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• spc-doc_PL 17780-0563

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ibuprofen and phenylephrine hydrochloride 200mg/5mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains ibuprofen 200 mg and phenylephrine hydrochloride 5.0 mg. For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet

Description: white to off- white biconvex film-coated tablets with diameter of approx. 10.6 mm.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

The product is designed for the relief of symptoms of cold and influenza with associated congestion including aches and pain, headache, fever, sore throat, blocked nose and sinuses.

4.2    Posology and method of administration

For oral administration and short-term use only.

Adults and adolescents aged 12 years and over:

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms. Adults should consult a doctor if symptoms persist or worsen, or if the product is required for more than 3-5 days.

If in adolescents (aged 12 years and over) this medicinal product is required for more than 3 days, or if symptoms worsen a doctor should be consulted.

Two tablets every 8 hours. Leave at least 4 hours between doses and do not exceed six tablets in any 24 hour period.

The product is not intended for children under 12 years.

Elderly

In elderly patients the dosage is the same as in adults, but increased caution is necessary (see section 4.4)

Method of administration

The tablet may be taken with or without food. If taken with food or shortly after eating, the onset of action may be delayed. However, taking it with food improves tolerability of the product and reduces probability of gastrointestinal problems.

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

4.3 Contraindications

-    Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

-    Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to aspirin or other non-steroidal antiinflammatory drugs (NSAIDs).

-    History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

-    Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes or proven ulceration or bleeding).

-    Severe hypertension, , renal or hepatic failure, severe heart failure (NYHA Class IV) (see section 4.4).

-    Disorders of haemocoaggulation and haemopoiesis.

-    Third trimester of pregnancy.

-    Hyperthyroidism.

-    Diabetes mellitus.

-    Narrow-angle glaucoma.

-    Urinary retention.

-    Phaeochromocytoma.

-    Patients who are currently taking tricyclic antidepressants or other sympathomimetic drugs, beta-blockers, and those who are currently taking or have taken monoamine oxidase inhibitors within the last two weeks.

4.4 Special warnings and precautions for use Ibuprofen

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

Elderly

The elderly 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 care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see section 4.8).

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 (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available.

In patients with increased risk of adverse reactions together with those on long term treatment with acetylsalicylic acid in antiaggregation doses or other drugs which increase GI risk (see section 4.5) concomitant use of protective agents such as misoprostol or proton pump inhibitors should be considered.

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 ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelets agents such as aspirin (see section 4.5).

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

Other NSAIDs

The use of this product with concomitant NSAIDs, including cyclo-oxygenase-2 selective inhibitors, should be avoided (see section 4.5).

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 ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ibuprofen after careful consideration and high doses (2400mg/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.

Dermatological

Serious skin reactions, some of them fatal, including exfoliating 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 of 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. This medicine should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

Respiratory

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

Increased attention is necessary in patients who suffer from hay fever, nasal polyps or chronic obstructive respiratory disorders as an increased risk exists for them of allergic reactions occurring. These may present as asthma attacks (so-called analgesic asthma), Quincke’s oedema or urticaria.

SLE and mixed connective tissue disease

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

Renal impairment

Renal impairment as renal function may further deteriorate (see sections 4.3 and 4.8).

Hepatic impairment

Hepatic dysfunction (see sections 4.3 and 4.8).

Impaired female fertility

There is limited 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. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of ibuprofen should be considered (see section 4.6).

Increased attention is necessary directly after major surgery.

Drinking of alcoholic beverages and smoking is not suitable during treatment.

Paediatric population

There is a risk of renal impairment in dehydrated children and adolescents.

Phenylephrine

Phenylephrine should be used with care in men with prostate hypertrophy as they may be predisposed to urinary retention.

The physician or pharmacist should check that sympathomimetic containing preparations are not simultaneously administered by several routes, i.e. orally and topically (nasal, aural and eye preparations).

4.5 Interaction with other medicinal products and other forms of interaction Ibuprofen

Ibuprofen should not be used in combination with:

Acetylsalicylic acid or other NSAIDs: increase in the risk of gastrointestinal adverse reactions.

