Gabapentin 100mg Capsules

1. Name Of The Medicinal Product

Gabapentin 100mg capsules

2. Qualitative And Quantitative Composition

Each capsule contains 100mg of gabapentin

For excipients, see 6.1

3. Pharmaceutical Form

Capsules,hard

Size 3, white-white, hard gelatin capsules printed with C and GJ .

4. Clinical Particulars

4.1 Therapeutic Indications

Epilepsy

Gabapentin is indicated as adjunctive therapy in the treatment of partial seizures with and without secondary generalisation in adults and children aged 6 years and above (see section 5.1).

Gabapentin is indicated as monotherapy in the treatment of partial seizures with and without secondary generalisation in adults and adolescents aged 12 years and above.

Treatment of peripheral neuropathic pain

Gabapentin is indicated for the treatment of peripheral neuropathic pain such as painful diabetic neuropathy and post-herpetic neuralgia in adults.

4.2 Posology And Method Of Administration

For oral use.

Gabapentin can be given with or without food and should be swallowed whole with sufficient fluid intake (e.g. a glass of water).

For all indications a titration scheme for the initiation of therapy is described in Table 1, which is recommended for adults and adolescents aged 12 years and above. Dosing instructions for children under 12 years of age are provided under a separate sub-heading later in this section.

Table 1
DOSING CHART – INITIAL TITRATION
Day 1	Day 2	Day 3
300mg once a day	300mg two times a day	300mg three times a day

Epilepsy

Epilepsy typically requires long-term therapy. Dosage is determined by the treating physician according to individual tolerance and efficacy. When in the judgment of the clinician there is a need for dose reduction, discontinuation, or substitution with an alternative medication, this should be done gradually over a minimum of one week.

Adults and adolescents:

In clinical trials, the effective dosing range was 900 to 3600mg/day. Therapy may be initiated by titrating the dose as described in Table 1 or by administering 300mg three times a day (TID) on Day 1. Thereafter, based on individual patient response and tolerability, the dose can be further increased in 300mg/day increments every 2-3 days up to a maximum dose of 3600mg/day. Slower titration of gabapentin dosage may be appropriate for individual patients. The minimum time to reach a dose of 1800mg/day is one week, to reach 2400mg/day is a total of 2 weeks, and to reach 3600mg/day is a total of 3 weeks.

Dosages up to 4800mg/day have been well tolerated in long-term open-label clinical studies. The total daily dose should be divided in three single doses, the maximum time interval between the doses should not exceed 12 hours to prevent breakthrough convulsions.

Children aged 6 years and above:

The starting dose should range from 10 to 15mg/kg/day and the effective dose is reached by upward titration over a period of approximately three days. The effective dose of gabapentin in children aged 6 years and older is 25 to 35mg/kg/day. Dosages up to 50mg/kg/day have been well tolerated in a long term clinical study. The total daily dose should be divided in three single doses, the maximum time interval between doses should not exceed 12 hours.

It is not necessary to monitor gabapentin plasma concentrations to optimize gabapentin therapy. Further, gabapentin may be used in combination with other antiepileptic medicinal products without concern for alteration of the plasma concentrations of gabapentin or serum concentrations of other antiepileptic medicinal products.

Peripheral neuropathic pain

Adults

The therapy may be initiated by titrating the dose as described in Table 1. Alternatively, the starting dose is 900mg/day given as three equally divided doses. Thereafter, based on individual patient response and tolerability, the dose can be further increased in 300mg/day increments every 2-3 days up to a maximum dose of 3600mg/day. Slower titration of gabapentin dosage may be appropriate for individual patients. The minimum time to reach a dose of 1800mg/day is one week, to reach 2400mg/day is a total of 2 weeks, and to reach 3600mg/day is a total of 3 weeks.

In the treatment of peripheral neuropathic pain such as painful diabetic neuropathy and post-herpetic neuralgia, efficacy and safety have not been examined in clinical studies for treatment periods longer than 5 months. If a patient requires dosing longer than 5 months for the treatment of peripheral neuropathic pain, the treating physician should assess the patient's clinical status and determine the need for additional therapy.

Instruction for all areas of indication

In patients with poor general health, i.e., low body weight, after organ transplantation etc., the dose should be titrated more slowly, either by using smaller dosage strengths or longer intervals between dosage increases.

Use in elderly patients (over 65 years of age)

Elderly patients may require dosage adjustment because of declining renal function with age (see Table 2). Somnolence, peripheral oedema and asthenia may be more frequent in elderly patients.

Use in patients with renal impairment Dosage adjustment is recommended in patients with compromised renal function as described in Table 2 and/or those undergoing haemodialysis. Gabapentin 100mg capsules can be used to follow dosing recommendations for patients with renal insufficiency.

Table 2
DOSAGE OF GABAPENTIN IN ADULTS BASED ON RENAL FUNCTION
Creatinine Clearance (ml/min)	Total Daily Dosea (mg/day)
	900-3600
50-79	600-1800
30-49	300-900
15-29	150b -600
<15c	150b -300

^a Total daily dose should be administered as three divided doses. Reduced dosages are for patients with renal impairment (creatinine clearance < 79ml/min).

^b To be administered as 300mg every other day.

^c For patients with creatinine clearance <15ml/min, the daily dose should be reduced in proportion to creatinine clearance (e.g., patients with a creatinine clearance of 7.5ml/min should receive one-half the daily dose that patients with a creatinine clearance of 15ml/min receive).

Use in patients undergoing haemodialysis

For anuric patients undergoing haemodialysis who have never received gabapentin, a loading dose of 300 to 400mg, then 200 to 300mg of gabapentin following each 4 hours of haemodialysis, is recommended. On dialysis-free days, there should be no treatment with gabapentin.

For renally impaired patients undergoing haemodialysis, the maintenance dose of gabapentin should be based on the dosing recommendations found in Table 2. In addition to the maintenance dose, an additional 200 to 300mg dose following each 4-hour haemodialysis treatment is recommended.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings And Precautions For Use

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for Gabapentin.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

If a patient develops acute pancreatitis under treatment with gabapentin, discontinuation of gabapentin should be considered (see section 4.8).

Although there is no evidence of rebound seizures with gabapentin, abrupt withdrawal of anticonvulsants in epileptic patients may precipitate status epilepticus (see section 4.2).

As with other antiepileptic medicinal products, some patients may experience an increase in seizure frequency or the onset of new types of seizures with gabapentin.

As with other anti-epileptics, attempts to withdraw concomitant anti-epileptics in treatment refractory patients on more than one anti-epileptic, in order to reach gabapentin monotherapy have a low success rate.

Gabapentin is not considered effective against primary generalized seizures such as absences and may aggravate these seizures in some patients. Therefore, gabapentin should be used with caution in patients with mixed seizures including absences.

No systematic studies in patients 65 years or older have been conducted with gabapentin. In one double blind study in patients with neuropathic pain, somnolence, peripheral oedema and asthenia occurred in a somewhat higher percentage in patients aged 65 years or above, than in younger patients. Apart from these findings, clinical investigations in this age group do not indicate an adverse event profile different from that observed in younger patients.

The effects of long-term (greater than 36 weeks) gabapentin therapy on learning, intelligence, and development in children and adolescents have not been adequately studied. The benefits of prolonged therapy must therefore be weighed against the potential risks of such therapy.

