In healthy elderly (65 and over) versus non-elderly subjects, the mean elimination half-life was prolonged (51.8 versus 33.8 hr) and the clearance was reduced (17.5 versus 18.2 l/hr). The pharmacokinetic variability observed in the elderly is within the range for the non-elderly. In 44 patients with schizophrenia >65 years of age, dosing from 5 to 20 mg/day was not associated with any distinguishing profile of adverse events.

In female versus male subjects, the mean elimination half-life was somewhat prolonged (36.7 versus 32.3 hr) and the clearance was reduced (18.9 versus 27.3 l/hr). However, olanzapine (5-20 mg) demonstrated a comparable safety profile in female (n = 467) as in male patients (n = 869).

In renally impaired patients (creatinine clearance <10 ml/min) versus healthy subjects, there was no significant difference in mean elimination half-life (37.7 versus 32.4 hr) or clearance (21.2 versus 25.0 l/hr). A mass balance study showed that approximately 57% of radiolabelled olanzapine appeared in urine, principally as metabolites.

In smoking subjects with mild hepatic dysfunction, mean elimination half-life (39.3 hr) was prolonged and clearance (18.0 l/hr) was reduced analogous to non-smoking healthy subjects (48.8 hr and 14.1 l/hr, respectively).

In non-smoking versus smoking subjects (males and females), the mean elimination half-life was prolonged (38.6 versus 30.4 hr) and the clearance was reduced (18.6 versus 27.7 l/hr).

The plasma clearance of olanzapine is lower in elderly versus young subjects, in females versus males, and in non-smokers versus smokers. However, the magnitude of the impact of age, gender, or smoking on olanzapine clearance and half-life is small in comparison to the overall variability between individuals.

In a study of Caucasians, Japanese, and Chinese subjects, there were no differences in the pharmacokinetic parameters among the three populations.

The plasma protein binding of olanzapine was about 93% over the concentration range of about 7 to about 1,000 ng/ml. Olanzapine is bound predominantly to albumin and alpha₁-acid-glycoprotein.

Paediatric population

Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar between adolescents and adults. In clinical studies, the average olanzapine exposure was approximately 27% higher in adolescents. Demographic differences between the adolescents and adults include a lower average body weight and fewer adolescents were smokers. Such factors possibly contribute to the higher average exposure observed in adolescents.

5.3 Pr

Mucodyne Capsules, Syrup and Paediatric Syrup

1. Name Of The Medicinal Product

Mucodyne Capsules: 375 mg

Mucodyne Syrup: Clear 250 mg/5 ml Syrup

Mucodyne Paediatric Syrup : 125 mg/5 ml Syrup

2. Qualitative And Quantitative Composition

Capsules: Carbocisteine 375 mg

Syrup: Each 5 ml of oral solution contains 250 mg of Carbocisteine. Also contains 2 g of sucrose, 70 mg of ethanol (1.6% v/v), 7.5 mg of methyl parahydroxybenzoate (E218) and 33 mg of sodium (1.4 mmol).

Paediatric Syrup: Carbocisteine 125 mg/5 ml.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Capsules: Yellow, size 1 capsules marked “MUCODYNE 375” in black and containing a white to off-white powder or friable plug.

Syrup: A clear amber coloured syrupy liquid

Paediatric Syrup: A rosy brown to red brown mobile liquid

4. Clinical Particulars

4.1 Therapeutic Indications

Carbocisteine is a mucolytic agent for the adjunctive therapy of respiratory tract disorders characterised by excessive, viscous mucus, including chronic obstructive airways disease.

4.2 Posology And Method Of Administration

Capsules and syrup:

Adults including the elderly:

Dosage is based upon an initial daily dosage of 2250mg carbocisteine in divided doses, reducing to 1500mg daily in divided doses when a satisfactory response is obtained e.g. two capsules three times a day reducing to one capsule four times a day, for normal syrup 15ml tds. reducing to 10ml tds.

Children:

The capsule and syrup formulations are not recommended for children. The normal daily dosage is 20mg/kg bodyweight in divided doses. It is recommended that this is achieved with Mucodyne Paediatric Syrup.

Mucodyne capsules and Syrup are for oral administration.

Paediatric Syrup:

Children 5 - 12 years: 10 ml three times daily.

Children 2 - 5 years: 2.5 - 5 ml four times daily.

Mucodyne Paediatric Syrup is for oral administration.

4.3 Contraindications

Capsules and Syrup:

Hypersensitivity to the active substance(s) or to any of the excipients.

Use in patients with active peptic ulceration.

Paediatric syrup:

Mucodyne paediatric is contraindicated for use in children less than 2 years age.

