TILODOL (60 tab/ 150 mg of tramadol hydrochloride in tablet)

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 Therapeutic indications

Treatment of moderate to severe pain

 Posology and method of administration


The dose should be adjusted to the intensity of the pain and the sensitivity of the individual patient. The lowest effective dose for analgesia should generally be selected.

Adults and adolescents above the age of 12 years:

The recommended doses are intended as a guideline. Patients should always receive the lowest dose that provides effective pain control. Chronic pain management should be preferably given on a fixed dosing schedule.

The starting dose is usually 100 mg tramadol hydrochloride as prolonged-release tablet twice daily, in the morning and in the evening. If the pain relief is not sufficient, the dose may be increased to 150 mg twice daily or 200 mg twice daily.

The dosage interval must not be less than 8 hours.

A total daily dose of 400 mg of tramadol hydrochloride should not be exceeded except in special clinical circumstances.

Tramadol hydrochloride should never be used longer than absolutely necessary for pain control. If the nature and severity of the underlying disease suggest the need for prolonged pain management, continued medical need for tramadol hydrochloride analgesia should be reviewed carefully at short, regular intervals (with breaks in treatment if necessary).

Paediatric populationTramadol prolonged-release tablets are not suitable for children under 12 years of age.

Older people A dose adjustment is not usually necessary in patients up to 75 years without clinically manifest hepatic or renal insufficiency. In older people over 75 years elimination may be prolonged. Therefore, if necessary the dosage interval is to be extended according to the patient's requirements.

Renal insufficiency/dialysis and hepatic impairment

In patients with renal and/or hepatic insufficiency the elimination of tramadol is delayed. In these patients prolongation of the dosage intervals should be carefully considered according to the patient's requirements. In cases of severe renal and/or severe hepatic insufficiency tramadol hydrochloride prolonged-release tablets are not recommended.

Method of administration

The prolonged-release tablets must be swallowed whole with sufficient liquid, irrespective of mealtimes.


Tramadol hydrochloride is contraindicated

• in hypersensitivity to the active substance or to any of the excipients listed in section 6.

• in acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids or other psychotropic medicinal products

• in patients who are receiving monoamine oxidase (MAO) inhibitors or who have taken them within the last 14 days (see section 4.5)

• in patients with epilepsy not adequately controlled by treatment

• for use in narcotic withdrawal treatment

 Special warnings and precautions for use

Tramadol hydrochloride may only be used with particular caution in

• opioid-dependent patients,

• patients with head injury, shock, a reduced level of consciousness of uncertain origin,

• disorders of the respiratory centre or function,

• increased intracranial pressure.

• renal and hepatic impairment (see section 4.2).

In patients sensitive to opiates tramadol hydrochloride should only be used with caution.

Tramadol hydrochloride has a low dependence potential. On long-term use tolerance, psychic and physical dependence may develop.

In patients with a tendency to drug abuse or dependence, treatment with tramadol hydrochloride should only be carried out for short periods under strict medical supervision.

Tramadol hydrochloride is not suitable as a substitute in opioid dependent patients. Although it is an opioid agonist, tramadol cannot suppress morphine withdrawal symptoms.

Convulsions have been reported in patients receiving tramadol at the recommended dose levels .The risk may be increased when doses of tramadol hydrochloride exceed the recommended upper daily dose limit (400 mg). In addition, tramadol may increase the seizure risk in patients taking other medicinal products that can lower the seizure threshold (see section 4.5). Patients with a history of epilepsy or those susceptible to seizures should only be treated with tramadol hydrochloride if there are compelling circumstances.

Care should be taken when treating patients with respiratory depression or if concomitant CNS-depressant medicinal products are being administered (see section 4.5) or if the recommended dose is significantly exceeded (see section 4.9) as the possibility of respiratory depression cannot be excluded in these situations.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.


 Interaction with other medicinal products and other forms of interaction

Tramadol hydrochloride must not be combined with monoamine oxidase (MAO).

 In patients treated with MAO inhibitors in the 14 days prior to the use of the opioid pethidine life-threatening interactions on the central nervous system respiratory and cardiovascular function have been observed. The same interactions with MAO inhibitors cannot be ruled out during treatment with tramadol hydrochloride.

Concomitant administration of tramadol hydrochloride with other centrally depressant medicinal products including alcohol may potentiate the CNS effects .

The results of pharmacokinetic studies have so far shown that on the concomitant or previous administration of cimetidine (enzyme inhibitor) clinically relevant interactions are unlikely to occur.

