Algezir Ultra

Adults:

Treatment of rheumatoid arthritis, osteoarthritis (degenerative arthritis), ankylosing spondylitis, acute gout, acute musculoskeletal disorders and dysmenorrhoea.

Children:

Juvenile rheumatoid arthritis

For oral administration

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

To be taken preferably with or after food

Rheumatic Disorders (Adults):

500mg to 1g taken in 2 doses at 12-hour intervals or alternatively, as a single administration. In the following cases a loading dose of 750mg or 1g per day for the acute phase is recommended:

a) In patients reporting severe night-time pain/or morning stiffness.

b) In patients being switched to Naprosyn from a high dose of another anti-rheumatic compound.

c) In osteoarthrosis where pain is the predominant symptom.

Children (over 5 years) : A dose of 10mg per kg body weight daily in two divided doses has been used in children over 5 years of age with juvenile rheumatoid arthritis.

Acute Gout (Adults): In acute gout an initial dose of 750 mg followed by 250mg every 8 hours until attack has passed; has been suggested.

Child: Not recommended in children under 16 years.

Musculoskeletal Disorders and Dysmenorrhoea (Adults); 500mg may be given initially followed by 250mg every 6 to 8 hours as required. Maximum daily dose after first day is 1250mg daily.

Child: Not recommended in children under 16 years.

The lowest recommended dose should be used especially in the elderly to reduce the risk of adverse reactions.

Elderly: Studies indicate that although total plasma concentration of Algezir Ultra is unchanged, the unbound plasma fraction of Algezir Ultra is increased in the elderly.

Renal/hepatic impairment: A lower dose should be considered in patients with renal or hepatic impairment. Naprosyn is contraindicated in patients with baseline creatinine clearance less than 30 ml/minute because accumulation of Algezir Ultra metabolites has been seen in patients with severe renal failure or those on dialysis.

Treatment should be reviewed at regular intervals and discontinued if no benefit is seen or intolerance occurs.

- Hypersensitivity to any of the constituents.

- Since the potential exists for cross-sensitivity reactions, Algezir Ultra is contraindicated in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, nasal polyps, angioedema or urticaria) in response to ibuprofen, aspirin, or other non-steroidal anti-inflammatory drugs. These reactions have the potential of being fatal. Severe anaphylactic-like reactions to Algezir Ultra have been reported in such patients.

- - Special warnings and precautions for use).

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- A history of gastrointestinal bleeding or perforation related to previous NSAIDs therapy. Active, or history of peptic ulcer/or active gastrointestinal bleeding (two or more distinct episodes of proven ulceration or bleeding).

- In principle, Algezir Ultra must not be administered to patients with gastrointestinal ulcerations, congestive gastritis or atrophic gastritis, gastrointestinal bleeding or other bleeding such as cerebrovascular bleeding.

- Hemorrhoids or predisposition to rectal bleeding.

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- A history of gastrointestinal bleeding or perforation related to previous NSAIDs therapy. Active, or history of peptic ulcer/or active gastrointestinal bleeding (two or more distinct episodes of proven ulceration or bleeding).

- In principle, Algezir Ultra must not be administered to patients with gastrointestinal ulcerations, congestive gastritis or atrophic gastritis, gastrointestinal bleeding or other bleeding such as cerebrovascular bleeding.

- Hemorrhoids or predisposition to rectal bleeding.

In all patients:

Patients treated with NSAIDs long-term should undergo regular medical supervision to monitor for adverse events.

Elderly:

Severe gastrointestinal side effects may occur in patients who use prostaglandin synthetase inhibitors. The risk of developing gastrointestinal ulcers or bleeding increases with the duration of use and dose of Algezir Ultra. This risk is not limited to a specific patient population, but the elderly and debilitated individuals exhibit poorer tolerance to gastrointestinal ulceration or bleeding than others. The majority of fatal gastrointestinal effects attributed to prostaglandin synthetase inhibitors occurred in this population.

The antipyretic and anti-inflammatory activities of Algezir Ultra may reduce fever and inflammation, thereby diminishing their utility as diagnostic signs.

Respiratory disorders:

Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.

Algezir Ultra decreases platelet aggregation and prolongs bleeding time. This effect should be kept in mind when bleeding times are determined.

