Pantoloc Control 20mg gastro-resistant tablets

1. Name Of The Medicinal Product

Pantoloc Control^® 20mg gastro-resistant tablets

2. Qualitative And Quantitative Composition

Each gastro-resistant tablet contains 20mg pantoprazole (as sodium sesquihydrate).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Gastro-resistant tablet

Yellow, oval biconvex film-coated tablets imprinted with “P20” in brown ink on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

PANTOLOC Control is indicated for short-term treatment of reflux symptoms (e.g. heartburn, acid regurgitation) in adults.

4.2 Posology And Method Of Administration

Posology

The recommended dose is 20mg pantoprazole (one tablet) per day.

It might be necessary to take the tablets for 2-3 consecutive days to achieve improvement of symptoms. Once complete relief of symptoms has occurred, treatment should be discontinued.

The treatment should not exceed 4 weeks without consulting a doctor.

If no symptom relief is obtained within 2 weeks of continuous treatment, the patient should be instructed to consult a doctor.

Special populations

No dose adjustment is necessary in elderly patients or in those with impaired renal or liver function.

Paediatric population

PANTOLOC Control is not recommended for use in children and adolescents below 18 years of age due to insufficient data on safety and efficacy.

Method of administration

PANTOLOC Control 20mg gastro-resistant tablets should not be chewed or crushed, and should be swallowed whole with liquid before a meal.

4.3 Contraindications

Hypersensitivity to the active substance, or to any of the excipients (see section 6.1).

Co-administration with atazanavir (see section 4.5).

4.4 Special Warnings And Precautions For Use

Patients should be instructed to consult a doctor if:

• They have unintentional weight loss, anaemia, gastrointestinal bleeding, dysphagia, persistent vomiting or vomiting with blood, since it may alleviate symptoms and delay diagnosis of a severe condition. In these cases, malignancy should be excluded.

• They have had previous gastric ulcer or gastrointestinal surgery.

• They are on continuous symptomatic treatment of indigestion or heartburn for 4 or more weeks.

• They have jaundice, hepatic impairment, or liver disease.

• They have any other serious disease affecting general well-being.

• They are aged over 55 years with new or recently changed symptoms.

Patients with long-term recurrent symptoms of indigestion or heartburn should see their doctor at regular intervals. Especially, patients over 55 years taking any non-prescription indigestion or heartburn remedy on a daily basis should inform their pharmacist or doctor.

Patients should not take another proton pump inhibitor or H₂ antagonist concomitantly.

Patients should consult their doctor before taking this medicinal product if they are due to have an endoscopy or urea breath test.

Patients should be advised that the tablets are not intended to provide immediate relief.

Patients may start to experience symptomatic relief after approximately one day of treatment with pantoprazole, but it might be necessary to take it for 7 days to achieve complete heartburn control. Patients should not take pantoprazole as a preventive medicinal product.

Decreased gastric acidity, due to any means - including proton pump inhibitors - increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with acid-reducing medicinal products leads to a slightly increased risk of gastrointestinal infections such as Salmonella, Campylobacter, or C. difficile.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

PANTOLOC Control may reduce the absorption of active substances whose bioavailability is dependent on the gastric pH (e.g. ketoconazole).

It has been shown that co-administration of atazanavir 300 mg/ritonavir 100 mg with omeprazole (40 mg once daily) or atazanavir 400 mg with lansoprazole (60 mg single dose) to healthy volunteers resulted in a substantial reduction in the bioavailability of atazanavir. The absorption of atazanavir is pH-dependent. Therefore, pantoprazole must not be co-administered with atazanavir (see section 4.3).

Pantoprazole is metabolized in the liver via the cytochrome P450 enzyme system. An interaction of pantoprazole with other substances which are metabolized by the same enzyme system cannot be excluded. However, no clinically significant interactions were observed in specific tests with carbamazepine, caffeine, diazepam, diclofenac, digoxin, ethanol, glibenclamide, metoprolol, naproxen, nifedipine, phenytoin, piroxicam, theophylline and an oral contraceptive containing levonorgestrel and ethinyl oestradiol.

Although no interaction during concomitant administration of phenprocoumon or warfarin has been observed in clinical pharmacokinetic studies, a few isolated cases of changes in International Normalised Ratio (INR) have been reported during concomitant treatment in the post-marketing period. Therefore, in patients treated with coumarin anticoagulants (e.g. phenprocoumon or warfarin), monitoring of prothrombin time/INR is recommended after initiation, termination or during irregular use of pantoprazole.

There were no interactions with concomitantly administered antacids.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of pantoprazole in pregnant women. Studies in animals have shown reproductive toxicity. Preclinical studies revealed no evidence of impaired fertility or teratogenic effects (see section 5.3). The potential risk for humans is unknown. PANTOLOC Control should not be used during pregnancy.

Breastfeeding

It is unknown whether pantoprazole is excreted in human breast milk. Animal studies have shown excretion of pantoprazole in breast milk. PANTOLOC Control should not be used during breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

Adverse drug reactions such as dizziness and visual disturbances may occur (see section 4.8). If affected, patients should not drive or operate machines.

4.8 Undesirable Effects

Approximately 5% of patients can be expected to experience adverse drug reactions (ADRs). The most commonly reported ADRs are diarrhoea and headache, both occuring in approximately 1% of patients. The following undesirable effects have been reported with pantoprazole.

Within the following table, undesirable effects are ranked under the MedDRA frequency classification:

Very common (

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1. Undesirable effects with pantoprazole in clinical trials and post-marketing experience

Frequency	Uncommon	Rare	Very rare	Not known
System Organ Class
Blood and lymphatic system disorders		Agranulocytosis	Thrombocytopenia; Leukopenia Pancytopenia
Nervous system disorders	Headache; Dizziness	Taste disorders
Eye disorders		Disturbances in vision / blurred vision
Gastrointestinal disorders	Diarrhoea; Nausea/vomiting; Abdominal distension and bloating; Constipation; Dry mouth; Abdominal pain and discomfort
Renal and urinary disorders				Interstitial nephritis
Skin and subcutaneous tissue disorders	Rash/exanthema/eruption; Pruritus	Urticaria; Angioedema		Stevens-Johnson syndrome; Lyell syndrome; Erythema multiforme; Photosensitivity
Musculoskeletal and connective tissue disorders		Arthralgia; Myalgia
Metabolism and nutrition disorders		Hyperlipidaemias and lipid increases (triglycerides, cholesterol); Weight changes		Hyponatraemia Hypomagnesaemia
General disorders and administration site conditions	Asthenia, fatigue and malaise	Body temperature increased; Oedema peripheral
Immune system disorders		Hypersensitivity (incl. anaphylactic reactions and anaphylactic shock)
Hepatobiliary disorders	Liver enzymes increased (transaminases, γ-GT)	Bilirubin increased		Hepatocellular injury; Jaundice; Hepatocellular failure
Psychiatric disorders	Sleep disorders	Depression (and all aggravations)	Disorientation (and all aggravations)	Hallucination; Confusion (especially in pre-disposed patients, as well as the aggravation of these symptoms in case of pre-existence)
Reproductive system and breast disorders		Gynaecomastia

4.9 Overdose

There are no known symptoms of overdose in man.