Simultaneous or previous administration of carbamazepine (enzyme inducer) may reduce the analgesic effect and shorten the duration of action.

Mixed agonists/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) : The analgesic effect of tramadol hydrochloride which is a pure agonist may be reduced, and a withdrawal syndrome may occur.

Tramadol can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and other seizure threshold-lowering medicinal products (such as bupropion, mirtazapine, tetrahydrocannabinol) to cause convulsions.

Concomitant therapeutic use of tramadol and serotonergic medicinal products, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors, tricyclic antidepressants and mirtazapine may cause serotonin toxicity. Serotonin syndrome is likely when one of the following is observed:

• Spontaneous clonus

• Inducible or ocular clonus with agitation or diaphoresis

• Tremor and hyperreflexia

• Hypertonia and body temperature > 38 °C and inducible or ocular clonus.

Withdrawal of the serotonergic medicinal products usually brings about a rapid improvement. Treatment depends on the type and severity of the symptoms.

Caution should be exercised during concomitant treatment with tramadol hydrochloride and coumarin derivatives (e.g. warfarin) due to reports of increased INR with major bleeding and ecchymosis in some patients.

Other active substances which inhibit the enzyme CYP3A4 such as ketoconazole, ritonavir and erythromycin, might inhibit the metabolism of tramadol (N-demethylation), and probably also the metabolism of the active O-demethylated metabolite. The clinical importance of such an interaction has not been studied.

The analgesic effect of tramadol hydrochloride is in part mediated by inhibition of the reuptake of norepinephrine and enhancement of the release of serotonin (5-HT). In a limited number of studies the pre- or post-operative application of the anti-emetic 5-HT3 antagonist ondansetron increased the requirement of tramadol hydrochloride in patients with post-operative pain. Although not tested, other 5-HT3-receptor antagonists would be expected to interact similarly with tramadol hydrochloride.

 Fertility, pregnancy and lactation


Tramadol hydrochloride crosses the placenta. Animal studies with tramadol hydrochloride revealed at very high doses effects on organ development, ossification and neonatal mortality. Teratogenic effects were not observed. There is inadequate evidence available on the safety of tramadol hydrochloride in human pregnancy. Therefore, tramadol hydrochloride should not be used in pregnant women.

Tramadol - administered before or during birth does not affect uterine contractility. In neonates it may induce changes in the respiratory rate which are usually not clinically relevant. Chronic use during pregnancy may lead to neonatal withdrawal symptoms.


During lactation about 0.1% of the maternal dose is secreted into the milk . Tramadol hydrochloride is not recommended during breast-feeding.

After a single administration of tramadol hydrochloride it is not usually necessary to interrupt breast-feeding.


Post marketing surveillance does not suggest an effect of tramadol on fertility.

Animal studies did not show an effect of tramadol on fertility.

 Effects on ability to drive and use machines

Even when taken according to instructions, tramadol hydrochloride may cause effects such as somnolence, dizziness and blurred vision and therefore may impair the reactions of drivers, machine operators and workers without a safe hold. This applies particularly in conjunction with alcohol and other psychotropic substances. If patients are affected they should be warned not to drive or operate machinery.

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

• The medicine is likely to affect your ability to drive

• Do not drive until you know how the medicine affects you

• It is an offence to drive while under the influence of this medicine

• However, you would not be committing an offence (called 'statutory defence') if:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely.

 Undesirable effects

The most commonly reported adverse reactions are nausea and dizziness, both occurring in more than 10 % of patients.

The frequencies are defined as follows:

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)

Not known (cannot be estimated from the available data)

Immune system disorders

Rare: allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis

Metabolism and nutrition disorders

Rare: changes in appetite

Not known: hypoglycaemia

Psychiatric disorders

Rare: hallucination, confusion, delirium, anxiety, sleep disturbances and nightmares. Psychic adverse reactions may occur following administration of tramadol hydrochloride which vary individually in intensity and nature ( depending on personality and duration of treatment). These include changes in mood (usually euphoric mood, occasionally dysphoria), changes in activity (usually suppression, occasionally increase) and changes in cognitive and sensorial capacity (e.g. decision behaviour, perception disorders).

Dependence may occur

Symptoms of drug withdrawal syndrome, similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms. Other symptoms that have very rarely been seen with tramadol discontinuation include: panic attacks, severe anxiety, hallucinations, paraesthesia, tinnitus and unusual CNS symptoms (i.e. confusion, delusions, depersonalisation, derealisation, paranoia).






