STREFLAM 8.75 MG LOZENGES - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Streflam 8.75mg lozenges

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One lozenge contains 8.75 mg of Flurbiprofen

Excipients:

Glucose 1069mg/lozenge

Sucrose 1407mg/lozenge

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Lozenge

A round, pale yellow to brown lozenge with an icon intagliated on both sides of the lozenge

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Streflam 8.75 mg lozenges are indicated for the short term symptomatic relief of sore throat in adults and children over the age of 12 years.

4.2 Posology and method of administration

Posology

Adults and children over the age of 12 years:

One lozenge sucked/dissolved slowly in the mouth every 3–6 hours as required.

Maximum 5 lozenges in a 24 hour period.

It is recommended that this product should be used for a maximum of three days.

Children: Not indicated for children under 12 years.

Elderly: A general dose recommendation cannot be given, since to date clinical experience is limited. The elderly are at increased risk of the serious consequences of adverse reactions.

Impaired hepatic: In patients with mild to moderate impairment of hepatic function no dose reduction is required. In patients with severe hepatic insufficiency flurbiprofen is contraindicated (see section 4.3).

Impaired renal: In patients with mild to moderate impairment of renal function no dose reduction is required. In patients with severe renal insufficiency flurbiprofen is contraindicated (see section 4.3).

Method of administration

For oromucosal administration and short-term use only.

As with all lozenges, to avoid local irritation, flurbiprofen 8.75 mg lozenges should be moved around the mouth whilst sucking.

The lowest effective dose should be administered for the shortest duration necessary to control symptoms (see section 4.4)

4.3 Contraindications

Hypersensitivity to flurbiprofen or any of the excipients in the product.

Patients who have previously shown hypersensitivity reactions (e.g. asthma, bronchospasm, rhinitis, angioedema or urticaria) in response to acetylsalicylic acid or other NSAIDs.

Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration) and intestinal ulceration.

History of gastrointestinal bleeding or perforation, severe colitis, haemorrhagic or haematopoietic disorders related to previous NSAID therapy.

Last trimester of pregnancy (See section 4.6)

Severe heart failure, severe renal failure or severe hepatic failure (see section 4.4).

4.4 Special warnings and precautions for use

Undesirable effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms

Elderly population

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.

Respiratory:

Bronchospasm may be precipitated in patients suffering from or with a previous history of bronchial asthma or allergic disease. Flurbiprofen spray should be used with caution in these patients

Other NSAIDs:

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

Systemic lupus erythematosus and mixed connective tissue disease:

Patients with systemic lupus erythematosus and mixed connective tissue disease may have an increased risk of aseptic meningitis (see section 4.8), however this effect is not usually seen with short term limited use products such as flurbiprofen lozenges.

Cardiovascular, Renal and Hepatic Impairment:

NSAIDs have been reported to cause nephrotoxicity in various forms including interstitial nephritis, nephrotic syndrome and renal failure. The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly, however, this effect is not usually seen with short term, limited use products such as flurbiprofen lozenges.

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 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 flurbiprofen when given at a daily dose of no more than 5 lozenges.

Hepatic:

Mild to moderate hepatic dysfunction (see sections 4.3 and 4.8)

Nervous System effects

Analgesic induced headache – In the event of prolonged use of analgesics or use beyond the regulations headache may occur, which must not be treated with increased doses of the medicinal product.

Gastrointestinal:

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

Gastrointestinal 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.

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, however this effect is not usually seen with short term limited use products such as flurbiprofen lozenges. Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) to their healthcare professional.

Caution should be advised in patients receiving concomitant medications which 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 acetylsalicylic acid (see section 4.5).

If GI bleeding or ulceration occurs in patients receiving flurbiprofen, the treatment should be withdrawn.

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 section 4.8). Flurbiprofen lozenges should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Infections:

Since in isolated cases an exacerbation of infective inflammations (e.g. development of necrotising fasciitis) has been described in temporal association with the use of systemic NSAIDs as a class, the patient is advised to consult a physician immediately if signs of a bacterial infection occur or worsen during the flurbiprofen lozenges therapy. It should be considered whether initiation of an anti-infective antibiotic therapy is indicated.

Sugar intolerance:

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

If the symptoms get worse or if new symptoms occur, the treatment should be reevaluated.

If mouth irritation occurs, treatment should be withdrawn.