Doses up to 240 mg administered intravenously over 2 minutes were well tolerated.

As pantoprazole is extensively protein bound, it is not readily dialysable.

In the case of overdose with clinical signs of intoxication, apart from symptomatic and supportive treatment, no specific therapeutic recommendations can be made.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Proton pump inhibitors, ATC code: A02BC02

Mechanism of action

Pantoprazole is a substituted benzimidazole which inhibits the secretion of hydrochloric acid in the stomach by specific blockade of the proton pumps of the parietal cells.

Pantoprazole is converted to its active form, a cyclic sulphenamide, in the acidic environment in the parietal cells where it inhibits the H+, K+-ATPase enzyme, i. e. the final stage in the production of hydrochloric acid in the stomach.

The inhibition is dose-dependent and affects both basal and stimulated acid secretion. In most patients, freedom from heartburn and acid reflux symptoms is achieved in 1 week. Pantoprazole reduces acidity in the stomach and thereby increases gastrin in proportion to the reduction in acidity. The increase in gastrin is reversible. Since pantoprazole binds to the enzyme distal to the receptor level, it can inhibit hydrochloric acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same whether the active substance is given orally or intravenously.

The fasting gastrin values increase under pantoprazole. On short-term use, in most cases they do not exceed the upper limit of normal. During long-term treatment, gastrin levels double in most cases. An excessive increase, however, occurs only in isolated cases. As a result, a mild to moderate increase in the number of specific endocrine (ECL) cells in the stomach is observed in a minority of cases during long-term treatment (simple to adenomatoid hyperplasia). However, according to the studies conducted so far, the formation of carcinoid precursors (atypical hyperplasia) or gastric carcinoids as were found in animal experiments (see section 5.3) have not been observed in humans.

Clinical efficacy

In a retrospective analysis of 17 studies in 5960 patients with gastro-oesophageal reflux disease (GORD) who were treated with 20 mg pantoprazole monotherapy, the symptoms associated with acid reflux e.g. heartburn and acid regurgitation were evaluated according to a standardised methodology. Studies selected had to have at least one acid reflux symptom recording point at 2 weeks. GORD diagnosis in these studies was based on endoscopic assessment, with the exception of one study in which the inclusion of the patients was based on symptomatology alone.

In these studies, the percentage of patients experiencing complete relief from heartburn after 7 days was between 54.0% and 80.6% in the pantoprazole group. After 14 and 28 days, complete heartburn relief was experienced in 62.9% to 88.6% and 68.1% to 92.3% of the patients, respectively.

For the complete relief from acid regurgitation, similar results were obtained as for heartburn. After 7 days the percentage of patients experiencing complete relief from acid regurgitation was between 61.5% and 84.4%, after 14 days between 67.7% and 90.4%, and after 28 days between 75.2% and 94.5%, respectively.

Pantoprazole was consistently shown to be superior to placebo and H2RA and non-inferior to other PPIs. Acid-reflux symptom relief rates were largely independent of the initial GORD stage.

5.2 Pharmacokinetic Properties

Pharmacokinetics do not vary after single or repeated administration. In the dose range of 10 to 80 mg, the plasma kinetics of pantoprazole are linear after both oral and intravenous administration.

Absorption

Pantoprazole is completely and rapidly absorbed after oral administration. The absolute bioavailability from the tablet was found to be about 77 %. On average, at about 2.0 h - 2.5 h post administration (t_max) of a single 20 mg oral dose, the maximum serum concentrations (C_max) of about 1-1.5 µg/ml are achieved, and these values remain constant after multiple administration. Concomitant intake of food had no influence on bioavailability (AUC or C_max), but increased the variability of the lag-time (t_lag).

Distribution

Volume of distribution is about 0.15 l/kg and serum protein binding is about 98%.

Metabolism and excretion

Clearance is about 0.1 l/h/kg, and terminal half-life (t_1/2) about 1 h. There were a few cases of subjects with delayed elimination. Due to the specific binding of pantoprazole to the proton pumps within the parietal cell, the elimination half-life does not correlate with the much longer duration of action (inhibition of acid secretion).

Pantoprazole is almost exclusively metabolized in the liver. Renal elimination represents the major route of excretion (about 80%) for the metabolites of pantoprazole; the rest is excreted with the faeces. The main metabolite in both serum and urine is desmethylpantoprazole, which is conjugated with sulphate. The half-life of the main metabolite (about 1.5 h) is not much longer than that of pantoprazole.

Special populations

Renal impairment

No dose reduction is recommended when pantoprazole is administered to patients with impaired renal function (including patients on dialysis, which removes only negligible amounts of pantoprazole). As with healthy subjects, the half-life of pantoprazole is short. Although the main metabolite has a longer half-life (2-3h), excretion is still rapid and thus accumulation does not occur.

Hepatic impairment

After administration of pantoprazole to patients with liver impairment (Child-Pugh classes A, B and C) the half-life values increased to between 3 and 7 h and the AUC values increased by a factor of 3-6, whereas the C_max only increased slightly by a factor of 1.3 compared with healthy subjects.

Elderly

The slight increase in AUC and C_max in elderly volunteers compared with younger subjects was not clinically relevant.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.

In the 2-year carcinogenicity studies in rats, neuroendocrine neoplasms were found. In addition, squamous cell papillomas were found in the forestomach of rats in one study. The mechanism leading to the formation of gastric carcinoids by substituted benzimidazoles has been carefully investigated and allows the conclusion that it is a secondary reaction to the massively elevated serum gastrin levels occurring in the rat during chronic high-dose treatment.

In the 2-year rodent studies an increased number of liver tumors was observed in rats (in one rat study only) and in female mice and was interpreted as being due to pantoprazole's high metabolic rate in the liver.

A slight increase of neoplastic changes of the thyroid was observed in the group of rats receiving the highest dose (200 mg/kg) in one 2-year study. The occurrence of these neoplasms is associated with the pantoprazole-induced changes in the breakdown of thyroxine in the rat liver. As the therapeutic dose in man is low, no side effects on the thyroid glands are expected.

