For the relief of mild to moderate pain including rheumatic and muscular pain, migraine (with or without aura), backache, headache, dental pain, dysmenorrhoea, feverishness and for the relief of symptoms of cold and influenza

For oral administration and short-term use only.

 

For all indications:

Adults, older people and children and adolescents between 12-18 years of age:  

 

If in children or adolescents between 12 -18 years of age, this medicinal product is required for more than 3 days, or if symptoms worsen, a doctor should be consulted.

 

For adults aged 18 years or older, the lowest effective dose should be used for the shortest duration necessary to relieve symptoms and minimise undesirable effects (see section 4.4).  The patient should consult a doctor if symptoms persist or worsen, or if the product is required for more than 10 days.

 

One capsule up to three times per day as required. The respective dosing interval should be chosen in line with the observed symptoms and the maximum recommended daily dose. Doses should be given approximately every 6-8 hours, with a minimum interval of 4 hours between each dose. A total dose of 1200 mg of ibuprofen (3 capsules) should not be exceeded in any 24 hour period. The capsules should be taken with water.

 

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

• Hypersensitivity to ibuprofen or any of the constituents in this 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, renal failure or severe heart failure (NYHA Class IV) (See section 4.4). • Use in last trimester of pregnancy (See section 4.6).

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 4.8)

• Renal impairment as renal function may deteriorate (see Section 4.3 and 4.8)

• Hepatic dysfunction (see 4.3 and 4.8)

 

Undesirable effects may be minimised by using the minimum effective dose for the shortest possible duration necessary to control symptoms. (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 cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).

 

Cardiovascular and cerebrovascular effects

Clinical studies suggest that use of ibuprofen, particularly at high doses (2400 mg/day) 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. ≤ 1200 mg daily) is associated with an increased risk of arterial thrombotic events.

Patients with uncontrolled hypertension, congestive heart failure (NYHA II-III), established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ibuprofen after careful consideration and high doses (2400 mg/day) should be avoided.

Careful consideration should also be exercised before initiating long-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking), particularly if high doses of ibuprofen (2400 mg/day) are required.

 

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

 

GI bleeding, ulceration and 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 (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. This medicine contains 40mg of potassium per dose. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet.

 

There is a risk of renal impairment in dehydrated children and adolescents, between the ages of 12-18 year olds.

 

The label will include:

 

12-18 years: if symptoms worsen, or persist for more than 3 days, or you get new symptoms consult your doctor.

 

Adults: if symptoms worsen, or persist for more than 10 days, or you get new symptoms consult your pharmacist or doctor.

Read the enclosed leaflet before taking this product.

 

Do not take if you:

• Have ever had a stomach ulcer, perforation or bleeding

• Are allergic to ibuprofen (or anything else in this medicine), aspirin or other related painkillers

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

• Are in the last 3 months of pregnancy.

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

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

• Are a smoker

• Are pregnant

Ibuprofen should not be used in combination with:

Acetylsalicylic acid

Concomitant administration of ibuprofen and aspirin (acetylsalicylic acid) is not generally recommended (unless low-dose aspirin (not above 75mg daily) has been advised by a doctor), as this combination may increase the risk of adverse reactions (see Section 4.4).

Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose aspirin (acetylsalicylic acid) on platelet aggregation when they are dosed concomitantly. Although there are uncertainties regarding extrapolation of these data to the clinical situation, the possibility that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low dose aspirin (acetylsalicylic acid) cannot be excluded. 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 effect of these drugs. Diuretics can increase the risk of nephrotoxicity of NSAIDs.
• Anticoagulants: NSAIDs may enhance the effects of anti-coagulants, 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

1-1-1       Use during pregnancy

 

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

During the third 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 an increased bleeding tendency in both mother and child (see Section 4.3).

1-1-2       Use during lactation

In limited studies, ibuprofen appears in the breast milk in very low concentrations, and is unlikely to affect the breast fed infant adversely

None expected at recommended doses and duration of therapy.

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, bronchospasm, 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 studies suggest that use of ibuprofen, particularly at a high dose (≥2400mg/day) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).

 

                     To report any side effect (s):

                     Saudi Arabia: National Pharmacovigilance & Drug Safety Centre (NPC)

q  Fax: +966-11-205-7662

q  Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.

q  Toll free phone: 8002490000

q  E-mail: npc.drug@sfda.gov.sa

q  Website: www.sfda.gov.sa/npc

     

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, hypokalaemia 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

Management should be symptomatic and supportive and include the 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.

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. From the same studies, a single dose of 200mg did not show significant differences in onset of analgesia when compared to 1000mg paracetamol.

 

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

Clinical evidence demonstrates that when 400 mg of ibuprofen are taken, pain relieving effects can last for up to 8 hours.

Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose aspirin (acetylsalicylic acid) on platelet aggregation when they are dosed concomitantly. Some pharmacodynamics studies show that when single doses of ibuprofen 400mg were taken within 8 hours before or within 30 min after immediate release aspirin (acetylsalicylic acid) dosing (81 mg), a decreased effect of aspirin (acetylsalicylic acid) on the formation of thromboxane or platelet aggregation occurred. Although there are uncertainties regarding extrapolation of these data to the clinical situation, the possibility that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose aspirin (acetylsalicylic acid) cannot be excluded. No clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 4.5).

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.         

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

1-1     List of excipients   

q  Polyethylene glycol 600

q  Potassium Hydroxide 50% solution

q   Anidrisorb 85/70

q  Gelatin 150 Bloom EP.

Not applicable

3 years

Store at temperature between 15-25°C.

DOLORAZ  400 Soft Gelatin Capsules are packed in boxes of 20 Tablets blistered in Aluminium Foil Blisters.

No special requirements.

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