Wednesday, September 14, 2016

Oraldene





1. Name Of The Medicinal Product



ORALDENE


2. Qualitative And Quantitative Composition



ORALDENE contains 0.1% w/v hexetidine.



3. Pharmaceutical Form



A clear red solution.



4. Clinical Particulars



4.1 Therapeutic Indications



ORALDENE is indicated for use in minor mouth infections including thrush, as an aid in the prevention and treatment of gingivitis, and in the management of sore throat and recurrent aphthous ulcers. ORALDENE is also of value in the alleviation of halitosis and pre- and post-dental surgery.



4.2 Posology And Method Of Administration



Adults and children 12 years and over:



Topical administration to the buccal cavity.



Rinse the mouth, or gargle with at least 15 ml of undiluted solution, two or three times a day.



ORALDENE should not be swallowed in large quantities.



Children aged 6 to 11 years:



As recommended for adults.



Children under 6 years:



Not recommended.



The Elderly:



As recommended for adults.



4.3 Contraindications



None known.



4.4 Special Warnings And Precautions For Use



None known.



4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction



No interactions are known.



4.6 Pregnancy And Lactation



No formal studies have been conducted in man. However, on the basis of animal studies and, in theory, the negligible systemic absorption it is considered highly unlikely that the use of ORALDENE during pregnancy will present a risk to the foetus.



It is not known whether hexetidine is excreted in human breast milk, however, in view of the negligible amount of hexetidine which could be predicted to be systemically absorbed, it is unlikely that concentrations of hexetidine in the milk will present any risk to the neonate/infant.



4.7 Effects On Ability To Drive And Use Machines



ORALDENE is unlikely affect ability to drive or operate machinery.



4.8 Undesirable Effects



ORALDENE is generally very well tolerated with a low potential for causing irritation, or sensitisation reactions. Prolonged use of ORALDENE is also well tolerated.



Patch testing with of hexetidine containing ointment was negative for irritation or sensitisation potential.



In a few individuals mild irritation (described as sore mouth, burning or itching) of the tongue and/or buccal tissues has been reported. Other side effects which are reported very rarely include transient anaesthesia and taste impairment.



4.9 Overdose



Signs and Symptoms of Overdose



There are no reports of alcohol intoxication from overdose with ORALDENE.



Hexetidine, at the strength present in ORALDENE, is non-toxic.



Acute alcoholic intoxication is extremely unlikely, however, it is theoretically possible that, if a massive dose were swallowed by a small child, alcoholic intoxication may occur due to the ethanol content.



There is no evidence to suggest that repeated, excessive administration of hexetidine would lead to hypersensitivity-type reactions.



Treatment of Overdose



Treatment of overdose is symptomatic, but rarely required. In the event of accidental ingestion of the contents of a bottle by a child, a doctor should be consulted immediately. Gastric lavage should be considered within two hours of ingestion and management should relate to treatment of alcoholic intoxication.



5. Pharmacological Properties



5.1 Pharmacodynamic Properties



Hexetidine is a broad spectrum antimicrobial. It is active both in vivo and in vitro, against gram positive and negative bacterium, as well as yeasts (Candida albicans) and fungi.



5.2 Pharmacokinetic Properties



Specific pharmacodynamic studies have not been carried out on ORALDENE in man.



The oral retention of hexetidine to mucous membranes and dental plaque has been observed. In studies using radiolabelled hexetidine it has been shown that retention on buccal tissues can extend to between 8 and 10 hours after a single oral rinse and in some cases hexetidine has been detected on oral tissues up to 65 hours post-treatment.



No absorption studies following the topical application of ORALDENE have been performed in man.



Pharmacokinetics in renal/hepatic impairment



There have been no specific studies of ORALDENE or hexetidine in renal/hepatic impairment.



Pharmacokinetics in elderly



There have been no specific studies of ORALDENE or hexetidine in the elderly.



5.3 Preclinical Safety Data



Pre-clinical safety data do not add anything of further significance to the prescriber.



6. Pharmaceutical Particulars



6.1 List Of Excipients



Polysorbate 60



Citric acid



Saccharin sodium



Peppermint flavour



Star Anise oil



Methyl salicylate



Levomenthol



Clove oil



Eucalyptus oil



Ethanol 96%



Azorubin (85%) (E122)



Purified water



6.2 Incompatibilities



None.



6.3 Shelf Life



24 months.



6.4 Special Precautions For Storage



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



6.5 Nature And Contents Of Container



ORALDENE is presented in a clear 100 ml, 200 ml and 30 ml glass bottles, with white aluminium ROPP cap or an HDPE plastic cap fitted with a polyterephthalate ethylene faced aluminium/expanded polyethylene laminated wad.



6.6 Special Precautions For Disposal And Other Handling



Shake well before use.



Administrative Data


7. Marketing Authorisation Holder



McNeil Products Limited



Foundation Park



Roxborough Way



Maidenhead



Berkshire



SL6 3UG



United Kingdom



8. Marketing Authorisation Number(S)



PL 15513/0067



9. Date Of First Authorisation/Renewal Of The Authorisation



29th April 1998



10. Date Of Revision Of The Text



14 January 2010




Orfadin 10 mg hard capsules





1. Name Of The Medicinal Product



Orfadin 10 mg hard capsules


2. Qualitative And Quantitative Composition



Each capsule contains 10 mg nitisinone.



For a full list of excipients, see section 6.1.



3. Pharmaceutical Form



Hard capsule.



White, opaque capsules imprinted “NTBC 10mg” in black on the body of the capsule.



The capsules contain a white to off white powder.



4. Clinical Particulars



4.1 Therapeutic Indications



Treatment of patients with confirmed diagnosis of hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine.



4.2 Posology And Method Of Administration



Posology



Nitisinone treatment should be initiated and supervised by a physician experienced in the treatment of HT-1 patients. Treatment of all genotypes of the disease should be initiated as early as possible to increase overall survival and avoid complications such as liver failure, liver cancer and renal disease. Adjunct to the nitisinone treatment, a diet deficient in phenylalanine and tyrosine is required and should be followed by monitoring of plasma amino acids (see sections 4.4 and 4.8).



The dose of nitisinone should be adjusted individually.



The recommended initial dose in the paediatric and adult population is 1 mg/kg body weight/day divided in 2 doses administered orally.



Dose adjustment



During regular monitoring, it is appropriate to follow urine succinylacetone, liver function test values and alpha-fetoprotein levels (see section 4.4). If urine succinylacetone is still detectable one month after the start of nitisinone treatment, the nitisinone dose should be increased to 1.5 mg/kg body weight/day divided in 2 doses. A dose of 2 mg/kg body weight/day may be needed based on the evaluation of all biochemical parameters. This dose should be considered as a maximal dose for all patients.



If the biochemical response is satisfactory, the dose should be adjusted only according to body weight gain.



However, in addition to the tests above, during the initiation of therapy or if there is a deterioration, it may be necessary to follow more closely all available biochemical parameters (i.e. plasma succinylacetone, urine 5-aminolevulinate (ALA) and erythrocyte porphobilinogen (PBG)-synthase activity).



Special populations



There are no specific dose recommendations for elderly or patients that have renal or hepatic impairment.



Paediatric population



The safety and effect of nitisinone have been studied in the paediatric population. The dose recommendation in mg/kg body weight is the same in children and adults.



Method of administration



The capsule may be opened and the content suspended in a small amount of water or formula diet immediately before intake.



4.3 Contraindications



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



Mothers receiving nitisinone must not breast-feed (see section 4.6 and 5.3).



4.4 Special Warnings And Precautions For Use



Monitoring of plasma tyrosine levels



It is recommended that a slit-lamp examination of the eyes is performed before initiation of nitisinone treatment. A patient displaying visual disorders during treatment with nitisinone should without delay be examined by an ophthalmologist. It should be established that the patient is adhering to his dietary regimen and the plasma tyrosine concentration should be measured. A more restricted tyrosine and phenylalanine diet should be implemented in case the plasma tyrosine level is above 500 micromol/l. It is not recommended to lower the plasma tyrosine concentration by reduction or discontinuation of nitisinone, since the metabolic defect may result in deterioration of the patient's clinical condition.



Liver monitoring



The liver function should be monitored regularly by liver function tests and liver imaging. It is recommended also to monitor serum alpha-fetoprotein concentration. Increase in serum alpha-fetoprotein concentration may be a sign of inadequate treatment. Patients with increasing alpha-fetoprotein or signs of nodules in the liver should always be evaluated for hepatic malignancy.