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

-    Other NSAIDs including cyclo-oxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs as this may increase the risk of adverse reactions (see section 4.4).

Ibuprofen should be used with caution in combination with:

-    Acetylsalicylic acid: Concomitant administration of ibuprofen and acetylsalicylic acid is not generally recommended because of the potential of increased adverse effects. Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose 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 acetylsalicylic acid cannot be excluded. No clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).

-    Anti-coagulants: NSAIDs may enhance the effects of anticoagulants such as warfarin (see section 4.4).

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

- Potassium sparing diuretics: the concomitant administration of ibuprofen and potassium-sparing diuretics may lead to hyperkalaemia (check of serum potassium is recommended).

-    Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (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, phenytoin, methotrexat, baclofen: there are clinical data indicating that NSAIDs may increase plasma level of these drugs.

-    Cyclosporin, tacrolimus: may increase the risk of nephrotoxicity on account of reduced synthesis of prostaglandins in the kidney. During combination treatment renal function must be closely monitored, especially in the elderly.

-    Zidovudine: increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of 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.

-    Sulfinpyrazone, probenecid: ibuprofen may reduce uricosuric effect of these drugs.

-    Sulphonylurea derivatives: concomitant use with ibuprofen may increase risk of hypoglycemia.

-    Aminoglycosides: since ibuprofen may decrease the clearance of aminoglycosides, their co-administration may increase the risk of nephrotoxicity and ototoxicity.

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

Phenylephrine

Phenylephrine should not be used in combination with:

-    Antidepressants: MAO inhibitors increase the effect of phenylephrine. Concomitant use of phenylephrine with MAO inhibitors and tricyclic antidepressants can lead to hypertensive crisis. Phenylephrine may enhance anticholinergic effect of tricyclic antidepressants.

-    Beta-blockers, antihypertensive drugs, methyldopa and reserpine: concomitant use of phenylephrine with these drugs can cause a hypertensive crisis.

Phenylephrine should be used with caution in combination with:

-    Sympathomimetics and vasodilators: phenylephrine may adversely interact with other sympathomimetics and vasodilators.

-    Digitalis glycosides: concomitant use with digitalis glycosides increases the risk of abnormal heart rhythm.

-    Ergot alkaloids: Concomitant use with ergot alkaloids (ergotamine and methysergide) increases the risk of ergotism.

4.6 Fertility, pregnancy and lactation Ibuprofen

Pregnancy

Inhibition of prostaglandin synthesis can unfavourably affect pregnancy and/or the development of embryos or foetuses. Data from epidemiological studies have indicated an enhanced risk of abortions, cardiac malformations after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations was enhanced from less than 1 % to approximately 1.5 %. The risk increases with a dose and length of treatment. In animals, the administration of prostaglandin synthesis inhibitors has indicated elevation of pre- and post-implantation losses and embryonic/foetal lethality. In addition, an elevated incidence of various malformations, including cardiovascular ones, has been described in animals treated with prostaglandin synthesis inhibitors during organogenesis.

If not explicitly inevitable, ibuprofen must not be administered in the course of the first and second trimesters of pregnancy. If ibuprofen is used by a woman who tries to become pregnant or during the first and second trimesters of pregnancy, the dose must be as low as possible and the length of treatment must be as short as possible.

In the course of the third trimester of gravidity, all prostaglandin synthesis inhibitors can expose the foetus to the following:

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

•    renal dysfunction which may progress up to renal failure with oligohydramnios;

mother and the neonate at the end of pregnancy can be exposed to

•    a potential prolongation of the time of bleeding,

•    to an inhibition of uterine contractions leading to delayed or protracted parturition.

Due to these facts, ibuprofen is contraindicated during the third trimester of pregnancy.

Breast-feeding

Ibuprofen and its metabolites penetrate to the milk of breast-feeding mothers at extremely low concentrations (according to one study the breastfed child would receive in mother’s milk only 0.0008 % of maternal weight-adjusted dosage). Due to minimal amount in breast milk, short elimination half-life and no records till now concerning harmful influence on infants, ibuprofen may be used during breast-feeding for short-term treatment of pain or inflammation signs. Safety after long-term use has not been established.