Renal and Hepatic Impairment:

There have been reports of impaired renal function, renal failure, acute interstitial nephritis, haematuria, proteinuria, renal papillary necrosis and occasionally nephrotic syndrome associated with Algezir Ultra.

Renal failure linked to reduced prostaglandin production

The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure.-Contraindications).

Use in patients with impaired renal function

As Algezir Ultra is eliminated to a large extent (95%) by urinary excretion via glomerular filtration, it should be used with great caution in patients with impaired renal function and the monitoring of serum creatinine and/or creatinine clearance is advised and patients should be adequately hydrated. Algezir Ultra is contraindicated in patients having a baseline creatinine clearance of less than 30ml/minute.

Haemodialysis does not decrease the plasma concentration of Algezir Ultra because of the high degree of protein binding.

Certain patients, specifically those whose renal blood flow is compromised, such as in extracellular volume depletion, cirrhosis of the liver, sodium restriction, congestive heart failure, and pre-existing renal disease, should have renal function assessed before and during Algezir Ultra therapy. Some elderly patients in whom impaired renal function may be expected, as well as patients using diuretics, may also fall within this category. A reduction in daily dosage should be considered to avoid the possibility of excessive accumulation of Algezir Ultra metabolites in these patients.

Use in patients with impaired liver function

Care should also be exercised in patients with hepatic insufficiency.

Caution is advised when high doses of Algezir Ultra are administered to elderly patients, because there are indications that the quantity of non-protein-bound Algezir Ultra increases in such patients. Since Algezir Ultra has an anti-inflammatory, analgesic and antipyretic effect, certain symptoms of infection can therefore be masked.

Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma concentration of Algezir Ultra, but the plasma concentration of unbound Algezir Ultra is increased. The implication of this finding for Algezir Ultra dosing is unknown but it is prudent to use the lowest effective dose.

As with other non-steroidal anti-inflammatory drugs, elevations of one or more liver function tests may occur. Hepatic abnormalities may be the result of hypersensitivity rather than direct toxicity. Severe hepatic reactions, including jaundice and hepatitis (some cases of hepatitis have been fatal) have been reported with this drug as with other non-steroidal anti-inflammatory drugs. Cross reactivity has been reported.

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.

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 , when used with alcohol, in smoking and in the elderly. These patients should commence treatment on the lowest dose available.

Patients with a history of GI 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 oral corticosteroid, or anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin. If a corticosteroid is replaced by Algezir Ultra and the substitution occurs partially or fully, the usual precautions which come into consideration when discontinuing corticosteroid treatment should be applied.

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

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.

Haematological

Patients who have coagulation disorders or are receiving drug therapy that interferes with haemostasis should be carefully observed if Algezir Ultra-containing products are administered.

Patients at high risk of bleeding or those on full anti-caogulation therapy, e.g. who use coumarin derivatives or heparin alongside Algezir Ultra have an increased risk of bleeding. The benefits in that case should be weighed up against the risks. In any case concomitant use of Algezir Ultra with a high dose of heparin (or derivatives thereof) is not recommended.

Anaphylactic (anaphylactoid) reactions

Hypersensitivity reactions may occur in susceptible individuals. Anaphylactic (anaphylactoid) reactions may occur both in patients with and without a history of hypersensitivity or exposure to aspirin, other non-steroidal anti-inflammatory drugs or Algezir Ultra-containing products. They may also occur in individuals with a history of angio-oedema, bronchospastic reactivity (e.g. asthma), rhinitis and nasal polyps.

Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome.

Steroids

If steroid dosage is reduced or eliminated during therapy, the steroid dosage should be reduced slowly and the patients must be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis.

Ocular effects

Studies have not shown changes in the eye attributable to Algezir Ultra administration. In rare cases, adverse ocular disorders including papillitis, retrobulbar optic neuritis and papilloedema, have been reported in users of NSAIDs including Algezir Ultra, although a cause-and-effect relationship cannot be established; accordingly, patients who develop visual disturbances during treatment with Algezir Ultra-containing products should have an ophthalmological examination.

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.

Mild peripheral oedema has been observed in a few patients receiving Algezir Ultra. Although sodium retention has not been reported in metabolic studies, it is possible that patients with questionable or compromised cardiac function may be at a greater risk when taking Algezir Ultra.