(10x1 ml each contains Diphenhydramine hydrochloride 14.0 mg and L-  menthol 2.0 mg in ml)

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 Therapeutic indications

BENYLIN CHESTY COUGHS (ORIGINAL) is indicated for the relief of cough and associated congestive symptoms.

 Posology and method of administration

For oral use

Adults and Children aged 12 years and over:

One 10 ml dose of syrup 4 times a day.

Maximum daily dose: 40 ml syrup.

Children under 12 years:

Benylin Chesty Coughs (Original) is contraindicated in children under the age of 12 years

The Elderly:

As for adults above (see Pharmacokinetics - The elderly).

Hepatic dysfunction

Caution should be exercised if moderate to severe hepatic dysfunction is present (see Pharmacokinetics - Hepatic dysfunction).

Renal dysfunction

It may be prudent to increase the dosage interval in subjects with moderate to severe renal failure (see Pharmacokinetics - Renal dysfunction).

Do not exceed the stated dose.

Keep out of the reach and sight of children.


BENYLIN CHESTY COUGHS (ORIGINAL) is contraindicated in individuals with known hypersensitivity to the product or any of its constituents.

Benylin Chesty Coughs (Original) is contraindicated in individuals with chronic or persistent cough, such as occurs with asthma, or where cough is accompanied by excessive secretions, unless directed by the physician.

Benylin Chesty Coughs (Original) should not be administered to patients currently receiving monoamine oxidase inhibitors (MAOI) or those patients who have received treatment with MAOIs within the last two weeks.

Not to be used in children under the age of 12 years.

 Special warnings and precautions for use

This product may cause drowsiness. If affected individuals should not drive or operate machinery.

Subjects with moderate to severe renal or hepatic dysfunction or urinary retention should exercise caution when using this product (see Pharmacokinetics - Renal/Hepatic Dysfunction).

This product contains diphenhydramine and therefore should not be taken by individuals with narrow-angle glaucoma or symptomatic prostatic hypertrophy.

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

 Interaction with other medicinal products and other forms of interaction

This product contains diphenhydramine and therefore may potentiate the effects of alcohol, codeine, antihistamines and other CNS depressants.

As diphenhydramine possesses some anticholinergic activity, the effects of anticholinergics (eg, some psychotropic drugs and atropine) may be potentiated by this product. This may result in tachycardia, dry mouth, gastrointestinal disturbances (eg, colic), urinary retention and headache.

 Pregnancy and lactation

Although diphenhydramine has been in widespread use for many years without ill consequence, it is known to cross the placenta and has been detected in breast milk. BENYLIN CHESTY COUGHS (ORIGINAL) should therefore only be used when the potential benefit of treatment to the mother exceeds any possible hazards to the developing foetus or suckling infant.

 Effects on ability to drive and use machines

This product may cause drowsiness. If affected, the patient should not drive or operate machinery.

 Undesirable effects

Side effects associated with the use of BENYLIN CHESTY COUGHS (ORIGINAL) are uncommon.

Diphenhydramine may cause drowsiness; dizziness; gastrointestinal disturbance; dry mouth; nose and throat; difficulty in urination or blurred vision.

Less frequently it may cause palpitations, tremor, convulsions or parasthesia.

Hypersensitivity reactions have been reported, in particular, skin rashes, erythema, urticaria and angiodema.

Adverse reactions to menthol at the low concentration present in BENYLIN CHESTY COUGHS (ORIGINAL) are not anticipated.


Symptoms and signs

The symptoms and signs of BENYLIN CHESTY COUGHS (ORIGINAL) overdose may include drowsiness, hyperpyrexia and anticholinergic effects. With higher doses, and particularly in children, symptoms of CNS excitation including hallucinations and convulsions may appear; with massive doses, coma or cardiovascular collapse may follow.


Treatment of overdose should be symptomatic and supportive. Measures to promote rapid gastric emptying (with Syrup of Ipecac-induced emesis or gastric lavage) and, in cases of acute poisoning, the use of activated charcoal may be useful. Seizures may be controlled with Diazepam or Thiopental Sodium. The intravenous use of Physostigmine may be efficacious in antagonising severe antichlolinergic symptoms.

 Pharmacological properties

 Pharmacodynamic properties

Diphenhydramine possesses antitussive, antihistaminic and anticholinergic properties. Experiments have shown that the antitussive effect (resulting from an action on the brainstem) is discrete from its antihistaminic effect.