4.5 Interaction with other medicinal products and other forms of interaction

No studies so far have revealed any interactions between flurbiprofen and tolbutamide or antacids.

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%, 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, flurbiprofen should not be given unless clearly necessary. If flurbiprofen 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 fœtus to:

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

o renal dysfunction, which may progress to renal failure with oligo-hydroamniosis;

the mother and the neonate, at the end of pregnancy, to:

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

o inhibition of uterine contractions resulting in delayed or prolonged labour.

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

Lactation

In limited studies, flurbiprofen appears in the breast milk in very low concentration and is unlikely to affect the breast-fed infant adversely. However, because of possible adverse effects of NSAIDs on breast-fed infants, Streflam 8.75mg lozenges are not recommended for use in nursing mothers. See section 4.4 regarding female fertility.

Fertility

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.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Hypersensitivity reactions to NSAIDs have been reported and these may consist of:

(a) Non-specific allergic reactions and anaphylaxis

(b) Respiratory tract reactivity, e.g. asthma, aggravated asthma, bronchospasm, dyspnoea

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

Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.

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), (see section 4.4). There is insufficient data to exclude such a risk for Flurbiprofen 8.75 mg lozenges

The following list of adverse effects relates to those experienced with flurbiprofen at OTC doses for short-term use.

(Very common (>1/10), Common (>1/100 to <1/10), Uncommon (>1/1000 to <1/100), Rare (>1/10000 to <1/1000), Very rare (<1/10000), not known (cannot be estimated from the available data))

Blood and lymphatic system disorders:

Not known: anaemia, thrombocytopenia.

Immune System disorders:

Rare: anaphylactic reaction

Psychiatric disorders:

Uncommon: insomnia

Cardiovascular and cerebrovascular disorders

Not known: Oedema, hypertension and cardiac failure

Nervous System disorders:

Common: dizziness, headache, paraesthesia

Uncommon: somnolence

Respiratory, thoracic and mediastinal disorders:

Common: throat irritation

Uncommon: exacerbation of asthma and bronchospasm, dyspnoea, wheezing, oropharyngeal blistering, pharyngeal hypoaesthesia.

Gastrointestinal disorders:

Common: diarrhoea, mouth ulceration, nausea, oral pain, paraesthesia oral, oropharyngeal pain, oral discomfort (warm or burning feeling or tingling of the mouth).

Uncommon: abdominal distension, abdominal pain, constipation, dry mouth, dyspepsia, flatulence, glossodynia, dysgeusia, oral dysaesthesia, vomiting

Hepatobiliary disorders:

Not known: hepatitis

Skin and subcutaneous tissue disorders:

Uncommon: various skin rashes, pruritus.

Not known: severe forms of skin reaction such as bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.

General disorders and administration site conditions:

Uncommon: pyrexia, pain

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.

4.9 Overdose

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 with NSAIDs, toxicity is seen in the central nervous system, manifesting as drowsiness, occasionally excitation, blurred vision and disorientation or coma. Occasionally patients develop convulsions. In serious poisoning with NSAIDs 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 or gastric lavage and if necessary correction of serum electrolytes if the patient presents within one hour of ingestion or a potentially toxic amount. If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma. There is no specific antidote to flurbiprofen.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic Group: Throat preparations, other throat preparations.

ATC Code: R02AX01

Flurbiprofen is a propionic acid derivative NSAID which acts through inhibition of prostaglandin synthesis. In humans flurbiprofen has potent analgesic, antipyretic and anti-inflammatory properties and the 8.75mg dose dissolved in artificial saliva has been shown to reduce prostaglandin synthesis in cultured human respiratory cells. According to studies using the whole blood assay, flurbiprofen is a mixed COX-1/COX-2 inhibitor with some selectivity towards COX-1.

Pre-clinical studies suggest that the R (-) enantiomer of flurbiprofen and related NSAIDs may act on the central nervous system; the suggested mechanism is by inhibition of induced COX-2 at the level of the spinal cord.

Flurbiprofen from the 8.75 mg lozenge has been shown to penetrate into the layers of the whole human pharynx tissue including the deeper layer in an ex vivo model.

In patients that experienced a meaningful pain relief at a median time of 42.9 minutes by a single dose of flurbiprofen 8.75 mg delivered locally to the throat in a lozenge, the first perceived relief (onset of analgesia) occurred at a median time of 13.2 minutes.