In animal studies (rats) 5 mg/kg was the observed NOAEL (No Observed Adverse Effect Level) for embryotoxicity. Investigations revealed no evidence of impaired fertility or teratogenic effects.

Penetration of the placenta was investigated in the rat and was found to increase with advanced gestation. As a result, concentration of pantoprazole in the foetus is increased shortly before birth.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Core

Sodium carbonate, anhydrous

Mannitol (E421)

Crospovidone

Povidone K90

Calcium stearate

Coating

Hypromellose

Povidone K25

Titanium dioxide (E171)

Yellow iron oxide (E172)

Propylene glycol

Methacrylic acid-ethyl acrylate copolymer (1:1)

Sodium laurilsulfate

Polysorbate 80

Triethyl citrate

Printing ink

Shellac

Red iron oxide (E172)

Black iron oxide (E172)

Yellow iron oxide (E172)

Ammonia solution, concentrated

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Store in the original package in order to protect from moisture.

6.5 Nature And Contents Of Container

Alu/Alu blisters containing 7 or 14 gastro-resistant tablets or Alu/Alu blisters with cardboard reinforcement containing 7 or 14 gastro-resistant tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Nycomed GmbH

Byk-Gulden-Str. 2

D-78467 Konstanz

Germany

Telephone: +49-(0)7531-84-0

Telefax: +49-(0)7531-84-2474

8. Marketing Authorisation Number(S)

EU/1/09/519/001-004

9. Date Of First Authorisation/Renewal Of The Authorisation

12 June 2009

10. Date Of Revision Of The Text

7 December 2011

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.emea.europa.eu/.

LEGAL CATEGORY

P

Palexia 75 mg film-coated tablets

1. Name Of The Medicinal Product

Palexia^® 75 mg film-coated tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 75 mg tapentadol (as hydrochloride).

Excipient(s):

Palexia 75 mg contains 37.11 mg lactose.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet (tablet)

Pale yellow round shaped film-coated tablets of 8 mm diameter, marked with Grünenthal logo on one side and “H7” on the other side.

4. Clinical Particulars

4.1 Therapeutic Indications

Palexia is indicated for the relief of moderate to severe acute pain in adults, which can be adequately managed only with opioid analgesics.

4.2 Posology And Method Of Administration

The dosing regimen should be individualised according to the severity of pain being treated, the previous treatment experience and the ability to monitor the patient.

Patients should start treatment with single doses of 50 mg tapentadol as film-coated tablet administered every 4 to 6 hours. Higher starting doses may be necessary depending on the pain intensity and the patient's previous history of analgesic requirements.

On the first day of dosing, an additional dose may be taken as soon as one hour after the initial dose, if pain control is not achieved. The dose should then be titrated individually to a level that provides adequate analgesia and minimises undesirable effects under the close supervision of the prescribing physician.

Daily doses greater than 700 mg tapentadol on the first day of treatment and maintenance daily doses greater than 600 mg tapentadol have not been studied and are therefore not recommended.

As soon as stable dosing regimen is achieved and longer treatment is anticipated, the possibility of switching the patient to therapy with the prolonged-release tablets (Palexia SR) should be considered.

As with all symptomatic treatments, the continued use of tapentadol must be evaluated on an ongoing basis.

Discontinuation of treatment

Withdrawal symptoms could occur after abrupt discontinuation of treatment with tapentadol (see section 4.8). When a patient no longer requires therapy with tapentadol, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.

Renal Impairment

In patients with mild or moderate renal impairment a dosage adjustment is not required (see section 5.2).

Palexia has not been studied in controlled efficacy trials in patients with severe renal impairment, therefore the use in this population is not recommended (see sections 4.4 and 5.2).

Hepatic Impairment

In patients with mild hepatic impairment a dosage adjustment is not required (see section 5.2).

Palexia should be used with caution in patients with moderate hepatic impairment. Treatment in these patients should be initiated at the lowest available dose strength, i.e. 50 mg tapentadol as film-coated tablet, and not be administered more frequently than once every 8 hours. At initiation of therapy a daily dose greater than 150 mg tapentadol as film-coated tablet is not recommended. Further treatment should reflect maintenance of analgesia with acceptable tolerability, to be achieved by either shortening or lengthening the dosing interval (see sections 4.4 and 5.2).

Palexia has not been studied in patients with severe hepatic impairment and therefore, use in this population is not recommended (see sections 4.4 and 5.2).

Elderly Patients (persons aged 65 years and over)

In general, a dose adaptation in elderly patients is not required. However, as elderly patients are more likely to have decreased renal and hepatic function, care should be taken in dose selection as recommended (see sections 4.2 and 5.2).

Paediatric Patients

The safety and efficacy of Palexia in children and adolescents below 18 years of age has not yet been established. Therefore Palexia is not recommended for use in this population.

Method of administration

Palexia should be taken with sufficient liquid. Palexia can be taken with or without food.

4.3 Contraindications

Palexia is contraindicated

• in patients with hypersensitivity to tapentadol or to any of the excipients (see section 6.1)

• in situations where active substances with mu-opioid receptor agonist activity are contraindicated, i.e. patients with significant respiratory depression (in unmonitored settings or the absence of resuscitative equipment), and patients with acute or severe bronchial asthma or hypercapnia

• in any patient who has or is suspected of having paralytic ileus

• in patients with acute intoxication with alcohol, hypnotics, centrally acting analgesics, or psychotropic active substances (see section 4.5)

4.4 Special Warnings And Precautions For Use

Potential for Abuse and Addiction/ Dependence Syndrome

Palexia has a potential for abuse and addiction. This should be considered when prescribing or dispensing Palexia in situations where there is concern about an increased risk of misuse, abuse, addiction, or diversion.

All patients treated with active substances that have mu-opioid receptor agonist activity should be carefully monitored for signs of abuse and addiction.

Respiratory Depression

At high doses or in mu-opioid receptor agonist sensitive patients, Palexia may produce dose-related respiratory depression. Therefore, Palexia should be administered with caution to patients with impaired respiratory functions. Alternative non-mu-opioid receptor agonist analgesics should be considered and Palexia should be employed only under careful medical supervision at the lowest effective dose in such patients. If respiratory depression occurs, it should be treated as any mu-opioid receptor agonist-induced respiratory depression (see section 4.9).