The duration of activity of diphenhydramine is between 4 and 8 hours.

Menthol has mild local anaesthetic and decongestant properties.

 Pharmacokinetic properties


Diphenhydramine and menthol are well absorbed from the gut following oral administration. Peak serum levels of diphenhydramine following a 50 mg oral dose are reached at between 2 and 2.5 hours.


Diphenhydramine is widely distributed throughout the body, including the CNS. Following a 50 mg oral dose of diphenhydramine, the volume of distribution is in the range 3.3 - 6.8 l/kg, and it is some 78% bound to plasma proteins.

Metabolism and Elimination

Diphenhydramine undergoes extensive first pass metabolism. Two successive N-demethylations occur, with the resultant amine being oxidised to a carboxylic acid. Values for plasma clearance of a 50 mg oral dose of diphenhydramine lie in the range 600-1300 ml/min and the terminal elimination half-life lies in the range 3.4 - 9.3 hours. Little unchanged drug is excreted in the urine. Menthol is hydroxylated in the liver by microsomal enzymes to p-methane-3,8 diol. This is then conjugated with glucuronide and excreted both in urine and bile as the Glucuronide.

The Elderly

Pharmacokinetic studies indicate no major differences in distribution or elimination of Diphenhydramine compared to younger adults.

Renal Dysfunction

The results of a review on the use of Diphenhydramine in renal failure suggest that in moderate to severe renal failure, the dose interval should be extended by a period dependent on Glomerular filtration rate (GFR).

Hepatic Dysfunction

After intravenous administration of 0.8 mg/kg Diphenhydramine, a prolonged half-life was noted in patients with chronic liver disease which correlated with the severity of the disease. However, the mean plasma clearance and apparent volume of distribution were not significantly affected.




ANADIN (50 tab/200 mg of  Ibuprofen in tablet)

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 Therapeutic indications


For the relief of mild to moderate pain including rheumatic and muscular pain, backache, neuralgia, migraine, headache, dental pain, dysmenorrhoea, feverishness and for the relief of the symptoms of cold and influenza.

 Posology and method of administration

For oral administration and short-term use only. Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).

Adults, the elderly, and children and adolescents over 12 years of age:

If in children and adolescents, between the age of 12 and 18 years, 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 minimum effective dose should be used for the shortest time necessary to relieve symptoms. If the product is required for more than 10 days or if the symptoms worsen, or persist, the patient should consult a pharmacist or a doctor.

1 or 2 tablets to be taken up to three times a day, as required. The tablets should be taken with water.

Leave at least 4 hours between doses and do not take more than 1200mg (6 tablets) in any 24 hour period.

Not to be given to children under 12 years of age.


Hypersensitivity to ibuprofen or any of the constituents in the product.

Ibuprofen is contra-indicated 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 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)

Use in last trimester of pregnancy .

 Special warnings and precautions for use

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 .

• Gastrointestinal disorders and chronic inflammatory intestinal disease as these conditions may be exacerbated (ulcerative colitis, Crohn's disease) .

• 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 .

• Renal impairment as renal function may deteriorate .

• Hepatic dysfunction .

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

The elderly are at increased risk of the serious consequences of adverse reactions especially gastrointestinal bleeding and perforation which may be fatal.

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

Use with concomitant NSAIDs including cyclo-oxygenase-2 specific inhibitors should be avoided .

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. ≤1200mg 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 on withdrawal of treatment.

Gastro-intestinal (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 effects (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 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 gastrotoxicity or bleeding, such as corticosteroids, or anticoagulants such as warfarin, selective serotonin 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.


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: 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 as this product contains sucrose.

Each tablet contains 67mg of sucrose. This should be taken into account in patients with diabetes mellitus.

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

 Interaction with other medicinal products and other forms of interaction

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 .

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 .

Other NSAIDs including cyclooxygenase-2 selective inhibitors: as these may increase the risk of adverse effects .

Ibuprofen should be used with caution in combination with:

Corticosteroids: may increase the risk of adverse reactions, especially of the gastrointestinal tract .

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

Anticoagulants: NSAIDS may enhance the effects of anticoagulants, such as warfarin .

Anti-platelet agents and selective serotonin-reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding .

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 increase 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.

 Pregnancy and lactation


While no teratogenic effects have been demonstrated in animal experiments, use of ibuprofen should, if possible, be avoided during the first 6 months of pregnancy.