Laboratory tests

False positive readings may be obtained in the semi-quantitative determination of total urine protein by dipstick tests. It is therefore recommended to verify such a positive dipstick test result by methods based on a different analytical principle such as the Biuret method, turbidimetric or dye-binding methods, or to use these alternative methods from the beginning.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In a study involving healthy volunteers (N=12), when a 60mg controlled-release morphine capsule was administered 2 hours prior to a 600mg gabapentin capsule, mean gabapentin AUC increased by 44% compared to gabapentin administered without morphine. Therefore, patients should be carefully observed for signs of CNS depression, such as somnolence, and the dose of gabapentin or morphine should be reduced appropriately.

No interaction between gabapentin and phenobarbital, phenytoin, valproic acid, or carbamazepine has been observed.

Gabapentin steady-state pharmacokinetics are similar for healthy subjects and patients with epilepsy receiving these antiepileptic agents.

Coadministration of gabapentin with oral contraceptives containing norethindrone and/or ethinyl estradiol, does not influence the steady-state pharmacokinetics of either component.

Coadministration of gabapentin with antacids containing aluminium and magnesium, reduces gabapentin bioavailability up to 24%. It is recommended that gabapentin be taken at the earliest two hours following antacid administration.

Renal excretion of gabapentin is unaltered by probenecid.

A slight decrease in renal excretion of gabapentin that is observed when it is coadministered with cimetidine is not expected to be of clinical importance.

4.6 Pregnancy And Lactation

Risk related to epilepsy and antiepileptic medicinal products in general

The risk of birth defects is increased by a factor of 2 – 3 in the offspring of mothers treated with an antiepileptic medicinal product. Most frequently reported are cleft lip, cardiovascular malformations and neural tube defects. Multiple antiepileptic drug therapy may be associated with a higher risk of congenital malformations than monotherapy, therefore it is important that monotherapy is practiced whenever possible. Specialist advice should be given to women who are likely to become pregnant or who are of childbearing potential and the need for antiepileptic treatment should be reviewed when a woman is planning to become pregnant. No sudden discontinuation of antiepileptic therapy should be undertaken as this may lead to breakthrough seizures, which could have serious consequences for both mother and child. Developmental delay in children of mothers with epilepsy has been observed rarely.

It is not possible to differentiate if the developmental delay is caused by genetic, social factors, maternal epilepsy or the antiepileptic therapy.

Risk related to gabapentin

There are no adequate data from the use of gabapentin in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Gabapentin should not be used during pregnancy unless the potential benefit to the mother clearly outweighs the potential risk to the foetus.

No definite conclusion can be made as to whether gabapentin is associated with an increased risk of congenital malformations when taken during pregnancy, because of epilepsy itself and the presence of concomitant antiepileptic medicinal products during each reported pregnancy.

Gabapentin is excreted in human milk. Because the effect on the breast-fed infant is unknown, caution should be exercised when gabapentin is administered to a breast-feeding mother. Gabapentin should be used in breast-feeding mothers only if the benefits clearly outweigh the risks.

4.7 Effects On Ability To Drive And Use Machines

Gabapentin may have minor or moderate influence on the ability to drive and use machines. Gabapentin acts on the central nervous system and may cause drowsiness, dizziness or other related symptoms.

Even, if they were only of mild or moderate degree, these undesirable effects could be potentially dangerous in patients driving or operating machinery. This is especially true at the beginning of the treatment and after increase in dose.

4.8 Undesirable Effects

The adverse reactions observed during clinical studies conducted in epilepsy (adjunctive and monotherapy) and neuropathic pain have been provided in a single list below by class and frequency (very common (> 1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100) and rare (>1/10,000; <1/1,000). Additional reactions reported from the post-marketing experience are included as frequency 'not known' (cannot be estimated from the available data). Where an adverse reaction was seen at different frequencies in clinical studies, it was assigned to the highest frequency reported.

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

Infections and infestations

Very Common: Viral infection

Common: Pneumonia, respiratory infection, urinary tract infection, infection, otitis media

Blood and the lymphatic system disorders

Common: leucopenia

Rare: thrombocytopenia

Immune system disorders

Rare: allergic reactions (e.g. urticaria)

Not known: Hypersensitive syndrome, a systemic reaction with a variable presentation that can include fever, rash, hepatitis lymphadenopathy, eosinophilia and sometimes other signs and symptoms.

Metabolism and Nutrition Disorders

Common: anorexia, increased appetite

Psychiatric disorders

Common: hostility, confusion and emotional lability, depression, anxiety, nervousness, thinking abnormal

Rare: hallucinations

Nervous system disorders

Very Common: somnolence, dizziness, ataxia,

Common: convulsions, hyperkinesias, dysarthria, amnesia, tremor, insomnia, headache, sensations such as paresthesia, hypaesthesia, coordination abnormal, nystagmus, increased, decreased, or absent reflexes

Uncommon: hypokinesia

Rare: movement disorders (e.g. choreoathetosis, dyskinesia, dystonia)

Not Known: myoclonus, syncope

Eye disorders

Common: visual disturbances such as amblyopia, diplopia

Ear and Labyrinth disorders

Common: vertigo

Rare: tinnitus

Cardiac disorders

Rare: palpitations

Vascular disorder

Common: hypertension, vasodilatation

Respiratory, thoracic and mediastinal disorders

Common: dyspnoea, bronchitis, pharyngitis, cough, rhinitis

Gastrointestinal disorders

Common: vomiting, nausea, dental abnormalities, gingivitis, diarrhoea, abdominal pain, dyspepsia, constipation, dry mouth or throat, flatulence

Rare: pancreatitis

Hepatobiliary disorders

Rare: hepatitis, jaundice

Skin and subcutaneous tissue disorders

Common: facial oedema, purpura most often described as bruises resulting from physical trauma, rash, pruritus, acne

Rare: Stevens-Johnson syndrome, angioedema, erythema multiforme, alopecia

Musculoskeletal, connective tissue and bone disorders

Common: arthralgia, myalgia, back pain, twitching

Renal and urinary disorders

Common: incontinence

Rare: acute renal failure

Reproductive system and breast disorders

Common: impotence

Not known: breast hypertrophy, gynaecomastia

General disorders and administration site conditions

Very Common: fatigue, fever

Common: peripheral or generalized oedema, abnormal gait, asthenia, pain, malaise, flu syndrome

Rare: withdrawal reactions (mostly anxiety, insomnia, nausea, pains, sweating), chest pain.

Sudden unexplained deaths have been reported where a causal relationship to treatment with gabapentin has not been established.

Investigations

Common: WBC (white blood cell count) decreased, weight gain

Rare: Blood glucose fluctuations in patients with diabetes, elevated liver function tests SGOT (AST), SGPT (ALT) and bilirubin

Injury and poisoning

Common: accidental injury, fracture, abrasion

Under treatment with gabapentin cases of acute pancreatitis were reported. Causality with gabapentin is unclear (see section 4.4).

Respiratory tract infections, otitis media, convulsions and bronchitis were reported only in clinical studies in children. Additionally, in clinical studies in children, aggressive behaviour and hyperkinesias were reported commonly.

In patients on haemodialysis due to end-stage renal failure, myopathy with elevated creatine kinase levels has been reported.

4.9 Overdose

Acute, life-threatening toxicity has not been observed with gabapentin overdoses of up to 49g. Symptoms of the overdoses included dizziness, double vision, slurred speech, drowsiness, lethargy and mild diarrhoea.

All patients recovered fully with supportive care. Reduced absorption of gabapentin at higher doses may limit drug absorption at the time of overdosing and, hence, minimize toxicity from overdoses.

Although gabapentin can be removed by haemodialysis, based on prior experience it is usually not required.

However, in patients with severe renal impairment, haemodialysis may be indicated.