Head Injury and Increased Intracranial Pressure

Palexia should not be used in patients who may be particularly susceptible to the intracranial effects of carbon dioxide retention such as those with evidence of increased intracranial pressure, impaired consciousness, or coma. Analgesics with mu-opioid receptor agonist activity may obscure the clinical course of patients with head injury. Palexia should be used with caution in patients with head injury and brain tumors.

Seizures

Palexia has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical trials. However, like other analgesics with mu-opioid agonist activity Palexia should be prescribed with care in patients with a history of a seizure disorder or any condition that would put the patient at risk of seizures.

Renal Impairment

Palexia has not been studied in controlled efficacy trials in patients with severe renal impairment, therefore the use in this population is not recommended (see section 4.2 and 5.2).

Hepatic Impairment

Subjects with mild and moderate hepatic impairment showed a 2-fold and 4.5-fold increase in systemic exposure, respectively, compared with subjects with normal hepatic function. Palexia should be used with caution in patients with moderate hepatic impairment (see section 4.2 and 5.2), especially upon initiation of treatment.

Palexia has not been studied in patients with severe hepatic impairment and therefore, use in this population is not recommended (see sections 4.2 and 5.2).

Use in Pancreatic/Biliary Tract Disease

Active substances with mu-opioid receptor agonist activity may cause spasm of the sphincter of Oddi. Palexia should be used with caution in patients with biliary tract disease, including acute pancreatitis.

Concomitant treatment with monoamine oxidase inhibitors (MAOI)

Treatment with Palexia should be avoided in patients who are receiving monoamine oxidase (MAO) inhibitors or who have taken them within the last 14 days due to potential additive effects on synaptic noradrenaline concentrations which may result in adverse cardiovascular events, such as hypertensive crisis (see section 4.5)

Palexia film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this medicinal product.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Treatment with Palexia should be avoided in patients who are receiving monoamine oxidase (MAO) inhibitors or who have taken them within the last 14 days due to potential additive effects on synaptic noradrenaline concentrations which may result in adverse cardiovascular events, such as hypertensive crisis (see section 4.4)

Medicinal products like benzodiazepines, barbiturates and opioids (analgesics, antitussives or substitution treatments) may enhance the risk of respiratory depression if taken in combination with Palexia. CNS depressants (e.g. benzodiazepines, antipsychotics, H1-antihistamines, opioids, alcohol) can enhance the sedative effect of tapentadol and impair vigilance. Therefore, when a combined therapy of Palexia with a respiratory or CNS depressant is contemplated, the reduction of dose of one or both agents should be considered.

In isolated cases there have been reports of serotonin syndrome in a temporal connection with the therapeutic use of tapentadol in combination with serotoninergic medicinal products such as selective serotonin re-uptake inhibitors (SSRIs). Signs of serotonin syndrome may be for example confusion, agitation, fever, sweating, ataxia, hyperreflexia, myoclonus and diarrhoea. Withdrawal of the serotoninergic medicinal products usually brings about a rapid improvement. Treatment depends on the nature and severity of the symptoms.

There is no clinical data on the concomitant use of Palexia with mixed mu-opioid agonist/antagonists (like pentazocine, nalbuphine) or partial mu-opioid agonists (like buprenorphine). As with pure mu-opioid agonists, the analgesic effect provided by the mu-opioid component of Palexia may be theoretically reduced in such circumstances. Therefore, care should be taken when combining Palexia with these medicinal products.

The major elimination pathway for tapentadol is conjugation with glucuronic acid mediated via uridine diphosphate transferase (UGT) mainly UGT1A6, UGT1A9 and UGT2B7 isoforms. Thus, concomitant administration with strong inhibitors of these isoenzymes may lead to increased systemic exposure of tapentadol. Interaction studies with active substances that potentially could affect the glucuronidation (paracetamol, acetylsalicylic acid, naproxen and probenecid) did not result in any clinically relevant effect on the serum concentrations of tapentadol (see section 5.2). Interaction studies with substances that can affect absorption of tapentadol (omeprazole and metoclopramide) did not result in any clinically relevant effect on the serum concentrations of tapentadol (see section 5.2).

For patients on tapentadol treatment, caution should be exercised if concomitant drug administration of strong enzyme inducing drugs (e.g. rifampicin, phenobarbital, St John's Wort (hypericum perforatum)) starts or stops, since this may lead to decreased efficacy or risk for adverse effects, respectively

4.6 Pregnancy And Lactation

Pregnancy

There is very limited amount of data from the use in pregnant women.

Studies in animals have not shown teratogenic effects. However, delayed development and embryotoxicity were observed at doses resulting in exaggerated pharmacology. Effects on the postnatal development were already observed at the maternal NOAEL (see section 5.3).

Palexia should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Labour and Delivery

The effect of tapentadol on labour and delivery in humans is unknown. Palexia is not recommended for use in women during and immediately before labour and delivery. Due to the mu-opioid receptor agonist activity of tapentadol, new-born infants whose mothers have been taking tapentadol should be monitored for respiratory depression.

Lactation

There is no information on the excretion of tapentadol in human milk. From a study in rat pups suckled by dams dosed with tapentadol it was concluded that tapentadol is excreted via milk (see section 5.3). Therefore, a risk to the suckling child cannot be excluded. Palexia should not be used during breast feeding.

4.7 Effects On Ability To Drive And Use Machines

Palexia may have major influence on the ability to drive and use machines due to the fact that it may adversely affect central nervous system functions (see section 4.8). This has to be expected especially at the beginning of treatment, at any change of dosage as well as in connection with alcohol or tranquilisers (see section 4.4). Patients should be cautioned as to whether driving or use of machines is permitted.

4.8 Undesirable Effects

The adverse drug reactions that were experienced by patients in the placebo controlled trials performed with Palexia were predominantly of mild and moderate severity. The most frequent adverse drug reactions were in the gastrointestinal and central nervous system (nausea, vomiting, somnolence, dizziness and headache).