During the 3rd 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 increased bleeding tendency in both mother and child .


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

 Effects on ability to drive and use machines

None expected at recommended doses and duration of therapy.

 Undesirable effects

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 or

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.


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.


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 patents develop convulsions. In serious poisoning, hypotension, hyperkalaemia, 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.


Should be symptomatic and supportive and include 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.





 (10 tab each contains Paracetamol 500 mg and Caffeine 65 mg in tablet)

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Therapeutic indications

Solpadeine Headache Soluble Tablets are a mild analgesic and antipyretic formulated to give extra pain relief. The soluble tablets are recommended for the treatment of most painful and febrile conditions, for example, headache including migraine, backache, toothache, colds and influenza, sore throat, rheumatic pain and dysmenorrhoea.

 Posology and method of administration

Solpadeine Headache Soluble Tablets should be dissolved in at least half a tumblerful of water.


Two tablets up to four times daily.

Do not exceed 8 tablets in 24 hours.


As for

adults. Children:

Not recommended for children under 12

years. Method of Administration

Solpadeine Headache Soluble Tablets are for oral administration only.


Hypersensitivity to paracetamol, caffeine or any of the other constituents.

 Special warnings and precautions for use

Care is advised in the administration of paracetamol to patients with renal or hepatic impairment. The hazard of overdose is greater in those with non- cirrhotic alcoholic liver disease.

Excessive intake of caffeine (e.g. coffee, tea and some canned drinks) should be avoided while taking this product.

Do not exceed the stated dose.

Patients should be advised to consult their doctor if their headaches become persistent.

Patients should be advised not to take other paracetamol-containing products concurrently.

Each 2 tablet dose contains 854 mg of sodium and should not be taken by patients on a low sodium diet.

Patients with rare hereditary problems of fructose intolerance should not take this medicine.

If symptoms persist consult your doctor.

Keep out of the reach and sight of children.

Pack label

Immediate medical advice should be sought in the event of an overdose, even if you feel well.

Do not take with any other paracetamol-containing products.

Patient Information Leaflet

Immediate medical advice should be sought in the event of an overdose, even if you feel well, because of the risk of delayed, serious liver damage.

 Interaction with other medicinal products and other forms of interaction

The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by cholestyramine. The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular daily use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

 Fertility, pregnancy and lactation

Paracetamol-caffeine is not recommended for use during pregnancy due to the possible increased risk of lower birth weight and spontaneous abortion associated with caffeine consumption.

Caffeine in breast milk may potentially have a stimulating effect on breast fed infants.

Due to the caffeine content of this product it should not be used if you are pregnant or breast feeding.

 Effects on ability to drive and use machines


 Undesirable effects

Adverse events from historical clinical trial data are both infrequent and from small patient exposure. Accordingly, events reported from extensive post- marketing experience at therapeutic/labelled dose and considered attributable are tabulated below by system class. Due to limited clinical trial data, the frequency of these adverse events is not known (cannot be estimated from available data), but post-marketing experience indicates that adverse reactions to paracetamol are rare and serious reactions are very rare.


Symptoms of paracetamol overdose in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, coma and death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported. Liver damage is possible in adults who have taken 10g or more of paracetamol. It is considered that excess quantities of a toxic metabolite (usually adequately detoxified by glutathione when normal doses of paracetamol are ingested), become irreversibly bound to liver tissue.

Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention and any patient who has ingested around 7.5g or more of paracetamol in the preceding 4 hours should undergo gastric lavage. Administration of oral methionine or intravenous N- acetylcysteine which may have a beneficial effect up to at least 48 hours after the overdose, may be required. General supportive measures must be available.

Overdose of caffeine may result in epigastric pain, vomitting, diuresis, tachycardia or cardia arrhythmia, CNS stimulation (insomnia, restlessness, excitement, agitation, jitteriness, tremors and convulsions).

It must be noted that for clinically significant symptoms of caffeine overdose to occur with this product, the amount ingested would be associated with serious paracetamol-related toxicity.

 Pharmacodynamic properties

The combination of paracetamol and caffeine is a well established analgesic combination.

 Pharmacokinetic properties

Paracetamol is rapidly and almost completely absorbed from the gastro- intestinal tract. It is relatively uniformly distributed throughout most body fluids and exhibits variable protein binding. Excretion is almost exclusively renal, in the form of conjugated metabolites.

