Saturday, October 22, 2016

Anadin Ultra Double Strength 400mg Capsules / Anadin LiquiFast 400mg Capsules





1. Name Of The Medicinal Product



Anadin Ultra Double Strength 400 mg Capsules



Anadin LiquiFast 400 mg Capsules


2. Qualitative And Quantitative Composition



Each capsule contains 400mg Ibuprofen



For excipients, see 6.1



3. Pharmaceutical Form



Soft capsule



A 14 oval capsule with a dye free, translucent gelatin shell, printed with '400' in black ink, and containing a clear liquid fill.



4. Clinical Particulars



4.1 Therapeutic Indications



For relief of rheumatic or muscular pain, pain of non-serious arthritic conditions, backache, neuralgia, migraine, headache, dental pain, dysmenorrhoea, feverishness, symptoms of colds and influenza.



4.2 Posology And Method Of Administration



For oral administration and short term use only.



Adults, the elderly and young persons over 12 years of age:



The minimum effective dose should be used for the shortest time necessary to relieve symptoms. If the product is required for more than 10 days or if the symptoms worsen, the patient should consult a doctor.



1 capsule up to 3 times a day, as required.



The capsules should be taken with water.



Leave at least 4 hours between doses and do not take more than 1200 mg (3 capsules) in any 24 hour period.



Not to be used for children under 12 years of age.



4.3 Contraindications



Hypersensitivity to ibuprofen or any of the constituents in the product.



Ibuprofen is contraindicated in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angiodema or urticaria) in response to aspirin or other non steroidal anti-inflammatory drugs.



Active or previous peptic ulcer (two or more distinct episodes of proven ulceration or bleeding).



History of upper gastrointestinal bleeding or perforation, related to previous NSAID therapy.



Patients with severe hepatic failure, severe renal failure or severe heart failure. (See section 4.4).



Use in third trimester of pregnancy (see section 4.6).



4.4 Special Warnings And Precautions For Use



Caution is required in patients with certain conditions:



- systemic lupus erythematosus as well as those with mixed connective tissue disease due to increased risk of aseptic meningitis (see section 4.8).



- gastrointestinal disorders and chronic inflammatory intestinal disease as these conditions may be exacerbated (ulcerative colitis, Crohn's disease) (see section 4.8).



- caution is required prior to starting treatment in patients with a history of hypertension and/or heart failure. Oedema, hypertension and/or cardiac impairment as renal function may deteriorate and/or fluid retention occur (see section 4.5).



- renal impairment as renal function may deteriorate (see section 4.3 and 4.8).



- hepatic dysfunction (see section 4.3 and 4.8).



Undesirable effects may be minimised by using the minimum effective dose for the shortest possible duration (see GI and cardiovascular risks below).



The elderly are at increased risk of the serious consequences of adverse reactions.



Bronchospasm may be precipitated in patients suffering from or with a previous history of bronchial asthma or allergic disease.



Use with concomitant NSAIDs including cyclo-oxygenase-2 specific inhibitors (See section 4.5).



Cardiovascular and cerebrovascular effects



Clinical trial and epidemiological data suggest that use of ibuprofen, particularly at high doses (2400mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g.



There is some evidence that drugs which inhibit cyclo-oxygenase/prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible on withdrawal of treatment.



GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events (including ulcerative colitis, Crohn's disease)..



The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID 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.



Patients with a history of GI toxicity, particularly the 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 gastrotoxicity or bleeding, such as corticosteroids, or anticoagulants such as warfarin, selective serotonin re-uptake inhibitors or anti-platelet agents such as aspirin (see section 4.5).



Where GI bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be withdrawn immediately.



Dermatological:



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 NSAIDSs (see section 4.8). Patients appear to be at highest risk for 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. Ibuprofen should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.



Patients with rare hereditary problems of fructose intolerance should not take this medicine.



The label will include:



Do not take if you:



• have (or have had two or more episodes of) a stomach ulcer, perforation or bleeding



• are allergic to ibuprofen or any other ingredient of the product, aspirin or other related painkillers



• are taking other NSAID painkillers, or aspirin with a daily dose above 75mg



Speak to a pharmacist or your doctor before taking if you:



• have or have had asthma, diabetes, high cholesterol, high blood pressure, a stroke, heart, liver, kidney or bowel problems



• are a smoker



• are pregnant



If symptoms persist or worsen, consult your doctor.



4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction



Ibuprofen should not be used in combination with:



Aspirin: unless low dose aspirin (not above 75mg daily) has been advised by a doctor, as this may increase the risk of adverse reactions (see section 4.4).



Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex-vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).



Other NSAIDs including cyclooxygenase-2 selective inhibitors, as these may increase the risk of adverse effects (see section 4.4).



Ibuprofen should be used with caution in combination with:



Corticosteroids: may increase the risk of adverse reactions, especially of the gastrointestinal tract (see section 4.4).