An oral lethal dose of gabapentin was not identified in mice and rats given doses as high as 8000mg/kg.

Signs of acute toxicity in animals included ataxia, laboured breathing, ptosis, hypoactivity, or excitation.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic groups: Other antiepileptics

ATC code: N03AX12

The precise mechanism of action of gabapentin is not known.

Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but its mechanism of action is different from that of several other active substances that interact with GABA synapses including valproate, barbiturates, benzodiazepines, GABA transaminase inhibitors, GABA uptake inhibitors, GABA agonists, and GABA prodrugs. In vitro studies with radiolabeled gabapentin have characterized a novel peptide binding site in rat brain tissues including neocortex and hippocampus that may relate to anticonvulsant and analgesic activity of gabapentin and its structural derivatives. The binding site for gabapentin has been identified as the alpha₂-delta subunit of voltage-gated calcium channels.

Gabapentin at relevant clinical concentrations does not bind to other common drug or neurotransmitter receptors of the brain including GABA_A, GABA_B, benzodiazepine, glutamate, glycine or N-methyl-daspartate receptors.

Gabapentin does not interact with sodium channels in vitro and so differs from phenytoin and carbamazepine. Gabapentin partially reduces responses to the glutamate agonist N-methyl-D-aspartate (NMDA) in some test systems in vitro, but only at concentrations greater than 100µM, which are not achieved in vivo. Gabapentin slightly reduces the release of monoamine neurotransmitters in vitro.

Gabapentin administration to rats increases GABA turnover in several brain regions in a manner similar to valproate sodium, although in different regions of brain. The relevance of these various actions of gabapentin to the anticonvulsant effects remains to be established. In animals, gabapentin readily enters the brain and prevents seizures from maximal electroshock, from chemical convulsants including inhibitors of GABA synthesis, and in genetic models of seizures.

A clinical trial of adjunctive treatment of partial seizures in paediatric subjects, ranging in age from 3 to 12 years, showed a numerical but not statistically significant difference in the 50% responder rate in favour of the gabapentin group compared to placebo. Additional post-hoc analyses of the responder rates by age did not reveal a statistically significant effect of age, either as a continuous or dichotomous variable (age groups 3-5 and 6-12 years). The data from this additional post-hoc analysis are summarised in the table below:

Response (
Age Category	Placebo	Gabapentin	P-Value
< 6 Years Old	4/21 (19.0%)	4/17 (23.5%)	0.7362
6 to 12 Years Old	17/99 (17.2%)	20/96 (20.8%)	0.5144

*The modified intent to treat population was defined as all patients randomised to study medication who also had evaluable seizure diaries available for 28 days during both the baseline and double-blind phases.

5.2 Pharmacokinetic Properties

Absorption

Following oral administration, peak plasma gabapentin concentrations are observed within 2 to 3 hours.

Gabapentin bioavailability (fraction of dose absorbed) tends to decrease with increasing dose. Absolute bioavailability of a 300mg capsule is approximately 60%. Food, including a high-fat diet, has no clinically significant effect on gabapentin pharmacokinetics.

Gabapentin pharmacokinetics are not affected by repeated administration. Although plasma gabapentin concentrations were generally between 2µg/ml and 20µg/ml in clinical studies, such concentrations were not predictive of safety or efficacy. Pharmacokinetic parameters are given in Table 3.

Table 3

Summary of gabapentin mean (%CV) steady-state pharmacokinetic parameters following every eight hours administration

Pharmacokinetic parameter	300mg (N = 7)	400mg (N = 14)	800mg (N=14)
	Mean	%CV	Mean	%CV	Mean	%CV
Cmax (μg/ml)	4.02	(24)	5.74	(38)	8.71	(29)
tmax (hr)	2.7	(18)	2.1	(54)	1.6	(76)
T1/2 (hr)	5.2	(12)	10.8	(89)	10.6	(41)
AUC (0-8) μg•hr/ml)	24.8	(24)	34.5	(34)	51.4	(27)
Ae% (%)	NA	NA	47.2	(25)	34.4	(37)
Cmax = Maximum steady state plasma concentration tmax = Time for Cmax T1/2 = Elimination half-life AUC(0-8) = Steady state area under plasma concentration-time curve from time 0 to 8 hours postdose Ae% = Percent of dose excreted unchanged into the urine from time 0 to 8 hours postdose NA = Not available

Distribution

Gabapentin is not bound to plasma proteins and has a volume of distribution equal to 57.7 litres. In patients with epilepsy, gabapentin concentrations in cerebrospinal fluid (CSF) are approximately 20% of corresponding steady-state trough plasma concentrations. Gabapentin is present in the breast milk of breast-feeding women.

Metabolism

There is no evidence of gabapentin metabolism in humans. Gabapentin does not induce hepatic mixed function oxidase enzymes responsible for drug metabolism.

Elimination

Gabapentin is eliminated unchanged solely by renal excretion. The elimination half-life of gabapentin is independent of dose and averages 5 to 7 hours.

In elderly patients, and in patients with impaired renal function, gabapentin plasma clearance is reduced.

Gabapentin elimination-rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance.

Gabapentin is removed from plasma by haemodialysis. Dosage adjustment in patients with compromised renal function or undergoing haemodialysis is recommended (see section 4.2).

Gabapentin pharmacokinetics in children were determined in 50 healthy subjects between the ages of 1 month and 12 years. In general, plasma gabapentin concentrations in children > 5 years of age are similar to those in adults when dosed on a mg/kg basis.

Linearity/Non-linearity

Gabapentin bioavailability (fraction of dose absorbed) decreases with increasing dose which imparts non-linearity to pharmacokinetic parameters which include the bioavailability parameter (F) e.g. Ae%, CL/F, Vd/F. Elimination pharmacokinetics (pharmacokinetic parameters which do not include F such as CLr and T1/2), are best described by linear pharmacokinetics. Steady state plasma gabapentin concentrations are predictable from single-dose data.

5.3 Preclinical Safety Data

Carcinogenesis

Gabapentin was given in the diet to mice at 200, 600, and 2000mg/kg/day and to rats at 250, 1000, and 2000mg/kg/day for two years. A statistically significant increase in the incidence of pancreatic acinar cell tumors was found only in male rats at the highest dose. Peak plasma drug concentrations in rats at 2000mg/kg/day are 10 times higher than plasma concentrations in humans given 3600mg/day. The pancreatic acinar cell tumors in male rats are low-grade malignancies, did not affect survival, did not metastasize or invade surrounding tissue, and were similar to those seen in concurrent controls. The relevance of these pancreatic acinar cell tumors in male rats to carcinogenic risk in humans is unclear.

Mutagenesis

Gabapentin demonstrated no genotoxic potential. It was not mutagenic in vitro in standard assays using bacterial or mammalian cells. Gabapentin did not induce structural chromosome aberrations in mammalian cells in vitro or in vivo, and did not induce micronucleus formation in the bone marrow of hamsters.

Impairment of Fertility

No adverse effects on fertility or reproduction were observed in rats at doses up to 2000mg/kg (approximately five times the maximum daily human dose on a mg/m² of body surface area basis).

Teratogenesis

Gabapentin did not increase the incidence of malformations, compared to controls, in the offspring of mice, rats, or rabbits at doses up to 50, 30 and 25 times respectively, the daily human dose of 3600mg, (four, five or eight times, respectively, the human daily dose on a mg/m² basis).