Platelet and white blood cell (WBC) monitoring



It is recommended that platelet and white cell counts are monitored regularly, as a few cases of reversible trombocytopenia and leucopenia were observed during clinical evaluation.



Monitoring visits should be performed every 6 months; shorter intervals between visits are recommended in case of adverse events.



4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction



No formal interaction studies with other medicinal products have been conducted.



Nitisinone is metabolised in vitro by CYP 3A4 and dose-adjustment may therefore be needed when nitisinone is co-administered with inhibitors or inducers of this enzyme.



Based on in vitro studies, nitisinone is not expected to inhibit CYP 1A2, 2C9, 2C19, 2D6, 2E1 or 3A4-mediated metabolism.



No formal food interactions studies have been performed. However, nitisinone has been co-administered with food during the generation of efficacy and safety data. Therefore, it is recommended that if nitisinone treatment is initiated with food, this should be maintained on a routine basis.



4.6 Pregnancy And Lactation



Pregnancy



There are no adequate data from the use of nitisinone in pregnant women. Studies in animals have shown reproductive toxicity (see sections 5.3). The potential risk for humans is unknown. Nitisinone should not be used during pregnancy unless clearly necessary.



Lactation



It is not known whether nitisinone is excreted in human breast milk. Animal studies have shown adverse postnatal effects via exposure of nitisinone in milk. Therefore, mothers receiving nitisinone must not breast-feed, since a risk to the suckling child cannot be excluded (see sections 4.3 and 5.3).



4.7 Effects On Ability To Drive And Use Machines



No studies on the effects on the ability to drive and use machines have been performed.



If the patient experiences adverse reactions affecting the vision, the ability to drive and use machines should be considered.



4.8 Undesirable Effects



The adverse reactions considered at least possibly related to treatment are listed below, by body system organ class, and absolute frequency. Frequency is defined as very common (



Blood and lymphatic system disorders



Common: thrombocytopenia, leucopenia, granulocytopenia



Uncommon: leucocytosis



Eye disorders



Common: conjunctivitis, corneal opacity, keratitis, photophobia, eye pain



Uncommon: blepharitis



Skin and subcutaneous tissue disorders



Uncommon: pruritus, exfoliative dermatitis, erythematous rash



Nitisinone treatment is associated with elevated tyrosine levels. Elevated levels of tyrosine have been associated with corneal opacities and hyperkeratotic lesions. Restriction of tyrosine and phenylalanine in the diet should limit the toxicity associated with this type of tyrosinemia (see section 4.4).



4.9 Overdose



No case of overdose has been reported. Accidental ingestion of nitisinone by individuals eating normal diets not restricted in tyrosine and phenylalanine will result in elevated tyrosine levels. Elevated tyrosine levels have been associated with toxicity to eyes, skin, and the nervous system. Restriction of tyrosine and phenylalanine in the diet should limit toxicity associated with this type of tyrosinemia. No information about specific treatment of overdose is available.



5. Pharmacological Properties



5.1 Pharmacodynamic Properties



Pharmacotherapeutic group: Other alimentary tract and metabolism products, Various alimentary tract and metabolism products, ATC code: A16A X04.



The biochemical defect in hereditary tyrosinemia type 1 (HT-1) is a deficiency of fumarylacetoacetate hydrolase, which is the final enzyme of the tyrosine catabolic pathway. Nitisinone is a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase, an enzyme which precedes fumarylacetoacetate hydrolase in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with HT-1, nitisinone prevents the accumulation of the toxic intermediates maleylacetoacetate and fumarylacetoacetate. In patients with HT-1, these intermediates are converted to the toxic metabolites succinylacetone and succinylacetoacetate. Succinylacetone inhibits the porphyrin synthesis pathway leading to the accumulation of 5-aminolevulinate.



Nitisinone treatment leads to normalised porphyrin metabolism with normal erythrocyte PBG- synthase activity and urine 5-ALA, decreased urinary excretion of succinylacetone, increased plasma tyrosine concentration and increased urinary excretion of phenolic acids. Available data from a clinical study indicates that in more than 90% of the patients urine succinylacetone was normalized during the first week of treatment. Succinylacetone should not be detectable in urine or plasma when the nitisinone dose is properly adjusted.



Effects on overall survival



When compared to data for historical controls, it can be seen that treatment with nitisinone together with dietary restriction results in a better survival probability in all HT-1 phenotypes. This is seen in the following table:


































Age at start of treatment or diagnosis




Survival probability


   


Nitisinone treatment




Dietary control *


   


5 years




10 years




5 years




10 years


 


< 2 months




82




--




28




--




> 2-6 months




95




95




51




34




> 6 months




92




86




93




59



*From Figure 1,Van Spronsen et al., 1994.



Treatment with nitisinone was also found to result in reduced risk for the development of hepatocellular carcinoma (2.3 to 3.7-fold) compared to historical data on treatment with dietary restriction alone. It was found that the early initiation of treatment resulted in a further reduced risk for the development of hepatocellular carcinoma (13.5-fold when initiated prior to the age of 12 months).



5.2 Pharmacokinetic Properties



Formal absorption, distribution, metabolism and elimination studies have not been performed with nitisinone. In 10 healthy male volunteers, after administration of a single dose of nitisinone capsules (1 mg/kg body weight) the terminal half-life (median) of nitisinone in plasma was 54 hours. Population pharmacokinetic analysis has been conducted on a group of 207 HT-1 patients. The clearance and half-life were determined to be 0.0956 l/kg body weight/day and 52.1 hours respectively.



In vitro studies using human liver microsomes and cDNA-expressed P450 enzymes have shown limited CYP 3A4-mediated metabolism.



5.3 Preclinical Safety Data



Nitisinone has shown embryo-foetal toxicity in the mouse and rabbit at clinically relevant dose levels. In the rabbit, nitisinone induced a dose-related increase in malformations (umbilical hernia and gastroschisis) from a dose level of 2.5-fold higher than the maximum recommended human dose (2 mg/kg/day).



A pre and postnatal development study in the mouse showed statistically significant reduced pup survival and pup growth during the weaning period at dose levels of 125- and 25-fold, respectively, the maximum recommended human dose, with a trend effect on pup survival starting from the dose of 5 mg/kg/day. In rats, exposure via milk resulted in reduced mean pup weight and corneal lesions.



No mutagenic but a weak clastogenic activity was observed in in vitro studies. There was no evidence of in vivo genotoxicity (mouse micronucleus assay and mouse liver unscheduled DNA synthesis assay). Carcinogenicity studies have not been performed.



6. Pharmaceutical Particulars



6.1 List Of Excipients



Capsule content



pregelatinised starch (maize)



Capsule shell



gelatin



titanium dioxide (E 171)



Imprint



black iron oxide (E 172),



shellac,



propylene glycol.



6.2 Incompatibilities



Not applicable.



6.3 Shelf Life



18 months.



6.4 Special Precautions For Storage



Store in a refrigerator (2°C – 8°C).



During the shelf life the patient may store the finished product for a single period of 3 months at a temperature not above 25°C, after which the product must be discarded.



6.5 Nature And Contents Of Container



High density polyethylene bottle with a tamper proof low density polyethylene cap, containing 60 capsules.



6.6 Special Precautions For Disposal And Other Handling



No special requirements.



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



7. Marketing Authorisation Holder



Swedish Orphan Biovitrum International AB



SE-112 76 Stockholm



Sweden



8. Marketing Authorisation Number(S)



EU/1/04/303/003



9. Date Of First Authorisation/Renewal Of The Authorisation



Date of first authorisation: 21/02/2005



Date of latest renewal: 21/02/2010



10. Date Of Revision Of The Text



09/2010



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




Orelox Tablets 100mg





Orelox 100mg Tablets



Cefpodoxime proxetil







Is this leaflet hard to see or read?



Phone 01483 505515 for help




Read all of this leaflet carefully before taking this medicine.



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


  • If you have any further questions, ask your doctor or your pharmacist.


  • This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same yours.


  • If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or your pharmacist.




In this leaflet:



  • 1. What Orelox Tablets are and what they are used for


  • 2. Before you take Orelox Tablets


  • 3. How to take Orelox Tablets


  • 4. Possible side effects


  • 5. How to store Orelox Tablets


  • 6. Further information





What Orelox Tablets are and what they are used for





Orelox Tablets contains a medicine called cefpodoxime proxetil. This belongs to a group of antibiotics called ‘cephalosporins’.