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

4.4 Special Warnings And Precautions For Use

Capsules:

Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.

Syrup and Paediatric syrup:

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None stated.

4.6 Pregnancy And Lactation

Although tests in mammalian species have revealed no teratogenic effects, Mucodyne is not recommended during the first trimester of pregnancy.

Use in lactation: Effects not known.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

Capsules, Syrup and Paediatric Syrup:

Immune System Disorders

There have been reports of anaphylactic reactions and fixed drug eruption.

Skin and subcutaneous tissue disorders

There have been reports of skin rashes and allergic skin eruptions.

Capsules and Syrup:

Gastrointestinal disorders

There have been rare reports of gastrointestinal bleeding occurring during treatment with Mucodyne.

4.9 Overdose

Gastric lavage may be beneficial, followed by observation. Gastrointestinal disturbance is the most likely symptom of Mucodyne overdosage.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC code: RO5CB03

Carbocisteine (S-carboxymethyl L-cysteine) has been shown in normal and bronchitic animal models to affect the nature and amount of mucus glycoprotein which is secreted by the respiratory tract. An increase in the acid:neutral glycoprotein ratio of the mucus and a transformation of serous cells to mucus cells is known to be the initial response to irritation and will normally be followed by hypersecretion. The administration of carbocisteine to animals exposed to irritants indicates that the glycoprotein that is secreted remains normal; administration after exposure indicates that return to the normal state is accelerated. Studies in humans have demonstrated that carbocisteine reduces goblet cell hyperplasia. Carbocisteine can therefore be demonstrated to have a role in the management of disorders characterised by abnormal mucus.

5.2 Pharmacokinetic Properties

Carbocisteine is rapidly absorbed from the GI tract. In an 'in-house' study, at steady state (7 days) Mucodyne capsules 375mg given as 2 capsules t.d.s. to healthy volunteers gave the following pharmacokinetic parameters:

Plasma Determinations	Mean	Range
T Max (Hr)	2.0	1.0-3.0
T½ (Hr)	1.87	1.4-2.5
KEL (Hr-1 )	0.387	0.28-0.50
AUC0-7.5 (mcg.Hr.ml-1 )	39.26	26.0-62.4
Derived Pharmacokinetic Parameters
*CLS (L.Hr-1 )	20.2	-
CLS (ml.min-1 )	331	-
VD (L)	105.2	-
VD (L.Kg-1 )	1/75	-
*Calculated from dose for day 7 of study

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the precriber, which are additional to those already included in other sections of the SmPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Capsules: Magnesium stearate (E572), Silica, anhydrous collodial (E551), Lactose monohydrate (spray dried), Sodium lauril sulphate, Size 1 yellow opaque gelatin capsules containing quinoline yellow (E104), sunset yellow (E110) and titanium dioxide (E171).

Syrup: Methyl parahydroxybenzoate (E218), Sucrose, Caramel powder (E150), Aromatic Elixir (containing ethyl alcohol, rum and aromatic rum flavour), Cinnamon oil, Sodium hydroxide, Purified water.

Paediatric syrup: Sucrose, Sodium methyl parahydroxybenzoate, Vanillin Raspberry flavour, Cherry flavour, Red Ponceau 4R (E124), Sodium hydroxide (E524), Hydrochloric acid (E507), Purified water

6.2 Incompatibilities

Capsules and Paediatric syrup: Not applicable

Syrup: Mixture with linctus of pholcodine causes precipitation of carbocisteine from solution.

6.3 Shelf Life

Capsules: 36 months.

Syrup: 36 months

Paediatric Syrup: 24 months

6.4 Special Precautions For Storage

Capsules: Do not store above 25°C.

Syrup and Paediatric Syrup: Store below 25°C.

6.5 Nature And Contents Of Container

Capsules: Blister packs of 120 capsules.

Syrup: 300ml Clear Glass (Ph Eur Type III) bottle. Polypropylene cap with polyethylene liner. Graduated polypropylene beaker

Paediatric Syrup: Clear Glass Type III bottle with a White Polypropylene child-resistant cap and Polyethylene liner, containing 300 ml (with graduated Polypropylene measuring beaker) and a tamper evident band.

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

8. Marketing Authorisation Number(S)

Capsules: PL 04425/0203

Syrup: PL 04425/0204

Paediatric Syrup: PL 04425/0205

9. Date Of First Authorisation/Renewal Of The Authorisation

Capsules: 7 February 2009

Syrup: 30 April 2003

Paediatric Syrup: 23 February 2004

10. Date Of Revision Of The Text

Capsules: 17^th January 2010

Syrup: 15th February 2011

Paediatric Syrup: 2^nd September 2010

LEGAL CLASSIFICATION

POM