The table below lists adverse drug reactions that were identified from clinical trials performed with Palexia. They are listed by class and frequency. Frequencies are defined as very common (

ADVERSE DRUG REACTIONS
System Organ Class	Frequency
Very common	Common	Uncommon	Rare
Immune system disorders				Hypersensitivity
Metabolism and nutrition disorders		Decreased appetite
Psychiatric disorders		Anxiety, Confusional state, Hallucination, Sleep disorder, Abnormal dreams	Depressed mood, Disorientation, Agitation, Nervousness, Restlessness, Euphoric mood	Thinking abnormal
Nervous system disorders	Dizziness, Somnolence, Headache	Tremor	Disturbance in attention, Memory impairment, Presyncope, Sedation, Ataxia, Dysarthria, Hypoaesthesia, Paraesthesia, Muscle contractions involuntary	Convulsion, Depressed level of consciousness, Coordination abnormal
Eye disorders			Visual disturbance
Cardiac disorders			Heart rate increased	Heart rate decreased
Vascular disorders		Flushing	Blood pressure decreased
Respiratory, thoracic and mediastinal disorders			Respiratory depression, Oxygen saturation decreased, Dyspnoea,
Gastrointestinal disorders	Nausea, Vomiting	Constipation, Diarrhoea, , Dyspepsia, Dry mouth	Abdominal discomfort	Impaired gastric emptying
Skin and subcutaneous tissue disorders		Pruritus, Hyperhidrosis, Rash	Urticaria
Musculoskeletal and connective tissue disorder		Muscle spasms	Sensation of heaviness
Renal and urinary disorders			Urinary hesitation, Pollakiuria
General disorders and administration site conditions		Asthenia, Fatigue, Feeling of body temperature change	Drug withdrawal syndrome, Oedema, Feeling abnormal, Feeling drunk, Irritability, Feeling of relaxation

Clinical trials performed with Palexia with patient exposure up to 90 days have shown little evidence of withdrawal symptoms upon abrupt discontinuations and these were generally classified as mild, when they occurred. Nevertheless, physicians should be vigilant for symptoms of withdrawal (see section 4.2) and treat patients accordingly should they occur.

The risk of suicidal ideation and suicides committed is known to be higher in patients suffering from chronic pain. In addition, substances with a pronounced influence on the monoaminergic system have been associated with an increased risk of suicidality in patients suffering from depression, especially at the beginning of treatment. For tapentadol data from clinical trials and post-marketing reports do not provide evidence for an increased risk

4.9 Overdose

Human Experience

Experience with overdose of tapentadol is very limited. Preclinical data suggest that symptoms similar to those of other centrally acting analgesics with mu-opioid receptor agonist activity are to be expected upon intoxication with tapentadol. In principle, these symptoms include, referring to the clinical setting, in particular miosis, vomiting, cardiovascular collapse, consciousness disorders up to coma, convulsions and respiratory depression up to respiratory arrest.

Management of Overdose

Management of overdose should be focused on treating symptoms of mu-opioid agonism. Primary attention should be given to re-establishment of a patent airway and institution of assisted or controlled ventilation when overdose of tapentadol is suspected.

Pure opioid receptor antagonists such as naloxone are specific antidotes to respiratory depression resulting from opioid overdose. Respiratory depression following an overdose may outlast the duration of action of the opioid receptor antagonist. Administration of an opioid receptor antagonist is not a substitute for continuous monitoring of airway, breathing, and circulation following an opioid overdose. If the response to opioid receptor antagonists is suboptimal or only brief in nature, an additional dose of antagonist (e.g. naloxone) should be administered as directed by the manufacturer of the product.

Gastrointestinal decontamination may be considered in order to eliminate unabsorbed active substance. Gastrointestinal decontamination with activated charcoal or by gastric lavage may be considered within 2 hours after intake. Before attempting gastrointestinal decontamination, care should be taken to secure the airway.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Analgesics; opioids; other opioids

ATC code: N02AX06

Tapentadol is a strong analgesic with µ-agonistic opioid and additional noradrenaline reuptake inhibition properties. Tapentadol exerts its analgesic effects directly without a pharmacologically active metabolite.

Tapentadol demonstrated efficacy in preclinical models of nociceptive, neuropathic, visceral and inflammatory pain; Efficacy has been verified in clinical trials with tapentadol film-coated tablets covering nociceptive pain conditions including postoperative orthopaedic and abdominal pain as well as chronic pain due to osteoarthritis of the hip or knee. In general the analgesic effect of tapentadol in nociceptive pain trials was similar to that observed with a strong opioid used as comparator.

Effects on the cardiovascular system: In a thorough human QT trial, no effect of multiple therapeutic and supratherapeutic doses of tapentadol on the QT interval was shown. Similarly, tapentadol had no relevant effect on other ECG parameters (heart rate, PR interval, QRS duration, T-wave or U-wave morphology).

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Palexia in all subsets of the paediatric population in moderate to severe acute pain.

See section 4.2 for information on paediatric use.

5.2 Pharmacokinetic Properties

Absorption

Tapentadol is rapidly and completely absorbed after oral administration of Palexia. Mean absolute bioavailability after single-dose administration (fasting) is approximately 32% due to extensive first-pass metabolism. Maximum serum concentrations of tapentadol are typically observed at around 1.25 hours after administration of film-coated tablets. Dose-proportional increases in the C_max and AUC values of tapentadol have been observed after administration of film-coated tablets over the oral therapeutic dose range.

A multiple (every 6 hour) dose trial with doses ranging from 75 to 175 mg tapentadol administered as film-coated tablets showed an accumulation ratio between 1.4 and 1.7 for the parent active substance and between 1.7 and 2.0 for the major metabolite tapentadol-O-glucuronide, which are primarily determined by the dosing interval and apparent half-life of tapentadol and its metabolite.

Food Effect

The AUC and C_max increased by 25% and 16%, respectively, when film-coated tablets were administered after a high-fat, high-calorie breakfast. The time to maximum plasma concentration was delayed by 1.5 hours under these conditions. Based on efficacy data obtained at early assessment time points during phase II/III trials, the food effect does not appear to be of clinical relevance Palexia may be given with or without food.

Distribution

Tapentadol is widely distributed throughout the body. Following intravenous administration, the volume of distribution (Vz) for tapentadol is 540 +/- 98 l. The serum protein binding is low and amounts to approximately 20%.

Metabolism and Elimination

In humans, the metabolism of tapentadol is extensive. About 97% of the parent compound is metabolised. The major pathway of tapentadol metabolism is conjugation with glucuronic acid to produce glucuronides. After oral administration approximately 70% of the dose is excreted in urine as conjugated forms (55% glucuronide and 15% sulfate of tapentadol). Uridine diphosphate glucuronyl transferase (UGT) is the primary enzyme involved in the glucuronidation (mainly UGT1A6, UGT1A9 and UGT2B7 isoforms). A total of 3% of active substance is excreted in urine as unchanged active substance. Tapentadol is additionally metabolised to N-desmethyl tapentadol (13%) by CYP2C9 and CYP2C19 and to hydroxy tapentadol (2%) by CYP2D6, which are further metabolised by conjugation. Therefore, active substance metabolism mediated by cytochrome P450 system is of less importance than phase 2 conjugation.

None of the metabolites contributes to the analgesic activity.