Orelox Tablets are used to treat infections caused by bacteria. These include infections of the:



  • nose, sinuses (such as sinusitis)


  • throat (such as tonsillitis, pharyngitis)


  • chest and lungs (such as bronchitis, pneumonia)


  • skin (such as an abscess, ulcer, infected wound, inflamed hair follicles, carbuncles, furuncles, infections around the finger nails, a type of skin infection called cellulitis)


  • urinary system (such as cystitis, and kidney infections)


  • the sexually transmitted infection, gonorrhoea





Before you take Orelox Tablets






Do not take this medicine and tell your doctor or pharmacist if:



  • You are allergic (hypersensitive) to cefpodoxime, any other antibiotics including penicillin or to any of the other ingredients of this medicine (see Section 6: Further Information).
    Signs of an allergic reaction include: a rash, swallowing or breathing problems, swelling of the lips, face, throat and tongue.

Do not take this medicine if the above applies to you. If you are not sure, talk to your doctor or pharmacist before taking Orelox Tablets.







Take special care with Orelox Tablets



Check with your doctor or your pharmacist before taking this medicine if you:



  • Have ever had colitis


  • Have kidney problems

If you are not sure if any of the above applies to you, talk to your doctor or pharmacist before taking this medicine.







Taking other medicines



Please tell your doctor or your pharmacist if you are taking or have recently taken any other medicines. This includes medicines you buy without a prescription, including herbal medicines. This is because Orelox Tablets can affect the way some other medicines work. Also some medicines can affect the way Orelox Tablets works.



In particular, tell your doctor if you are taking any of the following:



  • antacids (used to treat indigestion)


  • medicines for treating ulcers (such as ranitidine or cimetidine)


  • water tablets or injections (diuretics) used to increase the flow of your water (urine)


  • aminoglycoside antibiotics (used to treat infections)


  • probenecid (used with a medicine called cidofovir to stop kidney damage)


  • coumarin anti-coagulants such as warfarin (used to thin the blood)


  • oestrogens such as in the contraceptive pill

Take antacids and medicines for ulcers 2-3 hours after Orelox Tablets.





Tests



If you require any tests (such as blood or urine tests) while taking this medicine, please make sure your doctor knows that you are taking Orelox Tablets.





Pregnancy and breast-feeding



Talk to your doctor before taking Orelox Tablets if you are pregnant, might become pregnant or think you may be pregnant.



Do not breast-feed if you are taking Orelox Tablets. This is because small amounts may pass into the mother’s milk.



If you are pregnant or breast-feeding talk to your doctor or pharmacist before taking any medicine.







Driving and using machinery



You may feel dizzy while you are taking this medicine. If this happens, do not drive or use any tools or machines.





Important information about some of the ingredients of Orelox Tablets



Orelox Tablets contain:



  • Lactose: This is a type of sugar. If you have been told by your doctor that you cannot tolerate or digest some sugars talk to your doctor before taking this medicine.





How to take Orelox Tablets



Always take Orelox Tablets exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.




Taking this medicine



  • Take this medicine by mouth.


  • Take this medicine with or straight after food


  • If you feel the effect of your medicine is too weak or too strong, do not change the dose yourself, but ask your doctor.




How much to take



The dose of Orelox Tablets depends on your needs and the illness being treated. Your doctor will advise you:





Adults



Infections of the nose/throat



  • One tablet twice each day

Infection of the sinuses



  • Two tablets twice each day

Infections of the chest and lungs



  • One or two tablets, twice each day

Infections of the lower urinary system e.g. cystitis



  • One tablet twice each day

Gonorrhoea



  • Two tablets as a single dose

Infections of the upper urinary system such as kidney infections



  • Two tablets twice each day

Skin infections



  • Two tablets twice each day




People with kidney problems



Your doctor may need to give you a lower dose





Children



Children should be given Orelox Paediatric Granules


Your doctor will advise you of the best way to take your medicine. Always follow his advice about when and how to take your medicine and always read the label on the box. Your pharmacist will also be able to help you if you are not sure.






Blood tests



If you take this medicine for more than 10 days, the doctor or nurse may do a blood test. This is routine and nothing to worry about.





If you take more Orelox Tablets than you should



If you have too much of this medicine, talk to your doctor straight away. The following effects may happen: confusion, lack of emotion or interest in anything and agitation.





If you forget to take Orelox Tablets



If a dose is missed, do not worry. Just wait until the next dose is due. Do not take a double dose to make up for a forgotten dose.





If you stop taking Orelox Tablets



Do not stop taking your medicine without talking to your doctor. You should not stop taking Orelox Tablets just because you feel better. This is because the infection may come back or get worse again.







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






Possible side effects



Like all medicines, Orelox Tablets can cause side effects, although not everybody gets them.




Tell your doctor straight away or go to the nearest hospital casualty department if you notice any of the following serious side effects – you may need urgent medical treatment:



  • You have an allergic reaction. The signs may include: a rash, joint pain, swallowing or breathing problems, swelling of your lips, face, throat or tongue.


  • Blistering or bleeding of the skin around the lips, eyes, mouth, nose and genitals. Also flu-like symptoms and fever. This may be something called ‘Stevens-Johnson syndrome’.


  • Severe blistering rash where layers of the skin may peel off to leave large areas of raw exposed skin over the body. Also a feeling of being generally unwell, fever, chills and aching muscles. This may be something called ‘Toxic epidermal necrolysis’.


  • You have a skin rash or skin lesions with a pink/red ring and a pale centre which may be itchy, scaly or filled with fluid. The rash may appear especially on the palms or soles of your feet. These could be signs of a serious allergy to the medicine called ‘erythema multiforme’.


  • You get infections more easily than usual. This could be because of a blood disorder. This is more likely if you are taking the tablets for a long time.


  • Yellowing of the skin, eyes or mouth and feeling tired. You may also be more pale than normal. This could be because of a serious type of anaemia.




Stop taking your medicine and you contact your doctor without delay if you get:



  • Severe diarrhoea




Tell your doctor or pharmacist if any of the following side effects get serious or lasts longer than a few days



  • Feeling sick (nausea) or being sick (vomiting)


  • Stomach pains


  • Headaches


  • Feeling dizzy


  • Ringing in the ears


  • Feeling tired or weak


  • Itching skin without rash


  • Pins and needles


  • Numbness or tingling feelings

Tell your doctor if any of these side effects gets serious or lasts longer than a few days, or if you notice any side effects not listed in this leaflet.





Blood tests



Orelox Tablets can change the levels of liver enzymes shown up in blood tests. This can mean that your liver is not working properly.




If you think you are reacting badly to the medicine or having any problems, then discuss it with your doctor or your pharmacist.






How to store Orelox Tablets



Keep out of the reach and sight of children.



Store below 25°C.



Do not use Orelox 100mg Tablets after the expiry date which is stated on the label or carton after EXP. The expiry date refers to the last day of that month.



Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.





Further information




What Orelox Tablets contain



  • Each tablet contains 130mg of the active ingredient cefpodoxime proxetil (equivalent to 100mg cefpodoxime).

  • The other ingredients are lactose, magnesium stearate, carboxymethylcellulose calcium, hydroxypropylcellulose, sodium lauryl sulphate. The tablets are film coated with titanium dioxide, talc and hydroxypropylmethylcellulose 6CP.




What Orelox Tablets looks like and content of the pack



Orelox 100mg Tablets are biconvex cylindrical white tablets with “208” and beneath “A” engraved on one side.



Orelox is available in blister packs of 10 tablets.





Marketing Authorisation Holder and Manufacturer



Marketing Authorisation Holder




Sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

Tel:01483 505515

Fax:01483 535432



Manufacturer




Sanofi Winthrop Industrie

56, Route de Choisy–au–bac

60205 Compiegne

France




This leaflet does not contain all the information about your medicine. If you have any questions or are not sure about anything, ask your doctor or pharmacist.




This leaflet was last revised in July 2008.



© sanofi-aventis, 1998 - 2008



R752320






Orudis 50





1. Name Of The Medicinal Product



Orudis 50


2. Qualitative And Quantitative Composition



In terms of the active ingredient



Ketoprofen 50mg



3. Pharmaceutical Form



Capsules



4. Clinical Particulars



4.1 Therapeutic Indications



Recommended in the management of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute articular and periarticular disorders, (bursitis, capsulitis, synovitis, tendinitis), cervical spondylitis, low back pain (strain, lumbago, sciatica, fibrositis), painful musculoskeletal conditions, acute gout, dysmenorrhoea and control of pain and inflammation following orthopaedic surgery.