Caffeine is absorbed readily after oral administration, maximal plasma concentrations are achieved within one hour and the plasma half-life is about 3.5 hours. 65 - 80% of administered caffeine is excreted in the urine as 1- methyluric acid and 1-methylxanthine.





(10 ml each contains Cyclizine Tartrate 50mg/ml and Morphine Tartrate 10mg/ml Injection)

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 Therapeutic indications

This medicine is indicated for the relief of moderate to severe pain in all suitable medical and surgical conditions (see Contraindications and Precautions & Warnings) in which reduction of the nausea and vomiting associated with the administration of morphine is required.

Route Of Administration:

By subcutaneous, intramuscular or intravenous injection.

 Posology and method of administration

The usual dose is 10-20 mg morphine tartrate, given subcutaneously, intramuscularly or intravenously.

Additional doses may not be given more frequently than 4 hourly.

Not more than 3 doses (representing 150 mg cyclizine: i.e. 3 ml of Cyclizine Tartrate 50mg/ml and Morphine Tartrate 10mg/ml Injection or Cyclizine Tartrate 50mg/ml and Morphine Tartrate 15mg/ml Injection) should be given in any 24 hour period.

Use in the Elderly

Morphine doses should be reduced in elderly patients and titrated to provide optimal pain relief with minimal side effects since:

- Increased duration of pain relief from a standard dose of morphine has been reported in elderly patients.

- A review of pharmacokinetic studies has suggested that morphine clearance decreases and half-life increases in older patients.

- The elderly may be particularly sensitive to the adverse effects of morphine.


This medicine should not be used in children under 12 years of age.


This medicine is contraindicated in individuals with known hypersensitivity to morphine, cyclizine or any of the other constituents.

This medicine, like other opioid-containing preparations, is contraindicated in patients with respiratory depression. Patients with excessive bronchial secretions should not be given this medicine as morphine diminishes the cough response.

This medicine should not be given during an attack of bronchial asthma or in heart failure secondary to chronic lung disease.

This medicine is contra-indicated in patients with head injury or raised intra-cranial pressure.

Renal Impairment

Severe and prolonged respiratory depression may occur in patients with renal impairment given morphine; this is attributed to the accumulation of the active metabolite morphine-6-glucuronide. Therefore this medicine should not be administered to patients with moderate or severe renal impairment (glomerular filtration rate <20 ml/min).

Hepatic Impairment

As with other opioid analgesic containing preparations this medicine should not be administered to patients with severe hepatic impairment as it may precipitate coma.

This medicine is contra-indicated in the presence of acute alcohol intoxication. The anti-emetic properties of cyclizine may increase the toxicity of alcohol.

This medicine is contra-indicated in individuals receiving monoamine oxidase inhibitors or within 14 days of stopping such treatment

This medicine, as with other opioid containing preparations, is contra-indicated in patients with ulcerative colitis, since such preparations may precipitate toxic dilation or spasm of the colon.

This medicine is contra-indicated in biliary and renal tract spasm.

 Special warnings and precautions for use

In common with the other opioid containing preparations, this medicine has the potential to produce tolerance and physical and psychological dependence in susceptible individuals. Abrupt cessation of therapy after prolonged use may result in withdrawal symptoms.

This medicine should be used with caution in the debilitated since they may be more sensitive to the respiratory depressant effects.

This medicine should be used with caution (including consideration of dose administered) in the presence of the following:


Adrenocortical insufficiency


Prostatic hypertrophy


Diabetes mellitus

Extreme caution should be exercised when administering this medicine to patients with phaeochromocytoma, since aggravated hypertension has been reported in association with diamorphine

Cyclizine may cause a fall in cardiac output associated with increases in heart rate, mean arterial pressure and pulmonary wedge pressure. This medicine should therefore be used with caution in patients with severe heart failure.

Because cyclizine has anticholinergic activity it may precipitate incipient glaucoma. It should be used with caution and appropriate monitoring in patients with glaucoma and also in obstructive disease of the gastrointestinal tract.


 Interaction with other medicinal products and other forms of interaction

The central nervous system depressant effects of this medicine may be enhanced by other centrally-acting agents such as phenothiazines, hypnotics, neuroleptics, alcohol and muscle relaxants.

Monoamine oxidase Inhibitors (MAOIs) may prolong and enhance the respiratory depressant effects of morphine. Opioids and MAOI's used together may cause fatal hypotension and coma (see Contraindications).

