IBUPROFEN SODIUM 512 MG FILM-COATED TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Ibuprofen sodium 512 mg film-coated tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film coated tablet contains Ibuprofen 400mg (as Ibuprofen sodium 512mg).

Excipient(s) with known effect:

Each tablet contains 227.98 mg Lactose (as monohydrate)

Each tablet contains 41.056 mg of sodium

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablets

White to off-white, modified caplet shaped film coated tablets plain on both sides.

Dimensions of the tablet: 19.3 mm x 8.3 mm wide

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Symptomatic relief of mild to moderate pain, including headache, backache, menstrual pain, dental pain, neuralgia, rheumatic pain and muscle pain, the pain of non-serious arthritis, migraine, cold and flu symptoms, sore throat and fever.

4.2 Posology and method of administration

Posology

Adults, elderly and children and adolescents between 12 and 18 years:

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

Adults should consult a doctor if symptoms persist or worsen, or if the product is required for more than 10 days.

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

Children and Adolescents between 12 and 18 years:

Take one tablet, up to three times a day as

required. Adults: Take one tablet, up to

three times a day as required.

Leave at least four hours between doses and do not take more than 1200mg in any 24– hour period.

Paediatric population

Ibuprofen sodium should not be used in the children aged below 12 years.

Elderly

No special dosage

adjustments are required.

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms (see section 4.4).

Method of administration

For oral use.

Swallow whole with large amount of liquid.

4.3 Contraindications

Ibuprofen sodium is contraindicated in patients:

– with known hypersensitivity to the active substance or any of the excipients listed in section 6.1;

– with a history of bronchospasms, asthma, rhinitis, angioderma or urticaria, associated with aspirin or other non-steroidal anti- inflammatory drugs (NSAIDs);

– with a history or concurrent condition of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy;

– with active or a history of recurrent peptic ulcer/haemorrhaging (two or more distinct episodes of proven ulceration or bleeding);

– with severe liver, renal or heart failure (NYHA Class IV).

– during the third trimester of a pregnancy (see section 4.6).

4.4. Special warnings and precautions for use

Caution is required in patients with:

– systemic lupus erythematosus or mixed connective tissue disease (see section 4.8)

– gastrointestinal disorders and bowel inflammations (ulcerative colitis, Crohn's disease)

– hypertension and/or heart problems

– renal disorders

Undesirable effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, and gastrointestinal and cardiovascular risks below).

Respiratory:

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

Cardiovascular and cerebrovascular effects

Caution (discussion with doctor or pharmacist) is required prior to starting treatment in patients with a history of hypertension and/or heart failure, as fluid retention, hypertension and oedema have been reported in association with NSAID therapy.

Clinical studies suggest that use of ibuprofen, particularly at a high dose (2400 mg/day) may be associated with a small increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g. <1200 mg/day) is associated with an increased risk of arterial thrombotic events.

Patients with uncontrolled hypertension, congestive heart failure (NYHA II-III), established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ibuprofen after careful consideration. 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 and smoking).

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

Careful consideration should also be exercised before initiating longterm 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.

Impaired female fertility:

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 on withdrawal of treatment.

Gastrointestinal effects

Concomitant use of Ibuprofen sodium with other NSAIDs, including selective COX-2 inhibitors, should be avoided (see section 4.5).

Elderly patients:

Elderly patients have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal (see section 4.2).

Gastrointestinal bleeding, ulceration and perforation

NSAIDs should be given with caution to patients with a history of gastrointestinal disease (ulcerative colitis and Crohn’s disease), as these conditions may be exacerbated (see section 4.8).

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

The risk of GI bleeding, ulceration or perforation is higher with increasing doses, in patients with a history of ulcer, particularly if complicated by haemorrhaging or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available.

In these patients, concomitant use of protective medications (such as misoprostol or proton pump inhibitors) should be considered, as well as in patients requiring concomitant aspirin in low doses or other medications that are likely to increase GI risks (see section 4.5).

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 that could increase the risk of ulceration or bleeding, such as oral corticosteroids, 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 ibuprofen, the treatment should be withdrawn.

Dermatological effects

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 section 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: in the majority of cases, the onset of the reaction occurred within the first month of treatment. Ibuprofen sodium should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Severe skin reactions

Acute generalised exanthematous pustulosis (AGEP) has been reported in relation to ibuprofen containing products.