Orudis reduces joint pain and inflammation and facilitates increase in mobility and functional independence.



It does not cure the underlying disease.



4.2 Posology And Method Of Administration



Oral dosage 50 - 100mg twice daily, morning and evening, depending on patient's weight and on the severity of symptoms.



The maximum daily dose is 200mg. The balance of risks and benefits should be carefully considered before commencing treatment with 200mg daily, and higher doses are not recommended (see also section 4.4).



Best results are obtained by titrating dosage to suit each patient: start with a low dosage in mild chronic disease and a high dosage in acute or severe disease. Some patients derive greater benefit by treatment with capsules only, some with a combined capsule/suppository regimen and others with a higher dosage at night time than at early morning. Where patients require a maximum oral dosage initially, an attempt should be made to reduce this dosage for maintenance since lower dosage might be better tolerated for purposes of long-term treatment.



Elderly: The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy.



Paediatric dosage: Not established.



To limit occurrence of gastrointestinal disturbance, capsules should always be taken with food (milk, meals).



Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).



4.3 Contraindications



Ketoprofen is contraindicated in patients who have a history of hypersensitivity reactions such as bronchospasm, asthmatic attacks, rhinitis, angioedema, urticaria or other allergic-type reactions to ketoprofen, any other ingredients in this medicine, ASA or other NSAIDs. Severe, rarely fatal, anaphylactic reactions have been reported in such patients (see section 4.8 Undesirable effects).



Ketoprofen is contraindicated in patients with hypersensitivity to any of the excipients of the drug.



Ketoprofen is also contraindicated in the third trimester of pregnancy.



Ketoprofen is contraindicated in the following cases:



- severe heart failure



- active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding)



- history of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy



- haemorrhagic diathesis



- severe hepatic insufficiency



- severe renal insufficiency



- third trimester of pregnancy



Disease in children (safety/dosage during long-term treatment has not been established).



4.4 Special Warnings And Precautions For Use



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



Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2 Posology and method of administration, and GI and cardiovascular risks below).



The use of ketoprofen with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5 Interactions).



Elderly:



The elderly have an increased risk of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation which may be fatal (see Section 4.2 Posology and method of administration).



Cardiovascular, Renal and Hepatic impairment:



At the start of treatment, renal function must be carefully monitored in patients with heart impairment, heart failure, liver dysfunction, cirrhosis and nephrosis, in patients receiving diuretic therapy, in patients with chronic renal impairment, particularly if the patient is elderly. In these patients, administration of ketoprofen may induce a reduction in renal blood flow caused by prostaglandin inhibition and lead to renal decomposition. (see Section 4.3 Contra-indications).



NSAIDs have also been reported to cause nephrotoxicity in various forms and this can lead to interstitial nephritis, nephrotic syndrome and renal failure.



In patients with abnormal liver function tests or with a history of liver disease, transaminase levels should be evaluated periodically, particularly during long-term therapy. Rare cases of jaundice and hepatitis have been described with ketoprofen.



Cardiovascular and cerebrovascular effects



Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.



Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for ketoprofen.



Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ketoprofen after careful consideration. Similar consideration should be made before initiating long-term treatment in patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).



Respiratory disorders:



Patients with asthma combined with chronic rhinitis, chronic sinusitis, and/or nasal polyposis have a higher risk of allergy to aspirin and/or NSAIDs than the rest of the population. Administration of this medicinal product can cause asthma attacks or bronchospasm, particularly in subjects allergic to aspirin or NSAIDs (see section 4.3).



Gastrointestinal bleeding, ulceration and perforation:



GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events.



Some epidemiological evidence suggests that ketoprofen may be associated with a high risk of serious gastrointestinal toxicity, relative to some other NSAIDs, especially at high doses (see also section 4.2 and 4.3).



The risk of GI bleeding, ulceration or perforation is higher with increasing NSAlD doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).



NSAIDs should only be given with care to patients with a history of gastrointestinal disease (e.g. ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see Section 4.8 Undesirable effects).



Patients with a history of gastrointestinal toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding), particularly in the initial stages of treatment.



Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as corticosteroids, or anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (see Section 4.5).



When GI bleeding or ulceration occurs in patients receiving ketoprofen, the treatment should be withdrawn.



SLE and mixed connective tissue disease:



In patients with systemic lupus erythematosis (SLE) and mixed connective tissue disorders, there may be an increased risk of aseptic meningitis (see Section 4.8 Undesirable effects).



Female fertility:



The use of ketoprofen, as with other NSAIDs, may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulty conceiving or who are undergoing investigation of infertility, withdrawal of ketoprofen should be considered.



Skin reactions:



Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Treatment should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.



Infectious disease:



As with other NSAIDs, in the presence of an infectious disease, it should be noted that the anti-inflammatory, analgesic and the antipyretic properties of ketoprofen may mask the usual signs of infection progression such as fever.



Visual disturbances:



If visual disturbances such as blurred vision occur, treatment should be discontinued.



Patients with active or a past history of peptic ulcer.



4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction



Anticoagulants (heparin and warfarin) and platelet aggregation inhibitors (i.e. ticlopidine, clopidogrel):



Increased risk of bleeding (see section 4.4).



If coadministration is unavoidable, patient should be closely monitored.



Lithium:



Risk of elevation of lithium plasma levels sometimes reaching toxic levels due to decreased lithium renal excretion. Where necessary, plasma levels should be closely monitored and the lithium dosage levels adjusted during and after NSAIDs therapy.



Other analgesics/NSAIDs (including cyclooxygenase-2 selective inhibitors) and high dose salicylates:



Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects, particularly gastrointestinal ulceration and bleeding. (see Section 4.4 Special warnings and precautions for use).



Methotrexate:



Serious interactions have been recorded after the use of high dose methotrexate with NSAIDs, including ketoprofen, due to decreased elimination of methotrexate. At doses greater than 15mg/week:



Increased risk of haematologic toxicity of methotrexate, particularly if administered at high doses (> 15 mg/week), possibly related to displacement of protein-bound methotrexate and to its decreased renal clearance. At doses lower than 15mg/week: During the first weeks of combination treatment, full blood count should be monitored weekly. If there is any alteration of the renal function or if the patient is elderly, monitoring should be done more frequently.



Mifepristone:



NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.



Pentoxifylline:



There is an increased risk of bleeding. More frequent clinical monitoring and monitoring of bleeding time is required.



Antihypertensive agents: (beta-blockers, angiotensin converting enzyme inhibitors, diuretics):



Risk of decreased antihypertensive potency (inhibition of vasodilator prostaglandins by NSAIDs.



Diuretics:



Risk of reduced diuretic effect. Patients and particularly dehydrated patients taking diuretics are at a greater risk of developing renal failure secondary to a decrease in renal blood flow caused by prostaglandin inhibition. Such patients should be rehydrated before initiating coadministration therapy and renal function monitored when the treatment is started (see section 4.4 Special warnings and precautions for use).



Cardiac glycosides:



NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.



Ciclosporin:



Increased risk of nephrotoxicity, particularly in elderly subjects.



Corticosteroids:



Increased risk of gastrointestinal ulceration or bleeding. (see Section 4.4 Special warnings and precautions for use).



Quinolone antibiotics:



Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.



Tacrolimus:



Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus, particularly in elderly subjects.



Thrombolytics:



Increased risk of bleeding.



Probenecid:



Concomitant administration of probenecid may markedly reduce the plasma clearance of ketoprofen.



Anti-platelet agents and Selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (section 4.4 Special warnings and precautions for use).



ACE inhibitors and Angiotensin II Antagonists:



In patients with compromised renal function (e.g. dehydrated patients or elderly patients the co-administration of an ACE inhibitor or Angiotensin II antagonist and agents that inhibit cyclooxygenase may result in further deterioration of renal function, including possible acute renal failure.



Zidovudine:



Increased risk of haematological toxicity when NSAlDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.



4.6 Pregnancy And Lactation



Pregnancy



Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5%. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. During the first and second trimester of pregnancy, ketoprofen should not be given unless clearly necessary. If ketoprofen is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.



During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:



- cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);



- renal dysfunction, which may progress to renal failure with oligo-hydroamniosis; the mother and the neonate, at the end of the pregnancy, to:



- possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.