Tapentadol and its metabolites are excreted almost exclusively (99%) via the kidneys. The terminal half-life is on average 4 hours after oral administration. The total clearance is 1530 +/- 177 ml/min.

Special populations

Elderly

The mean exposure (AUC) to tapentadol was similar in a trial with elderly subjects (65-78 years of age) compared to young adults (19-43 years of age), with a 16% lower mean C_max observed in the elderly subject group compared to young adult subjects.

Renal Impairment

AUC and C_max of tapentadol were comparable in subjects with varying degrees of renal function (from normal to severely impaired). In contrast, increasing exposure (AUC) to tapentadol-O-glucuronide was observed with increasing degree of renal impairment. In subjects with mild, moderate, and severe renal impairment, the AUC of tapentadol-O-glucuronide are 1.5-, 2.5-, and 5.5-fold higher compared with normal renal function, respectively.

Hepatic Impairment

Administration of tapentadol resulted in higher exposures and serum levels to tapentadol in subjects with impaired hepatic function compared to subjects with normal hepatic function. The ratio of tapentadol pharmacokinetic parameters for the mild and moderate hepatic impairment groups in comparison to the normal hepatic function group were 1.7 and 4.2, respectively, for AUC; 1.4 and 2.5, respectively, for C_max; and 1.2 and 1.4, respectively, for t1/2. The rate of formation of tapentadol-O-glucuronide was lower in subjects with increased liver impairment.

Pharmacokinetic Interactions

Tapentadol is mainly metabolised by Phase 2 glucuronidation, and only a small amount is metabolised by Phase 1 oxidative pathways.

As glucuronidation is a high capacity/low affinity system, which is not easily saturated even in disease, and as therapeutic concentrations of active substances are generally well below the concentrations needed for potential inhibition of glucuronidation, any clinically relevant interactions caused by Phase 2 metabolism are unlikely to occur. In a set of drug-drug interaction trials using paracetamol, naproxen, acetylsalicylic acid and probenecid, a possible influence of these active substances on the glucuronidation of tapentadol was investigated. The trials with probe active substances naproxen (500 mg twice daily for 2 days) and probenecid (500 mg twice daily for 2 days) showed increases in AUC of tapentadol by 17% and 57%, respectively. Overall, no clinically relevant effects on the serum concentrations of tapentadol were observed in these trials.

Furthermore, interaction trials of tapentadol with metoclopramide and omeprazole were conducted to investigate a possible influence of these active substances on the absorption of tapentadol. These trials also showed no clinically relevant effects on tapentadol serum concentrations.

In vitro studies did not reveal any potential of tapentadol to either inhibit or induce cytochrome P450 enzymes. Thus, clinically relevant interactions mediated by the cytochrome P450 system are unlikely to occur.

Plasma protein binding of tapentadol is low (approximately 20%). Therefore, the likelihood of pharmacokinetic drug-drug interactions by displacement from the protein binding site is low.

5.3 Preclinical Safety Data

Tapentadol was not genotoxic in bacteria in the Ames test. Equivocal findings were observed in an in vitro chromosomal aberration test, but when the test was repeated the results were clearly negative. Tapentadol was not genotoxic in vivo, using the two endpoints of chromosomal aberration and unscheduled DNA synthesis, when tested up to the maximum tolerated dose. Long-term animal studies did not identify a potential carcinogenic risk relevant to humans.

Tapentadol had no influence on male or female fertility in rats but there was reduced in utero survival at the high dose. It is not known whether this was mediated via the male or the female. Tapentadol showed no teratogenic effects in rats and rabbits following intravenous and subcutaneous exposure; however, delayed development and embryotoxicity were observed after administration of doses resulting in exaggerated pharmacology.After intravenous dosing in rats reduced in utero survival was seen. In rats tapentadol caused increased mortality of the F₁ pups that were directly exposed via milk between days 1 and 4 post partum already at dosages that did not provoke maternal toxicities. There were no effects on neurobehavioral parameters.

Excretion into breast milk was investigated in rat pups suckled by dams dosed with tapentadol. Pups were dose-dependently exposed to tapentadol and tapentadol O-glucuronide. It is concluded that tapentadol is excreted via milk.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core:

Microcrystalline cellulose

Lactose monohydrate

Croscarmellose sodium

Povidone K30

Magnesium stearate

Tablet coat :

Polyvinylalcohol

Titanium dioxide (E 171)

Macrogol 3350

Talc

Yellow iron oxide (E 172)

Red iron oxide (E 172)

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

PVC/PVDC aluminium blisters

Packs with 5, 10, 14, 20, 28, 30, 40, 50, 56, 60, 90, 100 film-coated tablets.

PVC/PVDC aluminium perforated unit-dose blisters

Packs with 10x1, 14x1, 20x1, 28x1, 30x1, 50x1, 56x1, 60x1, 90x1, 100x1 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Grünenthal Ltd

Regus Lakeside House

1 Furzeground Way

Stockley Park East

Uxbridge

Middlesex UB11 1BD

United Kingdom

8. Marketing Authorisation Number(S)

PL 21727/0033

9. Date Of First Authorisation/Renewal Of The Authorisation

04 February 2011

10. Date Of Revision Of The Text

04 February 2011

Pentasa Sachet 2g

1. Name Of The Medicinal Product

PENTASA Sachet 2g prolonged release granules

2. Qualitative And Quantitative Composition

Each sachet contains mesalazine 2 g

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Prolonged release granules

White-grey to pale white-brown granules

4. Clinical Particulars

4.1 Therapeutic Indications

Mild to moderate ulcerative colitis

4.2 Posology And Method Of Administration

Ulcerative colitis

Adults

Active disease

Individual dosage, up to 4 g mesalazine daily divided into 2-4 doses.

Maintenance treatment

Individual dosage. Recommended dosage, 2 g mesalazine once daily.

Paediatric population:

There is only limited documentation for an effect in children (age 6-18 years).

Children 6 years of age and older:

Active disease: To be determined individually, starting with 30-50 mg/kg/day in divided doses. Maximum dose: 75 mg/kg/day in divided doses. The total dose should not exceed 4 g/day (maximum adult dose).

Maintenance treatment: To be determined individually, starting with 15-30 mg/kg/day in divided doses. The total dose should not exceed 2 g/day (recommended adult dose).

It is generally recommended that half the adult dose may be given to children up to a body weight of 40 kg; and the normal adult dose to those above 40 kg.

The granules must not be chewed.

The contents of the sachet should be emptied onto the tongue and washed down with some water or orange juice.