Gabapentin induced delayed ossification in the skull, vertebrae, forelimbs, and hind limbs in rodents, indicative of fetal growth retardation. These effects occurred when pregnant mice received oral doses of 1000 or 3000mg/kg/day during organogenesis and in rats given 500, 1000, or 2000mg/kg prior to and during mating and throughout gestation. These doses are approximately 1 to 5 times the human dose of 3600mg on a mg/m² basis.

No effects were observed in pregnant mice given 500mg/kg/day (approximately 1/2 of the daily human dose on a mg/m² basis).

An increased incidence of hydroureter and/or hydronephrosis was observed in rats given 2000mg/kg/day in a fertility and general reproduction study, 1500mg/kg/day in a teratology study, and 500, 1000, and 2000mg/kg/day in a perinatal and postnatal study. The significance of these findings is unknown, but they have been associated with delayed development. These doses are also approximately 1 to 5 times the human dose of 3600 mg on a mg/m² basis.

In a teratology study in rabbits, an increased incidence of post-implantation fetal loss, occurred in doses given 60, 300, and 1500mg/kg/day during organogenesis. These doses are approximately 1/4 to 8 times the daily human dose of 3600mg on a mg/m² basis.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose Monohydrate

Maize Starch

Talc

Capsule shell

Titanium dioxide, E171

Gelatin

Printing ink

Shellac , E904

Titanium dioxide , E171

Brilliant Blue FCF Lake, E133

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 25°C.

Store in the original package.

6.5 Nature And Contents Of Container

Aluminium/transparent PVC blisters

Each pack will contain either 30, 50, 60, 100 or 120 capsules.

Each blister strip will contain 10 capsules.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Actavis UK Limited

(Trading style: Actavis)

Whiddon Valley

Barnstaple

North Devon

EX32 8NS

8. Marketing Authorisation Number(S)

PL 0142/ 0566

9. Date Of First Authorisation/Renewal Of The Authorisation

28/10/05

10. Date Of Revision Of The Text

22/09/2010

Disipal Tablets

Disipal tablets 50 mg

(Orphenadrine hydrochloride)

What are Disipal Tablets?

Disipal tablets contain 50 mg orphenadrine hydrochloride.

They are available in packs of 250 tablets.

Disipal tablets also contain lactose, sucrose, acacia, maize starch, tribasic calcium phosphate, stearic acid, magnesium stearate, Opaseal (containing IMS, polyvinylacetate phthalate and stearic acid), calcium carbonate, talc, kaolin, titanium dioxide, gelatine, Opalux yellow (containing sucrose, titanium dioxide, tartrazine E102, sunset yellow E110, povidone, amaranth E123 and sodium benzoate E211), Opaglos (containing ethanol, shellac, beeswax and yellow carnuba wax) and black printing ink.

The product licence for Disipal tablets is held by

Astellas Pharma Ltd.

Lovett House

Lovett Road

Staines

Middlesex

TW18 3AZ

UK

They are manufactured by

Astellas Pharma Europe B.V. at their site at

Hogemaat 2

7942 JC Meppel

The Netherlands

What are Disipal tablets used for?

Disipal tablets are used in the treatment of all forms of Parkinsonism, a condition which can cause uncontrollable trembling of the hands, and other difficulties of movement, for example in standing or walking.

They are also used when other medicines have caused these problems.

Before using Disipal Tablets.

You should not take Disipal tablets if you have glaucoma (pressure in the eye), an enlarged prostate, have difficulties passing water, if you have a blockage in your digestive system or if you have the rare inherited disorder, porphyria, which affects the breakdown of the red blood cell pigment, haemoglobin. Disipal tablets should also not be taken if you have a particular disorder of movement called tardive dyskinesia, but your doctor will have taken this into consideration before prescribing the tablets for you.

You should also not take Disipal tablets if you are hypersensitive (allergic) to anything in the tablet.

If you are, or think you may be pregnant, or breast feeding, make sure that your doctor knows of this before you take any more of your tablets.

Also make sure that you have told your doctor if you have any heart condition, or any problem with your liver or kidneys. Disipal tablets are not intended to be taken by children.

You should not drive or operate machinery if you feel dizzy or have blurred vision whilst taking Disipal tablets.

Warning: The dyes E102, E110 and E123 used in the sugar coat, can cause allergic reactions, including asthma, in susceptible people, particularly those who are allergic to aspirin. The sodium benzoate E211 used in the sugar coat can be mildly irritating to the skin, eyes and mucous membranes.

How to take Disipal tablets

Unless told otherwise by your doctor, the following are the usual dosages for adults and the elderly:

To start with, three tablets daily in divided doses. Your doctor may increase this dose, if necessary, by one tablet every two to three days up to a maximum of eight tablets in a day.

If you forget to take a dose, then take the forgotten dose as soon as you remember, provided this does not result in taking a double dose. If that should be the case, omit the forgotten dose.

Usually you will need long term treatment with Disipal tablets. If you are to stop taking Disipal tablets then your doctor will make sure that the dose is gradually reduced over a number of days; you should not stop taking the tablets unless you have been told to do so.

After taking Disipal tablets.

You may find that you have a dry mouth when taking Disipal tablets.

If you find that you have any difficulty in seeing clearly, stomach upsets, dizziness, or difficulty in passing water, tell your doctor or pharmacist.

These effects only occasionally occur; they may disappear of their own accord, or you may need a slight reduction in your dosage. If you find that you develop a rapid heart beat, any kind of skin rash, irritation or redness, have any changes of mood, have a feeling of nervousness or anxiety, or have difficulty in sleeping, tell your doctor as soon as possible. If you are an older patient or you are taking a type of drug called an antimuscarinic, you may be more suspectible to these side effects.

Taking too many Disipal tablets could be dangerous. If you, or anyone else, should accidentally take too many tablets, you must phone your doctor or go to a hospital casualty department immediately.

You should also tell your doctor or pharmacist if you have any other undesirable effects after taking Disipal tablets.

General Information

All medicines should be kept out of the reach of children, but this is particularly important with Disipal tablets.

Do not take Disipal tablets after the expiry date printed on the package; keep them at normal room temperature (15°C - 25°C).

Remember your medicines have been prescribed for you. Never give your medicine to others, even if it does seem that they have the same condition as you.

This leaflet was last revised in August 2005.

Astellas Pharma Ltd.

Lovett House

Lovett Road

Staines

Middlesex

TW18 3AZ

UK

© Astellas Pharma Ltd., Leiderdorp, The Netherlands

Registered trademark of Astellas Pharma Ltd.

Daktacort Cream &amp; Ointment (Janssen-Cilag Ltd)

1. Name Of The Medicinal Product

Daktacort™ Cream.

2. Qualitative And Quantitative Composition

Miconazole nitrate 2% w/w and hydrocortisone 1% w/w.

3. Pharmaceutical Form

White, homogeneous cream.

4. Clinical Particulars

4.1 Therapeutic Indications

For the topical treatment of inflamed dermatoses where infection by susceptible organisms and inflammation co-exist, eg intertrigo and infected eczema.

Moist or dry eczema or dermatitis including atopic eczema, primary irritant or contact allergic eczema or seborrhoeic eczema including that associated with acne.

Intertriginous eczema including inflammatory intertrigo, perianal and genital dermatitis.

Organisms which are susceptible to miconazole are dermatophytes and pathogenic yeasts (eg Candida spp.). Also many Gram-positive bacteria including most strains of Streptococcus and Staphylococcus.

The properties of Daktacort indicate it particularly for the initial stages of treatment. Once the inflammatory symptoms have disappeared (after about 7 days), treatment can be continued where necessary with Daktarin™ Cream or Daktarin™ Powder.