- Inhibition of uterine contractions resulting in delayed or prolonged labour.



Consequently, ketoprofen is contraindicated during the third trimester of pregnancy.



Lactation



No data are available on excretion of ketoprofen in human milk. Ketoprofen is not recommended in nursing mothers.



4.7 Effects On Ability To Drive And Use Machines



Patients should be warned about the potential for somnolence, dizziness or convulsions, drowsiness, fatigue and visual disturbances and be advised not to drive or operate machinery if these symptoms occur.



4.8 Undesirable Effects



The following CIOMS frequency rating is used, when applicable:



Very common (



The following adverse reactions have been reported with Ketoprofen in adults:



Blood and lymphatic system disorders



- rare: haemorrhagic anaemia, anaemia due to bleeding



- not known: agranulocytosis, thrombocytopenia, bone marrow failure, neutropenia



Immune system disorders



- rare: anaphylactic reactions (including shock)



Psychiatric disorders



- not known: mood altered



Nervous system disorders



- uncommon: headache, dizziness, somnolence



- rare: paraesthesia



- not known: convulsions, dysgeusia, depression, confusion, hallucinations, vertigo, malaise, drowsiness, reports of aseptic meningitis (especially in patients with existing auto-immune disorders such as systemic lupus erythematosis, mixed connective tissue disease) with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (see section 4.4 Special warnings and precautions for use).



Eye disorders



- rare: visual disturbances such as blurred vision (see section 4.4 Special warnings and precautions for use)



- not known: optic neuritis



Ear and labyrinth disorders



- rare: tinnitus



Cardiac disorders



- not known: heart failure, oedema



Vascular disorders



- not known: hypertension, vasodilatation



Respiratory, thoracic and mediastinal disorders



- rare: asthma, asthmatic attack



- not known: bronchospasm (particularly in patients with known hypersensitivity to ASA and other NSAIDs), rhinitis, non-specific allergic reactions, dyspnoea



Gastrointestinal disorders



- common: dyspepsia, nausea, abdominal pain, vomiting



- uncommon: constipation, diarrhoea, flatulence, gastritis



- rare: stomatitis, peptic ulcer



- very rare: pancreatitis (very rare reports of pancreatitis have been noted with NSAIDs)



- not known: exacerbation of colitis and Crohn's disease, gastrointestinal haemorrhage and perforation, gastralgia, melaena, haematemesis



Gastrointestinal bleeding may sometimes be fatal, particularly in the elderly (see section 4.4 Special warnings and precautions for use).



Hepatobiliary disorders



- rare: hepatitis, transaminases increased, elevated serum bilirubin due to hepatitis disorders



- not known: abnormal liver function, jaundice



Skin and subcutaneous disorders



- uncommon: rash, pruritis



- not known: photosensitivity reactions, alopecia, urticaria, angioedema, bullous eruption including Stevens-Johnson syndrome and toxic epidermal necrolysis, exfoliative and bullous dermatoses (including epidermal necrolysis, erythema multiforme), purpura



Renal and urinary disorders



- not known: renal failure acute, tubulointerstitial nephritis, nephritic syndrome, renal function tests abnormal



General disorders and administration site conditions



- uncommon: oedema, fatigue



- not known: headache, taste perversion



Investigations



- rare: weight increased



Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4 Special warnings and precautions for use).



In all cases of major adverse effects Orudis should be withdrawn at once.



4.9 Overdose



Symptoms



Cases of overdose have been reported with doses up to 2.5g of ketoprofen. In most instances, the symptoms observed have been benign and limited to lethargy, drowsiness, nausea, vomiting and epigastric pain. Headache, rarely diarrhoea, disorientation, excitation, coma, dizziness, tinnitus, fainting, occasionally convulsions may also occur. Adverse effects seen after overdose with propionic acid derivatives such as hypotension, bronchospasm and gastro-intestinal haemorrhage should be anticipated.



In cases of significant poisoning, acute renal failure and liver damage are possible.



If renal failure is present, haemodialysis may be useful to remove circulating medicinal product.



Therapeutic measures:



There are no specific antidotes to ketoprofen overdosages. In cases of suspected massive overdosages, a gastric lavage is recommended and symptomatic and supportive treatment should be instituted to compensate for dehydration, to monitor urinary excretion and to correct acidosis, if present.



Within one hour of ingestion, consideration should be given to administering activated charcoal.



Alternatively, in adults, gastric lavage should be considered if the patient presents within 1 hour of ingesting a potentially toxic amount.



Good urine output should be ensured.



Renal and liver function should be closely monitored.



Patients should be observed for at least four hours after ingestion of potentially toxic amounts.



Frequent or prolonged convulsions should be treated with intravenous diazepam.



The benefit of gastric decontamination is uncertain.



Other measures may be indicated by the patient's clinical condition.



5. Pharmacological Properties



5.1 Pharmacodynamic Properties



Ketoprofen overall has the properties of a potent non-steroidal anti-inflammatory agent. It has the following pharmacological effects.



Anti-inflammatory



It inhibits the development of carageenan-induced abscesses in rats at 1mg/kg and UV-radiation induced erythema in guinea pigs at 6mg/kg. It is also a potent inhibitor of PGE2 and PGF synthesis in guinea pigs and human chopped lung preparations.



Analgesic



Ketoprofen effectively reduced visceral pain in mice caused by phenyl benzoquinone or by bradykinin following P.O. administration at about 6mg/kg.



Antipyretic



Ketoprofen (2 and 6mg/kg) inhibited hyperthermia caused by s.c. injection of brewer's yeast in rats and, at 1mg/kg, hyperthermia caused by i.v. administration of antigonococcal vaccine to rabbits.



Ketoprofen at 10mg/kg i.v. did not affect the cardiovascular, respiratory, central nervous system or autonomic nervous systems.



5.2 Pharmacokinetic Properties



Ketoprofen is completely absorbed from Orudis capsules and maximum plasma concentrations occur after ½ - 1 hour. It declines thereafter with a elimination half-life of about 2 - 3 hours. There is no accumulation on continued daily dosing.



5.3 Preclinical Safety Data



No additional data of relevance to the prescriber



6. Pharmaceutical Particulars



6.1 List Of Excipients



Lactose, magnesium stearate



Capsule shells (Elanco & Scherer)



Opaque purple cap: Brilliant Blue FCF (E133), Erythrosine (E127), Titanium Dioxide (E171), Gelatin. Opaque green base: Brilliant Blue FCF (E133), Yellow iron Oxide (E172), Titanium Dioxide (E171), Gelatin



Capsule shells (Capsulgel)



Opaque purple cap: Patent Blue V (E131), Erythrosine (E127), Titanium Dioxide (E171), Gelatin. Opaque green base: Yellow iron Oxide (E172), Patent Blue V (E131), Titanium Dioxide (E171), Gelatin



6.2 Incompatibilities



None stated



6.3 Shelf Life



60 months



6.4 Special Precautions For Storage



Store in a dry place below 25°C. Protect from light.



6.5 Nature And Contents Of Container



Cardboard carton containing blister packs of 112 capsules



6.6 Special Precautions For Disposal And Other Handling



None stated.



7. Marketing Authorisation Holder



Sanofi-aventis



One Onslow Street



Guildford



Surrey



GU1 4YS



UK



8. Marketing Authorisation Number(S)



PL 04425/0576



9. Date Of First Authorisation/Renewal Of The Authorisation



13/09/2006



10. Date Of Revision Of The Text



11 May 2011



11. LEGAL CLASSIFICATION


POM




Osmanil 50 micrograms / h transdermal patch





1. Name Of The Medicinal Product



Osmanil 50 micrograms/h transdermal patch


2. Qualitative And Quantitative Composition



Each patch releases 50 micrograms fentanyl per hour. Each patch of 15 cm2 contains 8.25 mg fentanyl.



For a full list of excipients, see section 6.1.



3. Pharmaceutical Form



Transdermal patch



Transparent and colourless patch with blue imprint on the backing foil: “fentanyl 50 μg/h“.



4. Clinical Particulars



4.1 Therapeutic Indications



The product is indicated in severe chronic pain which can be adequately managed only with opioid analgesics.



4.2 Posology And Method Of Administration



The dosing is individual and based on the patient's opioid history and takes into account:



- the possible development of tolerance,



- the current general condition,



- the medical status of the patient and



- the degree of severity of the disorder.