Relief of sore throat, including swollen and inflamed sore throats has also been demonstrated through a significant reduction (LS Mean Difference) in sore throat pain intensity from 22 minutes (-5.5mm), reaching a maximum at 70 minutes (-13.7mm) and remaining significant for up to 240 minutes (-3.5mm) including patients with streptococcal and non-streptococcal infections, reduction in difficulty swallowing from 20 minutes (-6.7mm), reaching a maximum at 110 minutes (-13.9mm) and for up to 240 minutes (-3.5mm) and reduction in the feeling of a swollen throat at 60 minutes (-9.9mm), reaching a maximum at 120 minutes (-11.4mm) and for up to 210 minutes (-5.1mm).

Multiple dose efficacy measured using Sum of Pain Intensity Differences (SPID) over 24 hours has demonstrated significant reduction in sore throat pain intensity (-473.7mm*h to –529.1mm*h), difficulty swallowing (-458.4mm*h to –575.0mm*h) and swollen throat (-482.4mm*h to –549.9mm*h) with statistically significant greater summed reduction in pain at each hourly interval over 23 hours for all three measures and statistically significantly greater sore throat relief each hour over the 6 hour assessment time. Efficacy of multiple doses after 24 hours and over 3 days has also been demonstrated.

For those patients taking antibiotics for streptococcal infection, there was statistically significant greater relief of sore throat pain intensity for flurbiprofen 8.75mg from 7 hours and onwards after antibiotics were taken. The analgesic effect of flurbiprofen 8.75 mg was not reduced by the administration of antibiotics to treat patients with streptococcal sore throat.

At 2 hours post first dose, flurbiprofen 8.75mg lozenges provided significant resolution of some of the associated symptoms of sore throat present at baseline including coughing (50% vs 4%), loss of appetite (84% vs 57%) and feverishness (68% vs 29%).

The lozenge has also been shown to be non-inferior to the flurbiprofen throat spray based on pain intensity difference from baseline to 2 hours post dose.

The lozenge format dissolves in the mouth over 5 – 12 minutes and provides a measurable soothing and coating effect at 2 minutes.

No specific studies in children have been undertaken. Efficacy and safety studies on flurbiprofen 8.75mg lozenges have included children aged 12 – 17 years, although small sample size means that no statistical conclusions can be drawn.

5.2 Pharmacokinetic properties

Absorption

Flurbiprofen 8.75mg lozenges dissolve over 5 – 12 minutes and the flurbiprofen is readily absorbed, with detection in the blood at 5 minutes and plasma concentrations peaking at 40 – 45 minutes after administration but remaining at a mean low level of 1.4pg/mL which is approximately 4.4 times lower than a 50mg tablet dose.

Absorption of flurbiprofen can occur from the buccal cavity by passive diffusion. Rate of absorption is dependent on pharmaceutical form with peak concentrations achieved more rapidly than, but of similar magnitude to, those achieved after an equivalent swallowed dose.

Distribution

Flurbiprofen is rapidly distributed throughout the body and is extensively bound to plasma proteins.

Metabolism / Excretion

Flurbiprofen is mainly metabolised by hydroxylation and excreted via the kidneys. It has an elimination half-life of 3 to 6 hours. Flurbiprofen is excreted in very small amounts in human milk (less than 0.05 pg/ml). Approximately 20–25% of a flurbiprofen oral dose is excreted unchanged.

Special Groups

No difference in pharmacokinetic parameters between elderly and young adult volunteers has been reported following oral administration of flurbiprofen tablets. No pharmacokinetic data have been generated in children below 12 years of age following administration of Flurbiprofen 8.75 mg however administration of both flurbiprofen syrup and suppository formulations indicate no significant differences in pharmacokinetic parameters compared with adults.

5.3 Preclinical safety data

There are no preclinical data of relevance additional to information already included in other relevant sections.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Macrogol 300

Potassium hydroxide

Lemon flavour

Levomenthol

Liquid sucrose

Liquid glucose

Honey

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store in the original carton

6.5 Nature and contents of container

6.6 Special precautions for disposal

7 MARKETING AUTHORISATION HOLDER

Reckitt Benckiser Healthcare (UK) Ltd

Slough

SL1 3UH

8 MARKETING AUTHORISATION NUMBER

PL 00063/0631

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

31/08/1999 / 31/08/2009