Clinical trial and epidemiological data suggest that use of coxibs and 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). Although data suggest that the use of Algezir Ultra (1000mg daily) may be associated with a lower risk, some risk cannot be excluded.

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

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 NSAIDs (see 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reactions occurring in the majority of cases within the first month of treatment. Algezir Ultra should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. If the skin becomes delicate or in the event of blistering or other symptoms of pseudoporphyria, treatment should be discontinued and the patient should be carefully monitored.

Combination with other NSAIDs including cyclooxygenase-2 selective inhibitors

The combination of Algezir Ultra-containing products and other NSAIDs, including cyclooxygenase-2 selective inhibitors, is not recommended, because of the cumulative risks of inducing serious NSAID-related adverse events.

SLE and mixed connective tissue disease:

Female fertility:

The use of Algezir Ultra, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Algezir Ultra should be considered.

Interference in tests:

It is suggested that Algezir Ultra therapy be temporarily discontinued 48 hours before adrenal function tests are performed, because Algezir Ultra may artifactually interfere with some tests for 17-ketogenic steroids. Similarly, Algezir Ultra may interfere with some assays of urinary 5-hydroxyindoleacetic acid.

Sporadic abnormalities in laboratory tests (e.g. liver function test) have occurred in patients on Algezir Ultra therapy, but no definite trend was seen in any test indicating toxicity.

Contains Lactose:

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

Undesirable effects such as dizziness, vertigo, insomnia, drowsiness, fatigue and visual disturbances or depression are possible after taking Algezir Ultra. If patient experiences these or similar undesirable effects, they should not drive or operate machinery.

Gastrointestinal disorders: The most commonly observed adverse events are gastrointestinal in nature. Heartburn, nausea, vomiting, constipation, diarrhoea, flatulence, dyspepsia, abdominal discomfort and epigastric distress. More serious reactions which may occur are gastro-intestinal bleeding, which is sometimes fatal, particularly in the elderly. Inflammation, ulceration (peptic or non-peptic), perforation, and obstruction of the upper and lower gastrointestinal tract, melaena, haematemesis, stomatitis, abdominal pain, dry mouth, throat irritation, decreased appetite, exacerbation of ulcerative colitis and Crohn's disease , oesophagitis, gastritis and pancreatitis.

Immune system disorders: Hypersensitivity reactions have been reported following treatment with NSAIDs in patients with, or without, a history of previous hypersensitivity reactions to NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angiodema and, more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme)

Metabolic and nutrition disorders: hyperkalaemia.

Psychiatric disorders: Insomnia, dream abnormalities, depression, confusion and hallucinations

Cardiac disorders: Oedema, angioneurotic edema, , peripheral odema, palpitations, cardiac failure and congestive heart failure have been reported in association with NSAID treatment..

Clinical trial and epidemiological data suggest that use of coxibs and 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).

Vascular disorders: Hypertension, vasculitis.

Other adverse events reported less commonly include:

Hepatic: abnormal liver function tests, hepatitis (including some fatalities) and jaundice.

Nervous system disorders: convulsions, dizziness, nervousness, euphoria, low temperature and drowsiness lightheadedness, inability to concentrate and cognitive dysfunction, retrobulbar optic neuritis, headaches, paraesthesia, exacerbation of parkinson's disease, reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever and disorientation.

Haematological: Thrombocytopenia, eosinophilia, leucopenia, neutropenia, agranulocytosis, decreased platelet aggregation, prolonged bleeding time, aplastic anaemia and haemolytic anaemia. decrease in hemoglobin levels and/or hematocrit, granulocytopenia

Eye Disorders: Corneal opacity, blurred vision, visual disturbances, papillitis and papilloedema.

Ear and Labyrinth disorders: hearing disturbances including impairment, tinnitus, and vertigo.

Respiratory, thoracic and mediastinal disorders: Dyspnoea, asthma, rhinitis, eosinophilic pneumonitis and pulmonary oedema.

Skin and subcutaneous tissue disorders: Skin rashes including fixed drug eruption, itching (pruritus), urticaria, ecchymoses, purpura, sweating. Alopecia, erythema multiforme, skin eruption, Stevens Johnson syndrome, erythema nodosum, lichen planus, pustular reaction, SLE, epidermal necrolysis, very rarely toxic epidermal necrolysis, photosensitivity reactions (including cases in which skin resembles porphyria cutanea tarda “pseudoporphyria”) or epidermolysis bullosa-like reactions which may occur rarely.