4.2 Posology And Method Of Administration

For topical administration.

Apply the cream two or three times a day to the affected area, rubbing in gently until the cream has been absorbed by the skin.

4.3 Contraindications

True hypersensitivity to any of the ingredients. Tubercular or viral infections of the skin or those caused by Gram-negative bacteria.

4.4 Special Warnings And Precautions For Use

When Daktacort is used by patients taking oral anticoagulants, the anticoagulant effect should be carefully monitored.

Severe hypersensitivity reactions, including anaphylaxis and angioedema, have been reported during treatment with miconazole topical formulations.

If a reaction suggesting hypersensitivity or irritation should occur, the treatment should be discontinued.

As with any topical corticosteroid, care is advised with infants and children when Daktacort is to be applied to extensive surface areas or under occlusive dressings including baby napkins; similarly, application to the face should be avoided.

In infants, long term continuous topical corticosteroid therapy should be avoided. Adrenal suppression can occur even without occlusion.

Because of its corticosteroid content avoid long-term treatment with Daktacort. Once the inflammatory symptoms have disappeared treatment may be continued with Daktarin cream or Daktarin Powder. (See Section 4.1)

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Miconazole administered systemically is known to inhibit CYP3A4/2C9. Due to the limited systemic availability after topical application (see Section 5.2 Pharmacokinetic properties), clinically relevant interactions are rare. However, in patients on oral anticoagulants, such as warfarin, caution should be exercised and anticoagulant effect should be monitored.

Miconazole is a CYP3A4 inhibitor that can decrease the rate of metabolism of hydrocortisone. Serum concentrations of hydrocortisone may be higher with the use of Daktacort compared with topical preparations containing hydrocortisone alone

4.6 Pregnancy And Lactation

Pregnancy

Clinical data on the use of Daktacort Cream in pregnancy are limited. Corticosteroids are known to cross the placenta and consequently can affect the foetus. (See Section 5.3). Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development. The relevance of these findings to humans has not been established.

As a precautionary measure, it is preferable to avoid the use of Daktacort during pregnancy. Treatment of large surfaces and the application under occlusive dressing is not recommended.

Breastfeeding

There are no adequate and well-controlled studies on the topical administration of Daktacort Cream during lactation. It is not known whether concomitant topical administration of Daktacort Cream to the skin could result in sufficient systemic absorption to produce detectable quantities of hydrocortisone and miconazole in breast milk in humans.

A risk to the newborn child cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Daktacort therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

The safety of Daktacort Cream was evaluated in 480 patients who participated in 13 clinical trials (six double-blind and seven open-label trials) of Daktacort Cream. These studies examined patients from 1 month to 95 years of age with infections of the skin caused by dermatophytes or Candida species in which inflammatory symptoms were prominent.

All Patients

No adverse drug reactions (ADRs) were reported by

The frequency categories use the following convention: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available clinical trial data).

Of the three ADRs identified from the 13 clinical trials of Daktacort Cream, skin irritation was reported in one clinical trial that included patients aged 17 to 84 years, skin burning sensation in two clinical trials that included patients aged 13 to 84 years, and irritability in one clinical trial of infants aged 1 to 34 months.

Paediatric Population

The safety of Daktacort Cream was evaluated in 63 paediatric patients (1 month to 14 years of age) who were treated with Daktacort Cream in 3 of the 13 clinical trials noted above. One ADR term (irritability) was reported in these 3 trials. The frequency of irritability in Daktacort Cream-treated paediatric patients was common (3.2%).

All events of irritability occurred in one clinical trial of infants (aged 1 to 34 months) with napkin (diaper) dermatitis. The frequency, type, and severity of other ADRs in paediatric patients are expected to be similar to those in adults.reactions (ADRs) were reported by

Adverse Drug Reactions in Adult and Paediatric Patients Treated With Daktacort Cream

System Organ Class	Adverse drug reactions
Frequency Category
Uncommon (	Not Known
Immune System Disorders		Anaphylactic reaction, Hypersensitivity
Skin and Subcutaneous Tissue Disorders	Skin irritation, Skin burning sensation, Urticaria, Pruritus	Angioedema, Rash, Contact dermatitis, Erythema, Skin inflammation, Skin hypopigmentation, Application site reaction
General Disorders and Administration Site Conditions	Irritability

4.9 Overdose

Topically applied corticosteroids can be absorbed in sufficient amounts to produce systemic effects. If accidental ingestion of large quantities of the product occurs, an appropriate method of gastric emptying may be used if considered necessary.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Miconazole nitrate is active against dermatophytes and pathogenic yeasts, and many Gram-positive bacteria. Hydrocortisone has anti-inflammatory activity.

5.2 Pharmacokinetic Properties

Absorption

Miconazole remains in the skin after topical application for up to 4 days. Systemic absorption of miconazole is limited, with a bioavailability of less than 1% following topical application of miconazole. Plasma concentrations of miconazole and/or its metabolites were measurable 24 and 48 hours after application. Approximately 3% of the dose of hydrocortisone is absorbed after application on the skin.

Distribution

Absorbed miconazole is bound to plasma proteins (88.2%) and red blood cells (10.6%). More than 90% of hydrocortisone is bound to plasma proteins.

Metabolism and elimination

The small amount of miconazole that is absorbed is eliminated predominantly in faeces as both unchanged drug and metabolites over a four-day post-administration period. Smaller amounts of unchanged drug and metabolites also appear in urine.

The half-life of hydrocortisone is about 100 minutes. Metabolism takes place in the liver and tissues and the metabolites are excreted with the urine, mostly as glucuronides, together with a very small fraction of unchanged hydrocortisone.

5.3 Preclinical Safety Data

Preclinical data on the drug product (miconazole nitrate + hydrocortisone) revealed no special hazard for humans based on conventional studies of ocular irritation, dermal sensitization, single dose oral toxicity, primary dermal irritation toxicity, and 21-day repeat dose dermal toxicity. Additional preclinical data on the individual active ingredients in this drug product reveal no special hazard for humans based on conventional studies of local irritation, single and repeated dose toxicity, genotoxicity, and for miconazole toxicity to reproduction. Miconazole has shown no teratogenic effects but is fetotoxic at high oral doses. Reproductive effects (fetotoxicty, reduced weight gain) and developmental abnormalities specifically craniofacial effects including cleft palate have been reported with hydrocortisone in various animal models.

6. Pharmaceutical Particulars

6.1 List Of Excipients

PEG-6, PEG-32 and glycol stearate

Oleoyl macroglycerides

Mineral oil

Benzoic acid

Disodium edetate

Butylated hydroxyanisole

Purified water

6.2 Incompatibilities

None.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Store in a refrigerator (2-8°C).

6.5 Nature And Contents Of Container

Aluminium tube with polypropylene cap.

Each tube contains 5 g, 10 g, 15 g, 30 g or 75 g cream.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Janssen-Cilag Ltd

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4 EG

UK

8. Marketing Authorisation Number(S)

PL 00242/0042

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of First Authorisation:	04/02/77
Renewal of Authorisation:	24/02/2009

10. Date Of Revision Of The Text

17 November 2011

LEGAL CATEGORY

POM.

Difflam Cream

1. Name Of The Medicinal Product

Difflam Cream

or

Difflam-P Cream

2. Qualitative And Quantitative Composition

Each tube of Difflam Cream/ Difflam-P Cream contains Benzydamine Hydrochloride 3% w/w.

3. Pharmaceutical Form

Cream.

4. Clinical Particulars

4.1 Therapeutic Indications

Difflam Cream/ Difflam-P Cream is a topical analgesic and non-steroidal anti-inflammatory agent.