The required fentanyl dosage is adjusted individually and should be assessed regularly after each administration.



Patients receiving opioid treatment for the first time



For initial dosing patches with a release rate of 12.5 micrograms/hour should be used. In very elderly or weak patients, it is not recommended to initiate an opioid treatment with Osmanil, due to their known susceptibility to opioid treatments. In these cases, it would be preferable to initiate a treatment with low doses of immediate release morphine and to prescribe Osmanil after determination of the optimal dosage.



Switching from other opioids



When changing over from oral or parenteral opioids to fentanyl treatment, the initial dosage should be calculated as follows:



1. The quantity of analgesics required over the last 24 hours should be determined.



2. The obtained sum should be converted to correspond the oral morphine dosage using Table 1.



3. The corresponding fentanyl dosage should be determined as follows:



a) using Table 2 for patients who have a need for opioid rotation (conversion ratio of oral morphine to transdermal fentanyl equal to150:1)



b) using Table 3 for patients on stable and well tolerated opioid therapy (conversion ratio of oral morphine to transdermal fentanyl equal to 100:1)



Table 1: Equianalgesic potency conversion



All dosages given in the table are equivalent in analgesic effect to 10 mg parenteral morphine.











































 



 




Equianalgesic doses (mg)


 


Active substance




Parenteral (im)




Oral




Morphine




10




30-40




Hydromorphone




1.5




7.5




Oxycodone




10-15




20-30




Methadone




10




20




Levorphanol




2




4




Oxymorphine




1




10 (rectal)




Diamorphine




5




60




Pethidine




75




-




Codeine




-




200




Buprenorphine




0.4




0.8 (sublingual)




Ketobemidone




10




20-30



Table 2: Recommended initial dose of transdermal fentanyl based on daily oral morphine dose (for patients who have a need for opioid rotation)































Oral morphine dose (mg/24 h)


Transdermal fentanyl release (micrograms/h)




< 44




12.5




45-134




25




135-224




50




225-314




75




315-404




100




405-494




125




495-584




150




585-674




175




675-764




200




765-854




225




855-944




250




945-1034




275




1035-1124




300



Table 3: Recommended initial dose of transdermal fentanyl based on daily oral morphine dose (for patients on stable and well tolerated opioid therapy)
































Oral morphine dose (mg/24 h)




Transdermal fentanyl release (micrograms/h)




< 60




12.5




60-89




25




90-149




50




150-209




75




210-269




100




270-329




125




330-389




150




390-449




175




450-509




200




510-569




225




570-629




250




630-689




275




690-749




300



By combining several transdermal patches, a fentanyl release rate of over 100 micrograms/h can be achieved.



The initial evaluation of the maximum analgesic effect of Osmanil should not be made before the patch has been worn for 24 hours. This is due to the gradual increase in serum fentanyl concentrations during the first 24 hours after application of the patch.



In the first 12 hours after changing to Osmanil the patient continues to receive the previous analgesic at the previous dose; over the next 12 hours this analgesic is administered according to need.



Dose titration and maintenance therapy



The patch should be replaced every 72 hours. The dose should be titrated individually until analgesic efficacy is attained. In patients who experience a marked decrease in the period 48-72 hours after application, replacement of fentanyl after 48 hours may be necessary. The dose 12.5 micrograms/hour is appropriate for dose titration in the lower dosage area. If analgesia is insufficient at the end of the initial application period, the dose may be increased after 3 days, until the desired effect is obtained for each patient. Additional dose adjustment should normally be performed in 25 micrograms/hour increments, although the supplementary analgesic requirements and pain status of the patient should be taken into account.



Patients may require periodic supplemental doses of a short-acting analgesic for breakthrough pain. Additional or alternative methods of analgesia or alternative administration of opioids should be considered when the Osmanil dose exceeds 300 micrograms/hour.



Withdrawal symptoms have been reported when changing from long-term treatment with morphine to transdermal fentanyl despite adequate analgesic efficacy. In case of withdrawal symptoms it is recommended to treat those with short-acting morphine in low doses.



Changing or ending therapy



If discontinuation of the patch is necessary, any replacement with other opioids should be gradual, starting at a low dose and increasing slowly. This is because fentanyl levels fall gradually after the patch is removed; it takes at least 17 hours for the fentanyl serum concentration to decrease by 50 %. As a general rule, the discontinuation of opioid analgesia should be gradual, in order to prevent withdrawal symptoms (nausea, vomiting, diarrhoea, anxiety and muscular tremor). Tables 2 and 3 should not be used to switch from transdermal fentanyl to a morphine treatment.



Method of administration



Directly after removal from the pack and the release liner, the patch is applied to a non-hairy area of skin on the upper body (chest, back, upper arm). To remove hair, scissors should be used instead of razors.



Prior to application, the skin should be carefully washed with clean water (no cleaning agents) and thoroughly dried. The transdermal patch is then applied using slight pressure with the palm of the hand for approximately 30 seconds. The skin area to which the patch is applied should be free of microlesions (e.g. due to irradiation or shaving) and skin irritation.



As the transdermal patch is protected by an outer waterproof backing film, it can also be worn while showering.



Occasionally, additional adhesion of the patch may be required.



If progressive dose increases are made, the active surface area required may reach a point where no further increase is possible.



Duration of administration



The patch should be changed after 72 hours. If an earlier change becomes necessary in individual cases, no change should be made before 48 hours have elapsed, otherwise a rise in mean fentanyl concentrations may occur. A new skin area must be selected for each application. A period of 7 days should be allowed to elapse before applying a new patch to the same area of skin. The analgesic effect may persist for some time after removal of the transdermal patch.



If traces of the transdermal patch remain on the skin after its removal, these can be cleaned off using copious amounts of soap and water. No alcohol or other solvents must be used for cleaning, as these may penetrate the skin due to the effect of the patch.



Paediatric population



Method of administration



In young children, the upper back is the preferred location to apply the patch, to minimize the potential of the child removing the patch.



Posology



Transdermal fentanyl should be administered only to opioid-tolerant paediatric patients (ages 2 to 16 years) who are already receiving at least 30 mg oral morphine equivalents per day.



To convert paediatric patients from oral or parenteral opioids to transdermal fentanyl, refer to “Equianalgesic potency conversion” (table 1), and “Recommended transdermal fentanyl dose based upon daily oral morphine dose (table 4).



Table 4: Recommended transdermal fentanyl dose based upon daily oral morphine dose1










Oral morphine dose



(mg/24 h)




Transdermal fentanyl release



(micrograms/h)




For paediatric patients2



30-44




For paediatric patients2



12.5




45-134




25



1In clinical trials these ranges of daily oral morphine doses were used as a basis for conversion to transdermal fentanyl



2For conversion to Osmanil doses greater than 25 micrograms/h a conversion ratio of oral morphine to transdermal fentanyl of 150:1 is recommended (see table 2)



For children who receive more than 90 mg oral morphine a day, only limited information is currently available from clinical trials. In the paediatric studies, the required fentanyl transdermal patch dose was calculated conservatively: 30 mg to 45 mg oral morphine per day or its equivalent opioid dose was replaced by one Fentanyl 12 micrograms/hour transdermal patch. It should be noted that this conversion schedule for children only applies to the switch from oral morphine (or its equivalent) to transdermal fentanyl. The conversion schedule could not be used to convert from transdermal fentanyl into other opioids, as overdose could than occur.



The analgesic effect of the first dose of transdermal fentanyl will not be optimal within the first 24 hours. Therefore, during the first 12 hours after switching to transdermal fentanyl, the patient should be given the previous regular dose of analgesics. In the next 12 hours, these analgesics should be provided based on clinical need.



Since peak fentanyl levels occur after 12 to 24 hours of treatment, monitoring of the patient for adverse events, which may include hypoventilation, is recommended for at least 48 hours after initiation of transdermal fentanyl therapy or up-titration of the dose (see also section 4.4).



Dose titration and maintenance



If the analgesic effect of transdermal fentanyl is insufficient, supplementary morphine or another short-duration opioid should be administered. Depending on the additional analgesic needs and the pain status of the child, it may be decided to use more patches. Dose adjustments should be done in 12.5 micrograms/h steps.



Use in elderly patients



Elderly should be observed carefully and the dose reduced if necessary (see sections 4.4 and 5.2).



Hepatic and renal impairment



Patients with hepatic or renal impairment should be observed carefully and the dose reduced if necessary (see section 4.4).