Fertility

There is limited 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. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of ibuprofen should be considered.

Phenylephrine

Pregnancy

Due to the vasoconstrictive properties of phenylephrine the product should be used with caution in patients with history of pre-eclampsia. Phenylephrine may reduce placental perfusion and the product should be used in pregnancy only if the benefits outweigh this risk.

Breast-feeding

Based on published data available on phenylephrine, it is not contraindicated during breast feeding. Animal data indicate that phenylephrine can decrease milk production, and therefore its use is not advisable at the beginning of lactation, within breast-feeding of new borns and especially premature babies.

Fertility

No fertility data are available.

4.7 Effects on ability to drive and use machines

Product has no influence on the ability to drive and operate machinery. However, in susceptible individuals it may induce dizziness. Patients should be advised not to drive or operate machinery if affected by dizziness.

4.8 Undesirable effects

The following tables summarise adverse drug reactions of ibuprofen and phenylephrine divided into groups according to MedDRA terminology together with their frequency: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to < 1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

TAB 1. Adverse reactions to ibuprofen

MedDRA system organ class	Frequency	Undesirable effect
Blood and lymphatic system disorders	Very rare	Anaemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis1
Immune system disorders	Uncommon	Hypersensitivity reactions - urticaria, pruritus

MedDRA system organ class	Frequency	Undesirable effect
Psychiatric disorders	Rare	Nervousness
Nervous system disorders	Common	Headache, dizziness, insomnia
Eye disorders	Not known	Eye pain and stinging, blurred vision, photophobia, acute angle closure glaucoma
Cardiac disorders	Very rare	Palpitations
	Not known	Arrhythmias, tachycardia
Vascular disorders	Very rare	Increased blood pressure
Gastrointestinal disorders	Very rare	Nausea, vomiting, diarrhoea

The most commonly observed adverse effects are gastrointestinal in nature. Peptic ulcer, perforation or gastrointestinal haemorrhage, sometimes fatal, may occur, particularly in the elderly.

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 (for example myocardial infarction or stroke) (see section 4.4).

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

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 (see section 4.4).

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Ibuprofen

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

Symptoms

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 drowsiness, occasionally excitation and disorientation or coma. Occasionally patients develop convulsions. In serious poisoning metabolic acidosis may occur and 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

There is no specific antidote.

Therapy of acute overdose: to carry out gastric lavage as soon as possible with administration of activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount and laxative or to evoke vomiting reflex.

Management should be supportive and symptomatic and include control and

adjustment of liquid and electrolyte balance, maintenance of respiratory and

cardiovascular functions, diazepam or lorazepam can be administered in the

case upon convulsions, plasma-expanders, eventually

dopamine or norepinephrine during hypotension. Give bronchodilators for

asthma.

Phenylephrine

Features of severe overdose of phenylephrine include haemodynamic changes and cardiovascular collapse with respiratory depression.

Treatment includes early gastric lavage and symptomatic and supportive measures.

Hypertensive effects may be treated with an intravenous alpha-receptor blocking agent.

Phenylephrine overdose is likely to result in: nervousness, headache, dizziness, insomnia, increased blood pressure, nausea, vomiting, mydriasis, acute angle closure glaucoma (most likely to occur in those with closed angle glaucoma), tachycardia, palpitations, allergic reactions (e.g. rash, urticaria, allergic dermatitis), dysuria, urinary retention (most likely to occur in those with bladder outlet obstruction, such as prostatic hypertrophy). In severe cases confusion, hallucinations, seizures and arrhythmias may occur.

5.    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: anti-inflammatory and antirheumatic products, non-steroids ATC code: M01AE51 - ibuprofen, combinations.