It is recommended as a short-term treatment for the relief of symptoms associated with painful inflammatory conditions of the musculo-skeletal system, including:

Acute inflammatory disorders such as myalgia and bursitis.

Traumatic conditions such as sprains, strains, contusions and the after-effects of fractures.

Difflam Cream/ Difflam-P Cream is well absorbed through the skin and has been shown to have anti-inflammatory and local anaesthetic actions.

4.2 Posology And Method Of Administration

Difflam Cream/ Difflam-P Cream should be massaged lightly into the affected area. Depending on the size of the site to be treated, 35 - 85 mm (1 - 2 g) should be applied three times daily and at the discretion of the doctor, up to six times daily in more severe conditions. It is recommended that treatment be limited to not more than ten days.

ELDERLY:

No special dosage recommendations are made for elderly patients.

4.3 Contraindications

Difflam Cream is contraindicated in patients with known hypersensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

To avoid possible irritation, Difflam Cream/ Difflam-P Cream should be kept away from eyes and mucosal surfaces.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None.

4.6 Pregnancy And Lactation

Difflam should not be used in pregnancy or lactation unless considered essential by the physician. There is no evidence of a teratogenic effect in animal studies.

4.7 Effects On Ability To Drive And Use Machines

None.

4.8 Undesirable Effects

Photosensitivity reactions have been reported and local skin reactions which have varied from erythema to papular eruption. The skin returned to normal on stopping treatment.

4.9 Overdose

Difflam is unlikely to cause adverse systemic effects, even if accidental ingestion should occur. No special measures are required.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Benzydamine exerts an anti-inflammatory and analgesic action by stabilising the cellular membrane and inhibiting prostaglandin synthesis.

5.2 Pharmacokinetic Properties

Following topical administration, benzydamine is absorbed through intact skin and reaches peak levels between 24 - 32 hours, amounting to about 20 - 25% of the plasma levels obtained after the oral administration of the same dose.

About half of the benzydamine is excreted unchanged via the kidney at a rate of 10% of the dose within the first 24 hours. The remainder is metabolised, mostly to N-oxide.

5.3 Preclinical Safety Data

Non-Clinical Data reveal no special hazards for humans based on conventional studies of safety pharmacology, repeated toxicity, genotoxicity, cardiogenic potential, and toxicity to reproduction.

6. Pharmaceutical Particulars

6.1 List Of Excipients

'Cutina' MD

Cetyl Alcohol USNF

'Cetiol' V

'Eumulgin' B1

Propylene Glycol Ph Eur

Perfume, 'Crematest' 0/064060

Methyl Hydroxybenzoate Ph Eur

Propyl Hydroxybenzoate Ph Eur

Purified Water Ph Eur

6.2 Incompatibilities

None known.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Store between 5 - 30°C. Do not freeze.

6.5 Nature And Contents Of Container

Collapsible Aluminium tube closed with plastic screwcap

or

Laminate tube closed with plastic screwcap.

Contents: 35 g, 50 g or 100 g

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Meda Pharmaceuticals Ltd

249 West George Street

Glasgow

G2 4RB

Trading as:

Meda Pharmaceuticals Ltd

Skyway House

Parsonage Road

Takeley

Bishop's Stortford

CM22 6PU

8. Marketing Authorisation Number(S)

PL 15142/0044

9. Date Of First Authorisation/Renewal Of The Authorisation

6 March 1980/ 6 September 2002

10. Date Of Revision Of The Text

17^th June 2011

Goddards Muscle Lotion

Goddards Muscle Lotion

(turpentine oil, dilute acetic acid, dilute ammonia)

Important information about Goddards Muscle Lotion

• This medicine relieves symptoms of rheumatic and muscular pains.


• It can be used by adults, the elderly and children.

Do not use on broken skin

Now read the rest of the leaflet before you use this medicine. It includes other information which might be especially important for you.

• Keep this leaflet. You may need to read it again.


• Ask your pharmacist if you need any more information or advice.


• If you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

What the medicine is for

Goddards Muscle Lotion is a topical emulsion which has warming and soothing properties. It is used to relieve the symptoms of muscle pain and stiffness, including backache, sciatica, lumbago, fibrositis, rheumatic pain and pain caused by bruises, sprains, strains, stiff
muscles and unbroken chilblains.

Before you use this medicine

Do not use the medicine if you or your child have broken skin.

Pregnant or breastfeeding

Ask your doctor or pharmacist for advice before using this medicine if you are pregnant, might be pregnant or are breastfeeding. Goddards Muscle Lotion should not be used in pregnancy unless the doctor has told you to do so.

How to use this medicine

Apply it to the skin

Adults, the elderly and children

• Shake the bottle thoroughly.


• Pour enough muscle lotion into the palm of your hand and rub into the affected area until dry, once or twice a day.


• Avoid contact with eyes and sensitive areas of the skin.


• Wash hands well after use.

For external use only.

If your symptoms persist you should ask your doctor for advice.

If you swallow some

If you accidentally swallow some, see a doctor straight away. Take the pack with you to show which medicine you have swallowed.

Possible side effects

There are no known side effects from using this medicine when used as directed.

If you notice any side effects, stop use and tell your doctor or pharmacist. They will tell you what to do.

Storing this medicine

• Keep it out of the reach and sight of children.


• There are no special conditions for storing this medicine.


• Do not use after the expiry date shown on the carton. The expiry date refers to the last day of that month.


• Medicine should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of any unused medicine. These measures will help to protect the environment.

Further information

What is in this medicine

The active ingredients are: turpentine oil 22% v/v, dilute acetic acid 30% v/v, dilute ammonia solution 14% v/v.

The other ingredients are: arlacel 83 V (sorbitan sesquioleate), PEG-8 oleate and purified water.

What the medicine looks like

Goddards Muscle Lotion is a creamy coloured emulsion which smells of turpentine and ammonia.

It is supplied in 200ml bottles.

Marketing authorisation holder

Actavis Group PTC ehf

Reykjavikurvegi 76-78

220 Hafnarfjordur

Iceland

Manufacturer

Thornton and Ross Ltd.

Huddersfield

HD7 5QH

UK

Goddards is a trade mark of Actavis Group PTC ehf.

This leaflet was revised in March 2009

Omeprazole 10mg Capsules (Actavis UK Ltd)

1. Name Of The Medicinal Product

OMEPRAZOLE 10mg CAPSULES

2. Qualitative And Quantitative Composition

Each capsule contains 10mg omeprazole.

Excipient: Contains sucrose, see section 4.4.

Each 10mg omeprazole capsule contains 51 to 58mg of sucrose.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

GASTRO-RESISTANT CAPSULES, HARD

Hard gelatine capsules of size 3, Opaque yellow cap and body containing white to off-white spherical pellets.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of duodenal ulcers

• Prevention of relapse of duodenal ulcers

• Treatment of gastric ulcers

• Prevention of relapse of gastric ulcers

• In combination with appropriate antibiotics, Helicobacter pylori (H. pylori) eradication in peptic ulcer disease

• Treatment of NSAID-associated gastric and duodenal ulcers

• Prevention of NSAID-associated gastric and duodenal ulcers in patients at risk

• Treatment of reflux oesophagitis

• Long-term management of patients with healed reflux oesophagitis

• Treatment of symptomatic gastro-oesophageal reflux disease

• Treatment of Zollinger-Ellison syndrome

Paediatric use

Children over 1 year of age and

• Treatment of reflux esophagitis

• Symptomatic treatment of heartburn and acid regurgitation in gastro-oesophageal reflux disease

Children and adolescents over 4 years of age

• In combination with antibiotics in treatment of duodenal ulcer caused by H. pylori

4.2 Posology And Method Of Administration

Posology in adults

Treatment of duodenal ulcers

The recommended dose in patients with an active duodenal ulcer is Omeprazole 20mg once daily. In most patients healing occurs within two weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further two weeks treatment period. In patients with poorly responsive duodenal ulcer Omeprazole 40mg once daily is recommended and healing is usually achieved within four weeks.