Because of its anticholinergic activity cyclizine may enhance the side effects of other anticholinergic drugs.

The analgesic effect of opioids tends to be enhanced by co-administration of dexamphetamine, hydroxyzine, and some phenothiazines, although respiratory depression may also be enhanced by the latter combination.

Morphine may reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

Propranolol has been reported to enhance the lethality of toxic doses of opioids in animals. Although the significance of this finding is not known for man, caution should be exercised when these drugs are administered concurrently.

Interference with Laboratory Tests

Morphine can react with Folin-Ciocalteau reagent in the Lowry method of protein estimation.

Morphine can also interfere with the determination of urinary 17-ketosteroids due to chemical structure effects in the Zimmerman procedure.

 Pregnancy and lactation


There is no evidence on the safety of the combination in human pregnancy nor is there evidence from animal work that the constituents are free from hazard. However, limited data from epidemiological studies of cyclizine and morphine in human pregnancies have found no evidence of teratogenicity. In the absence of definitive human data with the combination the use of this medicine in pregnancy is not advised.

Administration of morphine during labour may cause respiratory depression in the newborn infant.


Cyclizine is excreted in human milk, however, the amount has not been quantified.

Morphine can significantly suppress lactation. Morphine is excreted in human milk, but the amount is generally considered to be less than 1% of any dose.

 Effects on ability to drive and use machines

In common with other opioids, morphine may produce orthostatic hypotension and drowsiness in ambulatory patients. Sedation of short duration has been reported in patients receiving intravenous cyclizine. The CNS depressant effects of this medicine may be enhanced by combination with other centrally acting agents (see drug interactions). Patients should therefore be cautioned against activities requiring vigilance including driving vehicles and operating machinery.

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

• The medicine is likely to affect your ability to drive

• Do not drive until you know how the medicine affects you

• It is an offence to drive while under the influence of this medicine

• However, you would not be committing an offence (called 'statutory defence') if:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely

 Undesirable effects

As this medicine contains morphine and cyclizine, the type and frequency of adverse effects associated with such compounds may be expected.

Adverse reactions attributable to morphine include respiratory depression, raised intra-cranial pressure, orthostatic hypotension, drowsiness, confusion, dysphoria, restlessness, miosis, constipation, nausea, vomiting, skin reactions (e.g. urticaria) biliary tract and renal spasm, vertigo and difficulty with micturition.

Adverse reactions attributable to cyclizine include urticaria, drug rash, drowsiness/sedation, headache, dryness of the mouth, nose and throat, blurred vision, tachycardia, urinary retention, constipation, restlessness, nervousness, insomnia, auditory and visual hallucination have been reported, particularly when dosage recommendations have been exceeded.

Other Central Nervous System effects which have been reported rarely include dystonia, dyskenesia, extrapyramidal motor disturbances, tremor, twitching, muscle spasms, convulsions, disorientation, dizziness, decreased consciousness, transient speech disorders, hypertension and paraesthesia.

Cholestatic jaundice has occurred in association with cyclizine. Rare reports of cholestatic hepatitis and hypersensitivity reactions, including anaphylaxis, angioedema, allergic skin reactions and bronchospasm have been reported in association with cyclizine. There have also been a few reports of fixed drug eruption (rash), apnoea, generalised chorea, hypersensitivity hepatitis, hepatic dysfunction and agranulocytosis.

Anaphylaxis has been reported following intravenous administration of cyclizine co-administered in the same syringe as propanidid.

Anaphylactic shock is a rare adverse reaction to morphine.

A case of hyperactivity following intravenous administration of morphine during induction of anaesthesia has been reported.

A case of morphine-induced thrombocytopenia has been reported.

Morphine has a depressant effect on gonadal hormone secretion which can result in a reduction of testosterone leading to regression of secondary sexual characteristics in men on long-term therapy.

Injection site reactions including vein tracking, erythema, pain and thrombophlebitis have been reported rarely.

This medicine has demonstrated significant incidence of single cough or paroxysm of coughing immediately after its administration.

Reporting of side effects

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



The signs of overdosage with this medicine are those pathognomic of opioid poisoning i.e. respiratory depression, pin point pupils, hypotension, circulatory failure and deepening coma Mydriasis may replace miosis as asphyxia intervenes.

Drowsiness, floppiness, miosis and apnoea are signs of opioid overdosage in children as are convulsions.


It is imperative to maintain and support respiration and circulation.