SLE and mixed connective tissue disease:

Systemic lupus erythematosus and mixed connective tissue disease -increased risk of aseptic meningitis (see section 4.8).

Renal:

Renal impairment as renal function may further deteriorate (see

sections 4.3 and 4.8). There is a risk of renal impairment in dehydrated children and adolescents.

Hepatic:

Hepatic dysfunction or impaired liver function (see sections 4.3 and 4.8).

Additional comments

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 on withdrawal of treatment.

Exceptionally, varicella can be at the origin of serious infectious complications of the skin and soft tissues. To date, the contributing role of NSAIDs in the worsening of these infections cannot be ruled out. It is therefore advisable to avoid use of Ibuprofen sodium in case of varicella.

Prolonged use of any type of painkiller for headaches can make them worse. If this situation is experienced or suspected, medical advice should be obtained, and treatment should be discontinued. The diagnosis of headache due to medication overuse should be suspected in patients who have frequent or daily headaches despite (or because of) regular use of headache medications.

Masking of symptoms of underlying infections

Ibuprofen sodium can mask symptoms of infection, which may lead to delayed initiation of appropriate treatment and thereby worsening the outcome of the infection. This has been observed in bacterial community acquired pneumonia and bacterial complications to varicella. When Ibuprofen sodium is administered for fever or pain relief in relation to infection, monitoring of infection is advised. In non-hospital settings, the patient should consult a doctor if symptoms persist or worsen.

Excipients:

These tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicinal product contains 52 mg sodium per tablet, equivalent to 2.6% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5 Interaction with other medicinal products and other forms of interaction

Ibuprofen (like other NSAIDs) should not be used in combination with:

Aspirin

Concomitant administration of ibuprofen and aspirin is not generally recommended, because of the potential of increased adverse effects, unless low-dose aspirin (not above 75mg daily) has been advised by a doctor (see section 4.4), unless low-dose aspirin (not above 75mg daily) has been advised by a doctor (see section 4.4).

Experimental data suggest that, when dosed concomitantly, ibuprofen may competitively inhibit the effect of low dose aspirin on platelet aggregation. Although there are uncertainties regarding clinical extrapolation of these data, the possibility that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose aspirin cannot be excluded. No clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).

Ibuprofen should be used with caution in combination with:

– Other NSAIDs and glucocorticoids. They can increase the risk of intestinal effects.

– Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section 4.4).

– Antihypertensives (ACE inhibitors and Angiotensin II Antagonists) and diuretics: since NSAIDs may diminish the effects of these drugs. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administration of an ACE inhibitor or Angiotensin II antagonist and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. These interactions should be considered in patients taking a coxib concomitantly with ACE inhibitors or angiotensin II antagonists. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated, and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter.

– 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).

– Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): These can increase the 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 evidence for the potential increase in 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: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk haemarthroses and haematoma in HIV (+) 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 Fertility, 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% to 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, ibuprofen should not be given unless strictly necessary. If ibuprofen 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 the 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-hydramnios

and at the end of the pregnancy, they may expose the mother and neonate 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, ibuprofen is contraindicated during the third trimester of pregnancy.

Breastfeeding

Ibuprofen and its metabolites can appear in breast milk in very low concentrations (0.0008% of the initial dosage). There are no known adverse effects on the neonate.

Fertility

See section 4.4. regarding female fertility.

4.7 Effects on ability to drive and use machines

Ibuprofen sodium has no influence on the ability to drive and use machines.

No effects are expected at the recommended doses and duration of therapy.

4.8 Undesirable effects

Adverse events which have been associated with Ibuprofen are given below, listed by system organ class and frequency. Frequencies are defined as: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10,000 to

<1/1000), very rare (<1/10,000) and not known (cannot be

estimated from the available data). Within each frequency grouping, adverse events are presented in order of decreasing seriousness.

The list of the following adverse effects relates to those experienced with ibuprofen at OTC doses (maximum 1200mg per day), for shortterm use. In the treatment of chronic conditions, under long-term treatment, additional adverse effects may occur.

The most commonly observed adverse events are gastrointestinal in nature. Adverse events are mostly dose-dependent, in particular the risk of occurrence of gastrointestinal bleeding is dependent on the dosage range and duration oftreatment.

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).