Prevention of relapse of duodenal ulcers

For the prevention of relapse of duodenal ulcer in H. pylori negative patients or when H. pylori eradication is not possible the recommended dose is Omeprazole 20mg once daily. In some patients a daily dose of 10mg may be sufficient. In case of therapy failure, the dose can be increased to 40mg.

Treatment of gastric ulcers

The recommended dose is Omeprazole 20mg once daily. In most patients healing occurs within four weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further four weeks treatment period. In patients with poorly responsive gastric ulcer Omeprazole 40mg once daily is recommended and healing is usually achieved within eight weeks.

Prevention of relapse of gastric ulcers

For the prevention of relapse in patients with poorly responsive gastric ulcer the recommended dose is Omeprazole 20mg once daily. If needed the dose can be increased to Omeprazole 40mg once daily.

H. pylori eradication in peptic ulcer disease

For the eradication of H. pylori the selection of antibiotics should consider the individual patient's drug tolerance, and should be undertaken in accordance with national, regional and local resistance patterns and treatment guidelines.

• Omeprazole 20mg + clarithromycin 500mg + amoxicillin 1,000mg, each twice daily for one week, or

• Omeprazole 20mg + clarithromycin 250mg (alternatively 500mg) + metronidazole 400mg (or 500mg or tinidazole 500mg), each twice daily for one week or

• Omeprazole 40mg once daily with amoxicillin 500mg and metronidazole 400mg (or 500mg or tinidazole 500mg), both three times a day for one week.

In each regimen, if the patient is still H. pylori positive, therapy may be repeated.

Treatment of NSAID-associated gastric and duodenal ulcers

For the treatment of NSAID-associated gastric and duodenal ulcers, the recommended dose is Omeprazole 20mg once daily. In most patients healing occurs within four weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further four weeks treatment period.

Prevention of NSAID-associated gastric and duodenal ulcers in patients at risk

For the prevention of NSAID-associated gastric ulcers or duodenal ulcers in patients at risk (age> 60, previous history of gastric and duodenal ulcers, previous history of upper GI bleeding) the recommended dose is Omeprazole 20mg once daily.

Treatment of reflux oesophagitis

The recommended dose is Omeprazole 20mg once daily. In most patients healing occurs within four weeks. For those patients who may not be fully healed after the initial course, healing usually occurs during a further four weeks treatment period.

In patients with severe oesophagitis Omeprazole 40mg once daily is recommended and healing is usually achieved within eight weeks.

Long-term management of patients with healed reflux oesophagitis

For the long-term management of patients with healed reflux oesophagitis the recommended dose is Omeprazole 10mg once daily. If needed, the dose can be increased to Omeprazole 20-40mg once daily.

Treatment of symptomatic gastro-oesophageal reflux disease

The recommended dose is Omeprazole 20mg daily. Patients may respond adequately to 10mg daily, and therefore individual dose adjustment should be considered.

If symptom control has not been achieved after four weeks treatment with Omeprazole 20mg daily, further investigation is recommended.

Treatment of Zollinger-Ellison syndrome

In patients with Zollinger-Ellison syndrome the dose should be individually adjusted and treatment continued as long as clinically indicated. The recommended initial dose is Omeprazole 60mg daily. All patients with severe disease and inadequate response to other therapies have been effectively controlled and more than 90% of the patients maintained on doses of Omeprazole 20-120mg daily. When dose exceed Omeprazole 80mg daily, the dose should be divided and given twice daily.

Posology in children

Children over 1 year of age and 10 kg

Treatment of reflux oesophagitis

Symptomatic treatment of heartburn and acid regurgitation in gastro-oesophageal reflux disease

The posology recommendations are as follows:

Age Weight Posology

Reflux oesophagitis: The treatment time is 4-8 weeks.

Symptomatic treatment of heartburn and acid regurgitation in gastro-oesophageal reflux disease: The treatment time is 2–4 weeks. If symptom control has not been achieved after 2–4 weeks the patient should be investigated further.

Children and adolescents over 4 years of age

Treatment of duodenal ulcer caused by H. pylori

When selecting appropriate combination therapy, consideration should be given to official national, regional and local guidance regarding bacterial resistance, duration of treatment (most commonly 7 days but sometimes up to 14 days), and appropriate use of antibacterial agents.

The treatment should be supervised by a specialist.

The posology recommendations are as follows:

Weight	Posology
15-30kg	Combination with two antibiotics: Omeprazole 10mg, amoxicillin 25mg/kg body weight and clarithromycin 7.5mg/kg body weight are all administrated together two times daily for one week.
31-40kg	Combination with two antibiotics: Omeprazole 20mg, amoxicillin 750mg and clarithromycin 7.5mg/kg body weight are all administrated two times daily for one week.
>40kg	Combination with two antibiotics: Omeprazole 20mg, amoxicillin 1g and clarithromycin 500mg are all administrated two times daily for one week.

Special populations

Impaired renal function

Dose adjustment is not needed in patients with impaired renal function (see section 5.2).

Impaired hepatic function

In patients with impaired hepatic function a daily dose of 10–20mg may be sufficient (see section 5.2).

Elderly (> 65 years old)

Dose adjustment is not needed in the elderly (see section 5.2).

Method of administration

It is recommended to take Omeprazole capsules in the morning, preferably without food, swallowed whole with half a glass of water. The capsules must not be chewed or crushed.

For patients with swallowing difficulties and for children who can drink or swallow semi-solid food

Patients can open the capsule and swallow the contents with half a glass of water or after mixing the contents in a slightly acidic fluid e.g., fruit juice or applesauce, or in non-carbonated water. Patients should be advised that the dispersion should be taken immediately (or within 30 minutes) and always be stirred just before drinking and rinsed down with half a glass of water.

Alternatively patients can suck the capsule and swallow the pellets with half a glass of water. The enteric coated pellets must not be chewed.

4.3 Contraindications

Hypersensitivity to omeprazole, substituted benzimidazoles or to any of the excipients.

Omeprazole like other proton pump inhibitors (PPIs) must not be used concomitantly with nelfinavir (see section 4.5).

4.4 Special Warnings And Precautions For Use

In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment may alleviate symptoms and delay diagnosis.

Co-administration of atazanavir with proton pump inhibitors is not recommended (see section 4.5). If the combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring (e.g virus load) is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir; omeprazole 20 mg should not be exceeded.

Omeprazole, as all acid-blocking medicines, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B12 absorption on long-term therapy.

Omeprazole is a CYP2C19 inhibitor. When starting or ending treatment with omeprazole, the potential for interactions with drugs metabolised through CYP2C19 should be considered. An interaction is observed between clopidogrel and omeprazole (see section 4.5). The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of omeprazole and clopidogrel should be discouraged.

Some children with chronic illnesses may require long-term treatment although it is not recommended.

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

Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter (see section 5.1).

As in all long-term treatments, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Effects of omeprazole on the pharmacokinetics of other active substances

Active substances with pH dependent absorption

The decreased intragastric acidity during treatment with omeprazole might increase or decrease the absorption of active substances with a gastric pH dependent absorption.