4.3 Contraindications



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



- Acute or postoperative pain, since dosage titration is not possible during short-term use.



- Severe impairment of the central nervous system.



4.4 Special Warnings And Precautions For Use



The product should be used only as part of an integrated treatment of pain in cases where the patient is adequately assessed medically, socially and psychologically.



Treatment with Osmanil should only be initiated by an experienced physician familiar with the pharmacokinetics of fentanyl transdermal patches and the risk for severe hypoventilation.



After exhibiting a serious adverse reaction a patient should be monitored for 24 hours following removal of a transdermal patch due to the half life of fentanyl (see section 5.2).



In chronic non-cancer pain, it might be preferable to initiate the treatment with immediate-release strong opioids (e.g. morphine) and to prescribe fentanyl transdermal patch after determination of the efficacy and the optimal dosage of the strong opioid.



The transdermal patch should not be cut, since no information is available on the quality, efficacy and safety of such divided patches.



If higher dosages than 500 mg morphine-equivalent are needed, a reassessment of opioid-therapy is recommended.



The most common adverse reactions following administration at usual doses are drowsiness, confusion, nausea, vomiting and constipation. The first of these are transient and their cause should be investigated if symptoms persist. Constipation, on the other hand, does not stop if treatment continues. All of these effects can be expected and should, therefore, be anticipated in order to optimise treatment, especially constipation. Corrective treatment may often be required (see section 4.8).



The concomitant use of barbituric acid derivatives, buprenorphine, nalbuphine or pentazocine is not recommended (see also section 4.5).



Breakthrough pain



Studies have shown that almost all patients, despite treatment with a fentanyl patch, require supplemental treatment with potent rapid-release medicinal products to arrest breakthrough pain.



Respiratory depression



As with all potent opioids some patients may experience respiratory depression with Osmanil, and patients must be observed for this effect. Respiratory depression may persist beyond the removal of the patch. The incidence of respiratory depression increases as the fentanyl dose is increased. CNS active substances may worsen the respiratory depression (see section 4.5).



In patients with existing respiratory depression, fentanyl should only be used with caution and at a lower dose.



Chronic pulmonary disease



In patients with chronic obstructive or other pulmonary diseases fentanyl may have more severe adverse reactions, in such patients opioids may decrease respiratory drive and increase airway resistance.



Drug dependence



Tolerance and physical and psychological dependence may develop upon repeated administration of opioids, but is rare in treatment of cancer related pain.



Increased intracranial pressure



Osmanil should be used with caution in patients who may be particularly susceptible to the intracranial effects of CO2 retention such as those with evidence of increased intracranial pressure, impaired consciousness or coma.



Cardiac disease



Opioids may cause hypotension, especially in patients with hypovolemia. Caution should therefore be taken in treatment of patients with hypotension and/or patients with hypovolemia. Fentanyl may produce bradycardia. Osmanil should be administered with caution to patients with bradyarrhythmias.



Impaired liver function



Fentanyl is metabolised to inactive metabolites in the liver, so patients with hepatic disease might have a delayed elimination. Patients with hepatic impairment should be observed carefully and the dose reduced if necessary.



Renal impairment



Less than 10 % of fentanyl is excreted unchanged by the kidneys, and unlike morphine, there are no known active metabolites eliminated by the kidneys. Data obtained with intravenous fentanyl in patients with renal failure suggest that the volume of distribution of fentanyl may be changed by dialysis. This may affect serum concentrations. If patients with renal impairment receive transdermal fentanyl they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary.



Patients with fever/external heat



Significant increases in body temperature can potentially increase fentanyl absorption rate. Therefore patients who develop fever should be monitored for opioid adverse reactions. The patch application site should not be exposed to heat from external heat sources, e.g. sauna.



Elderly patients



Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life. Moreover elderly patients may be more sensitive to the active substance than younger patients. However, studies of fentanyl transdermal patch in elderly patients demonstrated fentanyl pharmacokinetics which did not differ significantly from young patients although serum concentrations tended to be higher. Elderly or cachectic patients should be observed carefully and the dose reduced if necessary.



Paediatric patients



Transdermal fentanyl should not be administered to opioid naïve paediatric patients (see section 4.2). The potential for serious or life-threatening hypoventilation exists regardless of the dose of transdermal fentanyl administered (see tables 1 and 4 in section 4.2).



Transdermal fentanyl was not studied in infants and toddlers under 2 years of age. Transdermal fentanyl should be administered only to opioid-tolerant children aged 2 years or older (see section 4.2). Transdermal fentanyl should not be used in infants and toddlers under 2 years of age.



To guard against accidental ingestion by children, use caution when choosing the application site for transdermal fentanyl patches (see section 4.2) and monitor adhesion of the patch closely.



Lactation



As fentanyl is excreted into breast milk, lactation should be discontinued under treatment with Osmanil (see also section 4.6).



Patients with myasthenia gravis



Non-epileptic (myo)clonic reactions can occur. Caution should be exercised when treating patients with myasthenia gravis.



4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction



The concomitant use of barbituric acid derivatives should be avoided, since the respiratory depressing effect of fentanyl may be increased.



The concomitant use of buprenorphine, nalbuphine or pentazocine is not recommended. They have high affinity to opioid receptors with relatively low intrinsic activity and therefore partially antagonise the analgesic effect of fentanyl and may induce withdrawal symptoms in opioid dependant patients (see also section 4.4).



The concomitant use of other CNS depressants may produce additive depressant effects and hypoventilation, hypotension as well as profound sedation or coma may occur. The CNS depressants mentioned above include:



- opioids



- anxiolytics and tranquilizers



- hypnotics



- general anaesthetics



- phenothiazines



- skeletal muscle relaxants



- sedating antihistamines



- alcoholic beverages



Therefore, the use of any of the above mentioned concomitant medicinal products and active substances require observation of the patient.



MAO-inhibitors have been reported to increase the effect of narcotic analgesics, especially in patients with cardiac failure. Therefore, fentanyl should not be used within 14 days after discontinuation of treatment with MAO-inhibitors.



Fentanyl, a high clearance active substance, is rapidly and extensively metabolised mainly by CYP3A4.



Itraconazole (a potent CYP3A4 inhibitor) at 200 mg/day given orally for four days had no significant effect on the pharmacokinetics of intravenous fentanyl. Increased plasma concentrations were, however, observed in individual subjects. Oral administration of ritonavir (one of the most potent CYP3A4 inhibitors) reduced the clearance of intravenous fentanyl by two thirds and doubled the half-life. Concomitant use of potent CYP3A4-inhibitors (e.g. ritonavir) with transdermally administered fentanyl may result in increased plasma concentrations of fentanyl. This may increase or prolong both the therapeutic effects and the adverse reactions, which may cause severe respiratory depression. In such cases increased care and observation of the patient should be undertaken. Combined use of ritonavir or other potent CYP3A4-inhibitors with transdermal fentanyl is not recommended, unless the patient is carefully observed.



4.6 Pregnancy And Lactation



The safety of fentanyl in pregnancy has not been established. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Fentanyl should only be used during pregnancy when clearly necessary.



Long-term treatment during pregnancy may cause withdrawal symptoms in the infant.



It is advised not to use fentanyl during labour and delivery (including caesarean section) since fentanyl passes the placenta and may cause respiratory depression in the new born infant.



Fentanyl is excreted into breast milk and may cause sedation and respiratory depression in the breast-fed infant. Lactation should therefore be discontinued during treatment and for at least 72 hours after the removal of Osmanil (see also section 4.4).



4.7 Effects On Ability To Drive And Use Machines



Osmanil has major influence on the ability to drive and use machines. This has to be expected especially at the beginning of treatment, at any change of dosage as well as in connection with alcohol or tranquilizers. Patients stabilized on a specific dosage will not necessarily be restricted. Therefore, patients should consult their physician as to whether driving or use of machines is permitted.



4.8 Undesirable Effects



The following frequencies are used for the description of the occurrence of adverse reactions:



Very common (



The most serious undesirable effect of fentanyl is respiratory depression.



Cardiac disorders



Uncommon: tachycardia, bradycardia.



Rare: arrhythmia.



Nervous system disorders



Very common: headache, dizziness.



Uncommon: tremor, paraesthesia, speech disorder.



Very rare: ataxia, seizures (including clonic and grand mal seizures).



Eye disorders



Very rare: amblyopia.



Respiratory, thoracic and mediastinal disorders



Uncommon: dyspnoea, hypoventilation.