Ibuprofen

Ibuprofen, derivative of propionic acid, is a non-steroidal antirheumatic with good analgesic, anti-inflammatory, and antipyretic effect. It has analgesic effect at lower doses, antiinflammatory at higher doses. Anti-inflammatory effect is due to the inhibition of cyclooxygenase with the following inhibition of prostaglandin biosynthesis. Reduction of the release of pro-inflammatory mediators from granulocytes, basophiles and mastocytes mitigates the inflammation. Furthermore ibuprofen reduces the vessel sensitivity to bradykinin and histamine, it affects lymphokine production in T lymphocytes and it inhibits vasodilatation. It also inhibits thrombocyte aggregation.

Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose acetylsalicylic acid on platelet aggregation when they are dosed concomitantly. Some pharmacodynamics studies show that when single doses of ibuprofen 400 mg were taken within 8h before or within 30 min after immediate release acetylsalcylic acid dosing (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).

Onset of analgesic effect is after 0.5 hour, maximal antipyretic effect is achieved after 2-4 hours. Antipyretic effect persists for 4-8 hours or even more hours, analgesic effect 4-6 hours.

Phenylephrine

Phenylephrine is a post-synaptic alpha-receptor agonist with low cardioselective beta-receptor affinity and minimal central stimulant activity. It is a recognised decongestant and acts by vasoconstriction to reduce oedema and nasal swelling.

5.2 Pharmacokinetic properties

Ibuprofen

It is quickly and well absorbed after oral administration, peak plasma concentration is achieved already after 45 minutes upon administration on empty stomach, when administered with meal after circa 1-3 hours. Ibuprofen is absorbed more slowly after rectal application, maximal serum concentration is achieved 2 hours after application. Ibuprofen is bound to plasma proteins, but the binding is reversible. It is relatively quickly metabolized in the liver and excreted by urine, mainly in the form of metabolites and their conjugates, minor part is excreted by bile into the feaces. Biological half-life is about 2 hours. Drug accumulation in the organism may occur in the case of decreased excretion. Ibuprofen excretion is finished 24 hours after the administration of the last dose. Presence of meal minimally alters its bioavailability. Ibuprofen passes through placental barrier, it is excreted into the breast milk at amount lower than l pg/ml.

Phenylephrine

Pre-systemic metabolism is high at about 60 %, resulting in systemic bioavailability of about 40 %. Peak plasma levels occur between 1 and 2 hours and the plasma half-life ranges between 2-3 hours. When taken by mouth as a nasal decongestant phenylephrine is usually given at intervals of 4-6 hours.

5.3 Preclinical safety data

Ibuprofen

The subchronic and chronic toxicity of ibuprofen in animal experiments was observed principally as lesions and ulcerations in the gastro-intestinal tract. In vitro and in vivo studies gave no clinically relevant evidence of a mutagenic potential of ibuprofen. In studies in rats and mice no evidence of carcinogenic effects of ibuprofen was found. Ibuprofen led to inhibition of ovulation in rabbits as well as disturbance of implantation in various animal species (rabbit, rat, mouse). Experimental studies have demonstrated that ibuprofen crosses the placenta. Following administration of maternally toxic doses, an increased incidence of malformations (e.g. ventricular septal defects) was observed in the progeny of rats.

Phenylephrine

Acute toxicity of phenylephrine (LD₅₀) is 120 mg/kg body weight in mice, but 350 mg/kg body weight in rats. Specific manifestations of toxicity have not been observed in animals after administration of phenylephrine.

Genotoxicity studies with phenylephrine have led to ambiguous results. Carcinogenic potential has not been observed in rodents after administration of phenylephrine.

Data on reproductive toxicity and foetotoxicity after administration of phenylephrine to animals are not available.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Maize starch

Maize starch, pregelatinised Sodium starch glycolate (type A)

Talc

Povidone 30

Silica, colloidal anhydrous Stearic acid 50 Hypromellose 2910/5 Macrogol 6000 Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

Shelf life

2 years

6.4 Special precautions for storage

Store below 25°C. Store in the original package in order to protect from light.

6.5 Nature and contents of container

Blister (transparent PVC/Al foil), paper folding box Size of packaging: 12 and 24 film-coated tablets. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS, UK

Trading as: Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS

8 MARKETING AUTHORISATION NUMBER(S)

PL 17780/0563

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

30/05/2013

10    DATE OF REVISION OF THE TEXT

06/11/2015