If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored.

Musculoskeletal and connective tissue disorders: Myalgia and muscle weakness.

Renal and urinary disorders: Including, but not limited to, glomerular nephritis, interstitial nephritis, nephrotic syndrome, pollakiuria, proteinuria, haematuria, nephropathy, renal insufficiency, renal papillary necrosis and renal failure.

Reproductive system and breast disorders: Female infertility.

General disorders and administration site conditions: Thirst, pyrexia, mild peripheral oedema, fatigue and malaise.

Investigations

Elevated transaminases or alkaline phosphatases, elevated bilirubin levels, elevated serum creatinine, increased blood pressure.

Symptoms:

Symptoms include headache , nausea , vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, heartburn, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions, transient changes in liver function, hypothrombinemia, apnea and metabolic acidosis. In cases of significant poisoning acute renal failure and liver damage are possible.

Respiratory depression and coma may occur after the ingestion of NSAIDs but are rare.

In one case of Algezir Ultra overdose, transient prolongation of the prothrombin time due to hypothrombinaemia may have been due to selective inhibition of the synthesis of vitamin-K dependent clotting factors.

A few patients have experienced seizures, but it is not known whether these were Algezir Ultra related or not. It is not known what dose of the drug would be life-threatening.

Therapeutic measure

Patient should be treated symptomatically as required.

Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose.

The acid-base status should be carefully monitored due to the possible occurrence of severe metabolic acidosis.

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.

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

Haemodialysis does not decrease the plasma concentration of Algezir Ultra because of the high degree of protein binding. However, haemodialysis may still be appropriate in a patient with renal failure who has taken Algezir Ultra.

Algezir Ultra has analgesic, anti-inflammatory and anti-pyretic actions.

Algezir Ultra is a non-steroidal anti-inflammatory analgesic compound with antipyretic properties as has been demonstrated in classical animal test systems. Algezir Ultra exhibits its anti-inflammatory effect even in adrenalectomised animals, indicating that its action is not mediated through the pituitary-adrenal axis.

Algezir Ultra inhibits prostaglandin synthetase (as do other NSAIDs). As with other NSAIDs, however, the exact mechanism of its anti-inflammatory action is not known.

Algezir Ultra is readily absorbed from the gastro-intestinal tract and peak plasma levels are reached in 2 to 4 hours. Algezir Ultra is present in the blood mainly as unchanged drug. It is extensively bound to plasma proteins and has a half-life of about 15 hours. enabling a steady state to be achieved within 3 days of initiation of therapy on a twice daily dose regimen. The degree of absorption is not significantly affected by either foods or most antacids. Excretion is almost entirely via the urine, mainly as conjugated Algezir Ultra, with some unchanged drug. Metabolism in children is similar to that in adults. Chronic alcoholic liver disease reduces the total plasma concentration of Algezir Ultra but the concentration of unbound Algezir Ultra increases. In the elderly, the unbound plasma concentration of Algezir Ultra is increased although total plasma concentration is unchanged.About half of the dose is excreted in the urine in 24 hours and about 94% in 5 days largely as the glucuronide.

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Carcinogenicity

Algezir Ultra was administered with food to Sprague-Dawley rats for 24 months at doses of 8, 16 and 24mg/kg/day. Algezir Ultra was not carcinogenic in rats.

Mutagenicity

Mutagenicity was not seet in Salmonella typhimurium (5 cell lines), Sachharomyces cerevisisae (1 cell line), and mouse lymphoma tests.

Fertility

Algezir Ultra did not affect the fertility of rats when administered orally at doses of 30mg/kg/day to males and 20mg/kg/day to females.

Teratogenicity

Algezir Ultra was not teratogenic when administered orally at dose of 20mg/kg/day during organogenesis to rats and rabbits.

Perinatal/Postnatal Reproduction

Oral administration of Algezir Ultra to pregnant rats at doses of 2, 10 and 20mg/kg/day during the third trimester of pregnancy resulted in difficult labour. These are known effects of this class of compounds and were demonstrated in pregnant rats with aspirin and indometacin.

None stated