Very rare: respiratory depression, apnoea.



Gastrointestinal disorders



Very common: nausea, vomiting, constipation.



Common: xerostomia, dyspepsia.



Uncommon: diarrhoea.



Rare: hiccup.



Very rare: painful flatulence, ileus.



Renal and urinary disorders



Uncommon: urinary retention.



Very rare: cystalgia, oliguria.



Skin and subcutaneous tissue disorders



Very common: sweating, pruritus.



Common: skin reactions on the application site.



Uncommon: exanthema, erythema.



Rash, erythema and pruritus will usually disappear within one day after the patch has been removed.



Vascular disorders



Uncommon: hypertension, hypotension.



Rare: vasodilatation.



General disorders and administration site conditions



Rare: oedema, cold feeling.



Immune system disorders



Very rare: anaphylaxis.



Psychiatric disorders



Very common: somnolence.



Common: sedation, nervousness, loss of appetite.



Uncommon: euphoria, amnesia, insomnia, hallucinations, agitation.



Very rare: delusional ideas, states of excitement, asthenia, depression, anxiety, confusion, sexual dysfunction, withdrawal symptoms.



Other undesirable effects



Not known (cannot be estimated from the available data): Long-term use of fentanyl can lead to development of tolerance and physical and psychological dependence. After switching from previously prescribed opioid analgesics to Osmanil or after abrupt discontinuation of therapy patients may show opioid withdrawal symptoms (for instance: nausea, vomiting, diarrhoea, anxiety and shivering).



The adverse event profile in children and adolescents treated with transdermal fentanyl was similar to that observed in adults. No risk was identified in the paediatric population beyond that expected with the use of opioids for the relief of pain associated with serious illness and there does not appear to be any paediatric-specific risk associated with transdermal fentanyl use in children as young as 2 years old when used as directed. Very common adverse events reported in paediatric clinical trials were fever, vomiting, and nausea.



4.9 Overdose



Symptoms



The symptoms of fentanyl overdose are an extension of its pharmacological actions, e.g. lethargy, coma, respiratory depression with Cheyne-Stokes respiration and/or cyanosis. Other symptoms may be hypothermia, decreased muscle tonus, bradycardia, hypotension. Signs of toxicity are deep sedation, ataxia, miosis, convulsions and respiratory depression, which is the main symptom.



Treatment



For management of respiratory depression immediate countermeasures should be started, including removing the patch and physically or verbally stimulating the patient. These actions can be followed by administration of a specific opioid antagonist such as naloxone.



A starting dose of 0.4-2 mg naloxone hydrochloride i.v. is recommended for adults. If needed, a similar dose can be given every 2 or 3 minutes, or be administered as continued infusion as 2 mg in 500 ml sodium chloride 9 mg/ml (0.9 %) solution for injection or glucose 50 mg/ml (5 %) solution. The infusion rate should be adjusted according to previous bolus injections and the individual response of the patient. If intravenous administration is impossible, naloxone hydrochloride can also be given intramuscularly or subcutaneously. Following intramuscular or subcutaneous administration the onset of action will be slower compared with intravenous administration. Intramuscular administration will give a more prolonged effect than intravenous administration. Respiratory depression due to overdose can persist longer than the effect of the opioid antagonist. Reversing the narcotic effect can give rise to acute pain and release of catecholamines. Intensive care unit treatment is important, if required by the patient's clinical condition. If severe or persistent hypotension occurs, hypovolemia should be considered, and the condition should be managed with appropriate parenteral fluid therapy.



5. Pharmacological Properties



5.1 Pharmacodynamic Properties



Pharmacotherapeutic group: opioids; Phenylpiperidine derivatives, ATC code: N02AB03



Fentanyl is an opioid analgesic which interacts predominantly with the μ-receptor. Its principal therapeutic effects are analgesia and sedation. The serum concentrations of fentanyl that cause a minimal analgesic effect in opioid-naive patients fluctuate between 0.3–1.5 ng/ml; an increased incidence of adverse reactions is observed if serum levels exceed 2 ng/ml.



Both the lowest effective fentanyl concentration and the concentration causing adverse reactions will increase with the development of increasing tolerance. The tendency to develop tolerance varies considerably between individuals.



The safety of transdermal fentanyl was evaluated in three open-label trials in 293 paediatric patients with chronic pain, 2 years of age through to 18 years of age, of which 66 children were aged 2 to 6 years. In these studies, 30 mg to 45 mg oral morphine per day was replaced by one patch with a release rate of 12.5 micrograms/h. Starting doses of 25 micrograms/h and higher were used by 181 patients who had been on prior daily opioid doses of at least 45 mg of oral morphine.



5.2 Pharmacokinetic Properties



Following administration of Osmanil, fentanyl is continuously absorbed through the skin over a period of 72 hours. Due to the polymer matrix and the diffusion of fentanyl through the skin layers, the release rate remains relatively constant.



Absorption



After the first application of Osmanil, serum fentanyl concentrations increase gradually, generally levelling off between 12 and 24 hours, and remaining relatively constant for the remainder of the 72-hour application period. The serum fentanyl concentrations attained are dependant on the fentanyl transdermal patch size. For all practical purposes by the second 72-hour application, a steady state serum concentration is reached and is maintained during subsequent applications of a patch of the same size.



Distribution



The plasma protein binding for fentanyl is 84 %.



Biotransformation



Fentanyl is metabolized primarily in the liver via CYP3A4. The major metabolite, norfentanyl, is inactive.



Elimination



When treatment with Osmanil is withdrawn, serum fentanyl concentrations decline gradually, falling approximately 50 % in 13-22 hours in adults or 22-25 hours in children, respectively. Continued absorption of fentanyl from the skin accounts for a slower reduction in serum concentration than is seen after an intravenous infusion.



Around 75 % of fentanyl is excreted into the urine, mostly as metabolites, with less than 10 % as unchanged active substance. About 9 % of the dose is recovered in the faeces, primarily as metabolites.



Pharmacokinetics in special groups



Elderly and debilitated patients may have reduced clearance of fentanyl leading to prolonged terminal half life. In patients with renal or hepatic impairment, clearance of fentanyl may be altered because of changes of plasma proteins and metabolic clearance resulting in increased serum concentrations.



Adjusting for body weight, clearance (l/h/kg) in paediatric patients, appears to be 82 % higher in children 2 to 5 years old and 25 % higher in children 6 to 10 years old when compared to children 11 to 16 years old, who are likely to have the same clearance as adults. These findings have been taken into consideration in determining the dosing recommendations for paediatric patients.



5.3 Preclinical Safety Data



Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.



Animal studies have shown reduced fertility and increased mortality in rat foetuses. Teratogenic effects have, however, not been demonstrated.



Long-term carcinogenicity studies have not been performed.



6. Pharmaceutical Particulars



6.1 List Of Excipients



Adhesive layer



Polyacrylate adhesive layer



Backing film



Polypropylene foil



Blue printing ink



Release liner



Polyethylene terephthalate foil (siliconised)



6.2 Incompatibilities



Not applicable.



6.3 Shelf Life



36 months



6.4 Special Precautions For Storage



Do not store above 30 °C.



6.5 Nature And Contents Of Container



Each transdermal patch is packed in a separate sachet.



- Sachets made of composite foil containing the following layers from outside to inside:



coated Kraft paper, low density polyethylene foil, aluminium foil, Surlyn (thermoplastic ethylene-methacrylic acid copolymer).



Pack containing 3, 5, 10 or 20 transdermal patches



- Child resistant sachets made of composite foil containing the following layers from outside to inside:



PET foil, adhesive, aluminium foil, adhesive, Surlyn (ionomer-coex foil).



Pack containing 3, 5, 10 or 20 transdermal patches



Not all pack sizes may be marketed.



6.6 Special Precautions For Disposal And Other Handling



High quantities of fentanyl remain in the transdermal patches even after use. Used transdermal patches should be folded with the adhesive surfaces inwards and discarded or whenever possible returned to the pharmacy. Any unused medicinal product should be discarded or returned to the pharmacy.



7. Marketing Authorisation Holder



Winthrop Pharmaceuticals UK Limited



One Onslow Street



Guildford



Surrey



GU1 4YS



United Kingdom



8. Marketing Authorisation Number(S)



PL 17780/0314



9. Date Of First Authorisation/Renewal Of The Authorisation



29 May 2008



10. Date Of Revision Of The Text



14 April 2010



Legal category


POM/CD2