Description of Selected Adverse Reactions

1 Hypersensitivity reactions have been reported following treatment with ibuprofen. These may consist of (a) non-specific allergic reactions and anaphylaxis, (b) respiratory tract activity comprising asthma, aggravated asthma, bronchospasm, dyspnoea or © assorted skin disorders, including rashes of various types pruritus, urticaria, purpura, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

2 The pathogenic mechanism of drug-Induced aseptic meningitis is not fully understood. However, the available data on NSAID-related aseptic meningitis points to a hypersensitivity reaction (due to a temporal relationship with drug intake, and disappearance of symptoms after drug discontinuation). Of note, single cases of symptoms of aseptic meningitis (such as stiff neck, headache, nausea, vomiting, fever or disorientation) have been observed during treatment with ibuprofen, in patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

In children ingestion of more than 400 mg/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

The symptoms of overdosing may include 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 drowsiness, occasionally excitation and disorientation or coma. Occasionally patients develop convulsions. In serious poisoning 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

No specific antidote is available.

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: propionic acid derivate

ATC Code: M01AE01

Mechanism of action

Ibuprofen is a NSAID. In conventional animal experiments, it has demonstrated its efficacy by inhibition of prostaglandin synthesis. In humans, ibuprofen reduces inflammatory pain, swelling and fever. Furthermore, ibuprofen reversibly inhibits platelet aggregation.

Clinical efficacy and safety

Clinical efficacy of ibuprofen has shown to be effective in headache, dental pain and dysmenorrhoea, and fever; as well as in patients with pain and fever in flue and common cold, and in pain models such as sore throat, muscle pain or bruising and backache.

Clinical evidence demonstrates that ibuprofen, in the form of salts such as ibuprofen sodium and ibuprofen lysine, acts significantly faster than standard ibuprofen acid tablets for the relief of mild-moderate pain.

Experimental data suggest that, if dosed concomitantly, ibuprofen may inhibit the effect of low dose acetylsalicylic acid (aspirin) on platelet aggregation. Some pharmacodynamic studies indicate that a single dose of ibuprofen 400 mg that was taken within 8 hours before or within 30 minutes after immediate release acetylsalicylic acid (81 mg), a decreased effect of 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 acetylsalicylic acid cannot be excluded. No clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 4.5).

There is clinical evidence that the intake of 512 mg ibuprofen sodium (corresponding with 400 mg ibuprofen) can provide sustained pain relief for up to 8 hours.

5.2 Pharmacokinetic properties

Absorption and Distribution

Ibuprofen is well absorbed from the gastrointestinal tract, is extensively bound to plasma proteins and diffuses into the synovial fluid.

Maximum plasma concentrations of ibuprofen are reached 45 minutes after ingestion if taken on an empty stomach. Ibuprofen is more rapidly absorbed from the gastrointestinal tract if it’s administrated in an empty stomach versus when taken with food (35 minutes vs. 1–2 hours). Peak plasma concentrations of ibuprofen sodium salt are 30% higher compared with ibuprofen acid. However, it has been demonstrated that this doesn’t result in a significantly faster effect.

Biotransformation

Ibuprofen is metabolised in the liver to two major metabolites, with primary excretion via the kidneys – either as such or as major conjugates – together with a negligible amount of unchanged ibuprofen. Excretion by the kidneys is both rapid and complete.

Elimination

Elimination half-life is approximately 2 hours.

No significant differences in the pharmacokinetic profile are observed in the elderly.

In limited studies, ibuprofen appears in the breast milk in very low concentrations.

5.3 Preclinical safety data

No relevant information, additional to that contained elsewhere in the SmPC.

6.1 List of excipients

Tablet core:

Lactose Monohydrate

Sodium Lauryl Sulphate (E487)

Crospovidone (E1201)

Povidone

Silica, colloidal hydrated

Talc (E553b)

Magnesium Stearate (E470b)

Film-coating:

Composition of Opadry:

Hypromellose

Lactose monohydrate

Macrogol

Titanium dioxide (E171)

Talc

Sodium citrate-dihydrate

Mica-Titanium dioxide (E555/E171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Alu/PVC/PVDC Blister packs of 2, 3, 4, 5, 6, 8, 10, 12, 14, 15, 16, 18, 20, 24, 28, 30,

32, 36, 48, 96’s tablets. Blisters are packed in the carton boxes.

6.6 Special precautions for disposal

No special precautions are required.

7 MARKETING AUTHORISATION HOLDER

Strides Pharma UK Ltd.,

Unit 4, Metro Centre,

Watford, Hertfordshire,

WD18 9SS United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 13606/0245

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

18/09/2020