4.3 Contraindications

Hypersensitivity to mesalazine, any other component of the product, or salicylates.

Severe liver and/or renal impairment.

4.4 Special Warnings And Precautions For Use

Caution is recommended when treating patients allergic to sulphasalazine (risk of allergy to salicylates). In case of acute symptoms of intolerance, i.e. cramps, abdominal pain, fever, severe headache and rash, the treatment should be discontinued immediately.

Caution is recommended in patients with impaired liver or renal function and in patients with haemorrhagic diathesis. The drug is not recommended for use in patients with renal impairment. The renal function should be regularly monitored (e.g. serum creatinine), especially during the initial phase of treatment. Mesalazine induced nephrotoxicity should be suspected in patients developing renal dysfunction during treatment.

Blood tests (differential blood count; liver function parameters like ALT or AST) should be assessed prior to and during treatment, at the discretion of the treating physician.

The concurrent use of other known nephrotoxic agents, such as NSAIDs and azathioprine, may increase the risk of renal reactions.

Caution is recommended in patients with active peptic ulcer.

Mesalazine-induced cardiac hypersensitivity reactions (myo- and pericarditis) have been reported rarely. Serious blood dyscrasias have been reported very rarely with mesalazine (see section 4.5). Treatment should be discontinued on suspicion or evidence of these adverse reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No specific interaction studies have been performed. Concomitant treatment with mesalazine can increase the risk of blood dyscrasia in patients receiving azathioprine or 6-mercaptopurine.

4.6 Pregnancy And Lactation

PENTASA Sachet should not be used during pregnancy and lactation except when the potential benefits of the treatment outweigh the possible hazards in the opinion of the physician.

Pregnancy:

Mesalazine is known to cross the placental barrier. The limited data available on the use of this compound in pregnant women do not allow assessment of possible adverse effects. No teratogenic effects have been observed in animal studies and in a controlled human study.

Blood disorders (leucopenia, thrombocytopenia, anaemia) have been reported in new-borns of mothers being treated with PENTASA.

Lactation:

Mesalazine is excreted in breast milk. The mesalazine concentration in breast milk is lower than in maternal blood, whereas the metabolite-acetyl mesalazine-appears in similar or increased concentrations. No controlled studies with PENTASA during breast-feeding have been carried out. Only limited experience during lactation in women after oral application is available to date. Hypersensitivity reactions like diarrhoea can not be excluded.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

The most frequent adverse reactions seen in clinical trials are diarrhoea (3%), nausea (3%), abdominal pain (3%), headache (3%), vomiting (1%) and rash (1%). Hypersensitivity reactions and drug fever may occasionally occur

Frequency of adverse effects, based on clinical trials and reports from post-marketing surveillance

System Organ Classes	Common	Rare	Very rare	Not Known
Blood and the lymphatic system disorders			Eosinophilia (as part of an allergic reaction) Anaemia Aplastic anaemia Leukopenia (incl. Granulocytopenia) Thrombocytopenia Agranulocytosis Pancytopenia
Immune system disorders				Hypersensitivity reaction
Nervous system disorders	Headache		Peripheral neuropathy Benign intracranial hypertension in adolescents
Cardiac disorders		Myocarditis* Pericarditis*
Respiratory, thoracic and mediastinal disorders			Allergic lung reactions (incl. dyspnoea, cough, allergic alveolitis, pulmonary eosinophilia, lung infiltration, pneumonitis)
Gastrointestinal disorders	Diarrhoea Abdominal pain Nausea Vomiting	Pancreatitis* Increased amylase (blood and/or urine)
Hepato-biliary disorders			Increased liver enzymes and bilirubin, hepatotoxicity (incl. hepatitis*, cirrhosis, hepatic failure)
Skin and subcutaneous tissue disorders	Rash, (incl. urticaria, erythematous rash		Reversible alopecia Quincke's oedema
Musculoskeletal, connective tissue and bone disorders			Myalgia Arthralgia Single cases of lupus erythematosus-like reactions
Renal and urinary disorders			Renal impairment, interstitial nephritis*, nephrotic syndrome, urine discolouration
General disorders and administration site conditions				Drug fever

(*) The mechanism of mesalazine-induced myo- and pericarditis, pancreatitis, nephritis and hepatitis is unknown, but it might be of allergic origin.

It is important to note that several of these disorders can also be attributed to the inflammatory bowel disease itself.

4.9 Overdose

Experience in animals:

A single intravenous dose of mesalazine in rats of 920 mg/kg and single oral doses of mesalazine in pigs up to 5g/kg were not lethal.

Human experience:

No experience

Management of overdose in man:

Symptomatic treatment at hospital. Close monitoring of renal function.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group : Intestinal anti-inflammatory agents

ATC-Code: A07E C02

Mesalazine is the active component of sulphasalazine, which has been used for a long time in the treatment of ulcerative colitis and Crohn's disease.

The therapeutic value of mesalazine appears to be due to local effect on the inflamed intestinal tissue, rather than to systemic effect.

Increased leucocyte migration, abnormal cytokine production, increased production of arachidonic acid metabolites particularly leukotriene B4, and increased free radical formation in the inflamed intestinal tissue are all present in patients with inflammatory bowel disease. Mesalazine has in-vitro and in-vivo pharmacological effects that inhibit leukocyte chemotaxis, decrease cytokine and leukotriene production and scavenge for free radicals. The mechanism of action of mesalazine is, however, still not understood.

5.2 Pharmacokinetic Properties

General characteristics of the active substance

PENTASA Sachet prolonged release granules consist of ethylcellulose coated microgranules of mesalazine. Following administration mesalazine is released continuously throughout the gastrointestinal tract in any enteral pH conditions. The microgranuales enter the duodenum within an hour of administration, independent of food co-administration. The average small intestinal transit time is approximately 3 – 4 hrs in healthy volunteers.

Biotransformation:

Mesalazine is metabolised into N-acetyl-mesalazine (acetyl mesalazine) both pre-systematically by the intestinal mucosa and systemically in the liver. Some acetylation also occurs through the action of colonic bacteria. The acetylation seems to be independent of the acetylator phenotype of the patient. Acetyl-mesalazine is believed to be clinically as well as toxicologically inactive.

Absorption:

30-50% of an oral dose is absorbed, predominantly from the small intestine. Maximum plasma concentrations are seen 1-4 hours post-dose. The plasma concentration of mesalazine decreases gradually and is no longer detectable 12 hours post-dose. The plasma concentration curve for acetyl-mesalazine follows the same pattern, but the concentration is generally higher and the elimination is slower.