The specific opioid antagonist naloxone is the treatment of choice for the reversal of coma and restoration of spontaneous respiration. The literature should be consulted for details of appropriate dosage.

The use of a specific opioid antagonist in patients tolerant to morphine may produce withdrawal symptoms.

Patients should be monitored closely for at least 48 hours in case of relapse.

 Pharmacological properties

 Pharmacodynamic properties

Cyclizine is a histamine H1 receptor antagonist of the piperazine class. It possesses anticholinergic and antiemetic properties. The exact mechanism by which cyclizine can prevent or suppress both nausea and vomiting from various causes is unknown. Cyclizine increases lower oesophageal sphincter tone and reduces the sensitivity of the labyrinthine apparatus.

Morphine is a competitive agonist at the µ-opioid receptor and is a potent analgesic. It is thought that activity at the μ1-receptor subtype may mediate the analgesic and euphoric actions of morphine whilst activity at the μ2-receptor subtype may mediate respiratory depression and inhibition of gut motility. An action at the K-opioid receptor may mediate spinal analgesia

 Pharmacokinetic properties

In a healthy adult volunteer the administration of a single oral dose of 50 mg cyclizine resulted in a peak plasma concentration of approximately 70ng/ml, occurring at about 2 hours after administration. Urine collected over 24 hours contained less than 1% of the total dose administered. In a separate study in one healthy adult volunteer the plasma elimination half-life of cyclizine was approximately 20 hours.

Cyclizine is metabolised to its N-dimethylated derivative norcyclizine, which has little antihistaminic (H1) activity compared to cyclizine.

The mean elimination half-life for morphine in blood and plasma is 2.7h (range 1.2-4.9h) and 2.95 (range 0.8-5h) respectively.

Morphine is extensively metabolised by hepatic biotransformation. In addition, the kidney has been shown to have the capacity to form morphine glucuronides. The major metabolite is morphine-3-glucuronide (approximately 45% of a dose). Morphine-6-glucuronide is a minor metabolite (approx. 5% of the dose) but is highly active. Although renal excretion is a minor route of elimination for unchanged morphine, it constitutes the major mechanism of elimination of conjugated morphine metabolites including the active morphine-6-glucuronide.

Morphine is bound to plasma proteins only to the extent of 25-35% and therefore functions that change the extent of protein binding will have only a minor impact on its pharmacodynamic effects.

 Preclinical safety data

A. Mutagenicity

Cyclizine was not mutagenic in an Ames test (at a dose level of 100 μg/plate), with or without metabolic activation.

No bacterial mutagenicity studies with morphine have been reported. A review of the literature has indicated that morphine was negative in gene mutation assays in Drosophilia melanogaster, but was positive in a mammalian spermatocyte test. The results of another study by the same authors has indicated that morphine causes chromosomal aberrations, in germ cells of male mice when given at dose levels of 10, 20, 40 or 60 mg/kg bodyweight for 3 consecutive days.

B. Carcinogenicity

No long term studies have been conducted in animals to determine whether cyclizine or morphine are potentially carcinogenic.

C. Teratogenicity

Some animal studies indicate that cyclizine may be teratogenic at dose levels up to 25 times the clinical dose level. In another study, cyclizine was negative at oral dose levels up to 65 mg/kg in rats and 75 mg/kg in rabbits.

Morphine was not teratogenic in rats when dosed for up to 15 days at 70 mg/kg/day. Morphine given subcutaneously to mice at very high doses (200, 300 or 400 mg/kg/day) on days 8 or 9 of gestation, resulted in a few cases of exencephaly and axial skeletal fusions. The hypoxic effects of such high doses could account for the defects seen.

Lower doses of morphine (40, 4.0 or 0.4 mg/ml) given to mice as a continuous iv. infusion (at a dose volume of 0.3 ml/kg) between days 7 and 10 of gestation, caused soft tissue and skeletal malformations as shown in previous studies.

D. Fertility

In a study involving prolonged administration of cyclizine to male and female rats, there was no evidence of impaired fertility after continuous treatment for 90-100 days at dose levels of approximately 15 and 25 mg/kg/day.

Effects of morphine exposure on sexual maturation of male rats, their reproductive capacity and the development of their progeny have been examined. Results indicated that exposure during adolescence led to pronounced inhibition of several indices of sexual maturation (e.g. hormone levels, reduced gonad weights), smaller litters and selective gender specific effects on endocrine function in the offspring.

A disruption in ovulation and amenorrhoea can occur in women given morphine.