Antihypertensives and diuretics: NSAIDs may diminish the effects of these drugs. Diuretics can increase the risk of nephrotoxicity of NSAIDs.



Anticoagulants: NSAIDS may enhance the effects of anticoagulants, such as warfarin (see section 4.4).



Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4)



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



Lithium: There is evidence for potential increase in plasma levels of lithium.



Methotrexate: There is the potential for increased plasma levels of methotrexate.



Ciclosporin: Increased risk of nephrotoxicity.



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



Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.



Zidovudine: There is evidence of an increased risk of haemarthroses and haematoma in HIV positive haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.



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.



4.6 Pregnancy And Lactation



Pregnancy



While no teratogenic effect has been demonstrated in animal experiments, use of Ibuprofen should be avoided during the first 6 months of pregnancy.



During the 3rd trimester, ibuprofen is contraindicated. As there is a risk of premature closure of the foetal ductus arteriosus with possible persistent pulmonary hypertension. The onset of labour may be delayed and duration of labour increased, with increased bleeding tendency in both mother and child (see section 4.3).



Lactation



Ibuprofen appears in breast milk in very low concentrations, and is unlikely to affect the breast fed infant adversely.



See section 4.4 regarding female fertility



4.7 Effects On Ability To Drive And Use Machines



None.



4.8 Undesirable Effects



Hypersensitivity reactions have been reported and these may consist of:



a) Non-specific allergic reactions and anaphylaxis,



b) Respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea,



c) Various skin reactions, e.g. pruritus, urticaria, angioedema and more rarely, exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).



The list of the following adverse effects relates to those experienced with ibuprofen at OTC doses, from short-term use. In chronic conditions, under long-term treatment, additional adverse effects may occur. The most commonly-observed adverse events are gastrointestinal in nature.
































































Blood and lymphatic disorders




Very rare:




Haematopoietic disorders (anaemia, hemolytic anemia, aplastic anemia), leucopenia, thrombocytopenia, pancytopenia, agranulocytosis). First signs are: fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, nose and skin bleeding.




Immune system disorders




Uncommon:




Hypersensitivity reactions with urticaria and pruritus.



 


Very rare:




In patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease) during treatment with ibuprofen, single cases of symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever or disorientation have been observed.



Severe hypersensitivity reactions. Symptoms could be: facial, tongue and larynx swelling, dyspnoea, tachycardia, hypotension, (anaphylaxis, angioedema or severe shock).



Exacerbation of asthma and bronchospasm.




Psychiatric disorders




Very rare:




Nervousness




Nervous System




Uncommon:




Headache



 


Very rare:




Aseptic meningitis




Eye disorders




Very rare:




Visual disturbance




Ear and labyrinth disorders




Very rare:




Tinnitus and vertigo




Cardiac disorders




Very rare:




Cardiac failure, angina pectoris




Vascular disorders




Very rare:




Hypertension




Respiratory, thoracic and mediastinal disorders




Very rare:




Asthma, broncospasm, dyspnoea and wheezing




Gastrointestinal disorders




Uncommon:




Abdominal pain, abdominal distension dyspepsia and nausea.



 


Rare:




Diarrhoea, flatulence, constipation and vomiting



 


Very rare:




Peptic ulcer, perforation or gastrointestinal haemorrhage, melaena, haematemesis, sometimes fatal, particularly in the elderly (see section 4.4). Exacerbation of ulcerative colitis and Crohn's disease (see section 4.4). Mouth ulceration.




Hepatobiliary disorders




Very rare:




Liver disorders, especially in long-term treatment, hepatitis and jaundice




Skin and subcutaneous tissue disorders




Uncommon:




Various skin rashes



 


Very rare:




Severe forms of skin reactions such as bullous reactions, including Stevens-Johnson Syndrome, erythema multiforme and epidermal necrolysis can occur.




Renal and urinary disorders




Very rare:




Acute renal failure, papillary necrosis, especially in long-term use, associated with increased serum urea and oedema. Haematuria, interstitial nephritis, nephritic syndrome, proteinuria.




General disorders and administration site conditions




Very rare:




Oedema, peripheral oedema




Investigations




Very rare:




Decreased hematocrit and hemoglobin levels



Clinical trial and epidemiological data suggest that use of ibuprofen (particularly at high doses 2400mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).



4.9 Overdose



In children ingestion of more than 400mg/kg may cause symptoms. In adults the dose response effect is less clear cut. The half-life in overdose is 1.5-3 hours.



Symptoms – Most patients who have ingested clinically important amounts of NSAIDs will develop no more than nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache and gastrointestinal bleeding are also possible. In more serious poisoning, toxicity is seen in the central nervous system, manifesting as vertigo, headache, respiratory depression, dyspnoea, drowsiness, occasionally excitation and disorientation or coma. Occasionally patients develop convulsions. In serious poisoning, hypotension, hyperkalaemia, and metabolic acidosis may occur and the prothrombin time / INR may be prolonged, probably due to interference with the actions of circulating clotting factors. Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in asthmatics.