The metabolic ratio of acetyl-mesalazine to mesalazine in plasma after oral administration ranges from 3.5 to 1.3 after daily doses of 500mg x 3 and 2g x 3, respectively, implying a dose-dependent acetylation which may be subject to saturation.

Mean steady-state plasma concentrations of mesalazine are approximately 2µmol/l, 8µmol/l and 12µmol/l after 1.5g, 4g and 6g daily dosages, respectively. For acetyl-mesalazine the corresponding concentrations are 6µmol/1, 13µmol/1 and 16µmol/1.

The transit and release of mesalazine after oral administration are independent of food co-administration, whereas the systemic absorption will be reduced.

Distribution:

Mesalazine and acetyl-mesalazine do not cross the blood-brain barrier. Protein binding of mesalazine is approximately 50% and of acetyl-mesalazine about 80%.

Elimination:

The plasma half-life following i.v. administration of mesalazine is approximately 40 minutes and for acetyl-mesalazine approximately 70 minutes. Due to the continuous release of mesalazine throughout the gastrointestinal tract, the elimination half-life cannot be determined after oral administration. Tests have shown that steady-state is reached after a treatment period of 5 days following oral administration.

Both mesalazine and acetyl-mesalazine are excreted with the urine and faeces. The urinary excretion consists mainly of acetyl-mesalazine.

Characteristics in patients

The delivery of mesalazine to the intestinal mucosa after oral administration is only slightly affected by pathophysiologic changes such as diarrhoea and increased bowel acidity observed during active inflammatory bowel disease. A reduction in systemic absorption to 20-25% of the daily dose has been observed in patients with accelerated intestinal transit. Likewise, a corresponding increase in faecal excretion has been seen.

In patients with impaired liver and kidney functions, the resultant decrease in the rate of elimination may constitute an increased risk of nephrotoxic adverse reactions.

5.3 Preclinical Safety Data

Definitive nephrotoxicity and possible gastrointestinal toxicity is demonstrated in all species examined, and nephrotoxicity is evident with doses 5 – 10 times those used in humans.

In vitro test systems and in-vivo studies showed no evidence of mutagenic effects. Studies on the tumourigenic potential carried out in rats showed no evidence of any substance-related increase in the incidence of tumours.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Ethylcellulose, povidone

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

2 years

The granules should be used immediately after first opening of the sachet.

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

Aluminium foil single dose container

Pack sizes:

1 x 120 sachets

1 x 60 sachets

1 x 10 sachets

Not all pack sizes may be marketed

6.6 Special Precautions For Disposal And Other Handling

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

7. Marketing Authorisation Holder

Ferring Pharmaceuticals Ltd

The Courtyard

Waterside Drive

Langley

Berkshire SL3 6EZ.

United Kingdom

8. Marketing Authorisation Number(S)

PL 03194/0102

9. Date Of First Authorisation/Renewal Of The Authorisation

12^th December 2007

10. Date Of Revision Of The Text

10^th September 2010

Panadol OA 1000mg Tablets

1. Name Of The Medicinal Product

Panadol OA 1000 mg Tablets

2. Qualitative And Quantitative Composition

Each tablet contains paracetamol 1000 mg

For full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

White, capsule-shaped tablets having flat edges, debossed with 'PAN 1G' on one side with a break-line on both sides.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4. Clinical Particulars

4.1 Therapeutic Indications

For the management of mild to moderate pain, including osteoarthritis and for pyrexia.

4.2 Posology And Method Of Administration

Panadol OA 1000 mg Tablets are for oral administration.

Adults (including the elderly):

One tablet up to 4 times daily as required.

Not to be given to children under 12 years.

The minimum dosing interval is 4 hours and the maximum daily dose is 4000 mg (4 tablets).

4.3 Contraindications

Hypersensitivity to paracetamol or any of the other constituents.

4.4 Special Warnings And Precautions For Use

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

Do not exceed the stated dose.

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

This product should only be used by the person for whom it is prescribed when clearly necessary.

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.

4.5 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 colestyramine. 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.

4.6 Pregnancy And Lactation

Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use. Paracetamol is excreted in breast milk, but not in a clinically significant amount. Available published data do not contraindicate breast feeding.

4.7 Effects On Ability To Drive And Use Machines

None.

4.8 Undesirable Effects

Adverse effects of paracetamol are rare but hypersensitivity including skin rash may occur.

There have been very rare reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to paracetamol.

4.9 Overdose

Paracetamol

Liver damage is possible in adults who have taken 10 g or more of paracetamol. Ingestion of 5 g or more of paracetamol may lead to liver damage if the patient has risk factors (see below).

Risk Factors:

If the patient

• Is on long term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St John's Wort or other drugs that induce liver enzymes.

Or

• Regularly consumes ethanol in excess of recommended amounts.

Or

• Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.

Symptoms

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, haemorrhage, hypoglycaemia, cerebral oedema and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Management

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. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Management should be in accordance with established treatment guidelines, see BNF overdose section.

Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of paracetamol, however, the maximum protective effect is obtained up to 8 hours post-ingestion. The effectiveness of the antidote declines sharply after this time. If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital. Management of patients who present with serious hepatic dysfunction beyond 24h from ingestion should be discussed with the NPIS or a liver unit.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Paracetamol is an antipyretic analgesic. The mechanism of action is probably similar to that of aspirin and dependent on the inhibition of prostaglandin synthesis. This inhibition appears, however to be on a selective basis.

5.2 Pharmacokinetic Properties

Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. Concentration in plasma reaches a peak in 30 to 60 minutes. Plasma half-life is 1 - 4 hours

Paracetamol is relatively uniformly distributed throughout most body fluids. Binding of the drug to plasma proteins is variable; 20 to 30% may be bound at the concentrations encountered during acute intoxication. Following therapeutic doses 90-100% of the drug may be recovered in the urine within the first day. However, practically no paracetamol is excreted unchanged and the bulk is excreted after hepatic conjugation. Excretion is almost exclusively renal, in the form of conjugated metabolites.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Maize starch

Pregelatinised starch

Potassium sorbate

Talc

Stearic acid

Povidone

Film coat:

Hypromellose

Triacetin.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Opaque high density, polyethylene (HDPE) bottles with a polypropylene screw closure and induction seal liner, containing 100 tablets.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

SmithKline Beecham (SWG) Limited

980 Great West Road

Brentford

Middlesex

TW8 9GS

United Kingdom

8. Marketing Authorisation Number(S)

PL 00071/0456

9. Date Of First Authorisation/Renewal Of The Authorisation

24/08/2009

10. Date Of Revision Of The Text

24/08/2009