Management – should be symptomatic and supportive and include maintenance of a clear airway and monitoring of cardiac and vital signs until stable. Consider oral administration of activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount. If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma.



5. Pharmacological Properties



5.1 Pharmacodynamic Properties



Pharmacotherapeutic group: Propionic acid derivatives



ATC code: M01AE



Ibuprofen is a phenylpropionic acid derivative NSAID that has demonstrated its efficacy by inhibition of prostaglandin synthesis. In humans, ibuprofen reduces inflammatory pain, swellings and fever. Furthermore, ibuprofen reversibly inhibits platelet aggregation.



Single-dose clinical studies demonstrate that the pain relieving effects of ibuprofen liquigels are evident within around 30 minutes of dosing. The effects of a 400mg dose of ibuprofen liquigels are statistically superior to 1000mg paracetamol tablets both in the speed of onset and extent of analgesia. The differences in onset (see table below) are between 0.6 and 14 min. Ibuprofen 400mg pain relieving effects can last for up to 8 hours.

























































































Clinical Parameters




Ibuprofen Liquigels



200mg




Ibuprofen Liquigels



400mg




Acetaminophen



1g (2 x 500mg)




Placebo




Packman et al



 

 

 

 


Total Pain Relief (TOTPAR)




N/A




N/A




N/A




N/A




Sum of Pain Relief & Pain Intensity Difference (SPID)




N/A




15.2




12.2




5.8




Time to Meaningful Relief (mins)




N/A




39




53




>180




Hersch et al



 

 

 

 


Total Pain Relief (TOTPAR)




14.72




16.56




11.99




5.25




Sum of Pain Relief & Pain Intensity Difference (SPID)




6.93




8.07




5.05




0.46




Time to Meaningful Relief (mins)




30.0




28.8




29.4




>360




Olson et al



 

 

 

 


Total Pain Relief (TOTPAR)




N/A




17.42




13.30




4.33




Sum of Pain Relief & Pain Intensity Difference (SPID)




N/A




11.77




8.36




2.60




Time to Meaningful Relief (mins)




N/A




24.2




29.9




>360




Kellstein et al



 

 

 

 


Total Pain Relief (TOTPAR)




36




30




N/A




52




Pain Intensity Difference (PID) after 2 hours




0.98




0.97




N/A




0.87




Time to Meaningful Relief (mins)




N/A




N/A




N/A




N/A



Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400mg was taken within 8 h before or within 30 min after immediate release aspirin dosing (81mg), a decreased effect of aspirin on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex-vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use.



5.2 Pharmacokinetic Properties



Ibuprofen is rapidly absorbed following administration and is rapidly distributed throughout the whole body. The excretion is rapid and complete via the kidneys. Compared to standard tablet formulations, ibuprofen administered in liquid-filled capsules reaches maximum plasma concentrations significantly faster. Peak plasma concentrations were achieved in around 35 minutes for liquigels compared to around 90 minutes for standard ibuprofen tablets.



The half life of ibuprofen is about 2 hours. In limited studies, ibuprofen appears in breast milk in very low concentrations.



5.3 Preclinical Safety Data



No relevant information additional to that already contained elsewhere in the SPC.



6. Pharmaceutical Particulars



6.1 List Of Excipients



Capsule Contents:



Macrogol 600



Potassium hydroxide



Capsule shell:



Sorbitol liquid, partially dehydrated (containing sorbitan and mannitol)



Gelatin



Purified water



Processing Aids:



Lecithin



Triglycerides (medium chain)



Glyceryl stearate



Oleic acid



Ascorbyl palmitate



Printing Ink:



Opacode black ink [iron oxide black (E172), propylene glycol, polyvinyl acetate phthalate (PVAP), macrogol 400].



6.2 Incompatibilities



None known.



6.3 Shelf Life



3 years



6.4 Special Precautions For Storage



Do not store above 25°C.



6.5 Nature And Contents Of Container



Anadin Ultra Double Strength 400 mg Capsules are packed into blister strips in a cardboard box.



Pack A: Blister: White opaque thermoformed unplasticised PVC (250 μm) / Polyethylene extrusion coating (30 μm) / PVdC (90 gsm) heat sealed to the foil.



Pack B: Blister: White opaque thermoformed unplasticised PVC (250 μm) / PVdC coating (60 gsm) heat sealed to the foil.



Foil: Glassine (35 gsm) / Lamination adhesive / Aluminium foil (9 μm) / Heat seal lacquer (7 gsm).



6.6 Special Precautions For Disposal And Other Handling



No special instructions.



7. Marketing Authorisation Holder



Pfizer Consumer Healthcare Ltd



Ramsgate Road



Sandwich



Kent



CT13 9NJ



United Kingdom



8. Marketing Authorisation Number(S)



PL 00165/0148



9. Date Of First Authorisation/Renewal Of The Authorisation



11/05/2006 / 03/06/2011



10. Date Of Revision Of The Text



October 2011





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