Nelfinavir, atazanavir

The plasma levels of nelfinavir and atazanavir are decreased in case of co-administration with omeprazole.

Concomitant administration of omeprazole with nelfinavir is contraindicated (see section 4.3). Co-administration of omeprazole (40 mg once daily) reduced mean nelvinavir exposure by ca. 40% and the mean exposure of the pharmacologically active metabolite M8 was reduced by ca. 75 –90%. The interaction may also involve CYP2C19 inhibition.

Concomitant administration of omeprazole with atazanavir is not recommended (see section 4.4). Concomitant administration of omeprazole (40 mg once daily) and atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a 75% decrease of the atazanavir exposure. Increasing the atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure. The co-administration of omeprazole (20 mg once daily) with atazanavir 400 mg/ritonavir 100 mg to healthy volunteers resulted in a decrease of approximately 30% in the atazanavir exposure as compared to atazanavir 300 mg/ritonavir 100 mg once daily.

Digoxin

Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10%. Digoxin toxicity has been rarely reported. However caution should be exercised when omeprazole is given at high doses in elderly patients. Therapeutic drug monitoring of digoxin should be then be reinforced.

Clopidogrel

In a crossover clinical study, clopidogrel (300 mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as clopidogrel) were administered for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together. Mean inhibition of platelet aggregation (IPA) was diminished by 47% (24 hours) and 30% (Day 5) when clopidogrel and omeprazole were administered together. In another study it was shown that administering clopidogrel and omeprazole at different times did not prevent their interaction that is likely to be driven by the inhibitory effect of omeprazole on CYP2C19.

Inconsistent data on the clinical implications of this PK/PD interaction in terms of major cardiovascular events have been reported from observational and clinical studies.

Other active substances

The absorption of posaconazole, erlotinib, ketoconazol and itraconazol is significantly reduced and thus clinical efficacy may be impaired. For posaconazol and erlotinib concomitant use should be avoided.

Active substances metabolised by CYP2C19

Omeprazole is a moderate inhibitor of CYP2C19, the major omeprazole metabolising enzyme. Thus, the metabolism of concomitant active substances also metabolised by CYP2C19, may be decreased and the systemic exposure to these substances increased. Examples of such drugs are R-warfarin and other vitamin K antagonists, cilostazol, diazepam and phenytoin.

Cilostazol

Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased Cmax and AUC for cilostazol by 18% and 26% respectively, and one of its active metabolites by 29% and 69% respectively.

Phenytoin

Monitoring phenytoin plasma concentration is recommended during the first two weeks after initiating omeprazole treatment and, if a phenytoin dose adjustment is made, monitoring and a further dose adjustment should occur upon ending omeprazole treatment.

Unknown mechanism

Saquinavir

Concomitant administration of omeprazole with saquinavir/ritonavir resulted in increased plasma levels up to approximately 70% for saquinavir associated with good tolerability in HIV-infected patients.

Tacrolimus

Concomitant administration of omeprazole has been reported to increase the serum levels of tacrolimus. A reinforced monitoring of tacrolimus concentrations as well as renal function (creatinine clearance) should be performed, and dosage of tacrolimus adjusted if needed.

Effects of other active substances on the pharmacokinetics of omeprazole

Inhibitors CYP2C19 and/or CYP3A4

Since omeprazole is metabolised by CYP2C19 and CYP3A4, active substances known to inhibit CYP2C19 or CYP3A4 (such as clarithromycin and voriconazole) may lead to increased omeprazole serum levels by decreasing omeprazole's rate of metabolism. Concomitant voriconazole treatment resulted in more than doubling of the omeprazole exposure. As high doses of omeprazole have been well-tolerated adjustment of the omeprazole dose is not generally required. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated.

Inducers of CYP2C19 and/or CYP3A4

Active substances known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St John's wort) may lead to decreased omeprazole serum levels by increasing omeprazole's rate of metabolism.

4.6 Pregnancy And Lactation

Results from three prospective epidemiological studies (more than 1000 exposed outcomes) indicate no adverse effects of omeprazole on pregnancy or on the health of the foetus/newborn child. Omeprazole can be used during pregnancy.

Omeprazole is excreted in breast milk but is not likely to influence the child when therapeutic doses are used.

4.7 Effects On Ability To Drive And Use Machines

Omeprazole is not likely to affect the ability to drive or 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 machinery.

4.8 Undesirable Effects

The most common side effects (1-10% of patients) are headache, abdominal pain, constipation, diarrhoea, flatulence and nausea/vomiting.

The following adverse drug reactions have been identified or suspected in the clinical trials programme for omeprazole and post-marketing. None was found to be dose-related. Adverse reactions listed below are classified according to frequency and System Organ Class (SOC). Frequency categories are defined according to the following convention: Very common (

SOC/frequency	Adverse reaction
Blood and lymphatic system disorders
Rare:	Leukopenia, thrombocytopenia
Very rare:	Agranulocytosis, pancytopenia
Immune system disorders
Rare:	Hypersensitivity reactions e.g. fever, angioedema and anaphylactic reaction/shock
Metabolism and nutrition disorders
Rare:	Hyponatraemia
Very rare:	Hypomagnesaemia
Psychiatric disorders
Uncommon:	Insomnia
Rare:	Agitation, confusion, depression
Very rare:	Aggression, hallucinations
Nervous system disorders
Common:	Headache
Uncommon:	Dizziness, paraesthesia, somnolence
Rare:	Taste disturbance
Eye disorders
Rare:	Blurred vision
Ear and labyrinth disorders
Uncommon:	Vertigo
Respiratory, thoracic and mediastinal disorders
Rare:	Bronchospasm
Gastrointestinal disorders
Common:	Abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting
Rare:	Dry mouth, stomatitis, gastrointestinal candidiasis
Hepatobiliary disorders
Uncommon:	Increased liver enzymes
Rare:	Hepatitis with or without jaundice
Very rare:	Hepatic failure, encephalopathy in patients with pre-existing liver disease
Skin and subcutaneous tissue disorders
Uncommon:	Dermatitis, pruritus, rash, urticaria
Rare:	Alopecia, photosensitivity
Very rare:	Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN)
Musculoskeletal and connective tissue disorders
Rare:	Arthralgia, myalgia
Very rare:	Muscular weakness
Renal and urinary disorders
Rare:	Interstitial nephritis
Reproductive system and breast disorders
Very rare:	Gynaecomastia
General disorders and administration site conditions
Uncommon:	Malaise, peripheral oedema
Rare:	Increased sweating

Paediatric population

The safety of omeprazole has been assessed in a total of 310 children aged 0 to 16 years with acid-related disease. There are limited long term safety data from 46 children who received maintenance therapy of omeprazole during a clinical study for severe erosive esophagitis for up to 749 days. The adverse event profile was generally the same as for adults in short- as well as in long-term treatment. There are no long term data regarding the effects of omeprazole treatment on puberty and growth.

4.9 Overdose

There is limited information available on the effects of overdoses of omeprazole in humans. In the literature, doses of up to 560 mg have been described, and occasional reports have been received when single oral doses have reached up to 2,400 mg omeprazole (120 times the usual recommended clinical dose). Nausea, vomiting, dizziness, abdominal pain, diarrhoea and headache have been reported. Also apathy, depression and confusion have been described in single cases.

The symptoms described have been transient, and no serious outcome has been reported. The rate of elimination was unchanged (first order kinetics) with increased doses. Treatment, if needed, is symptomatic.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group:

Selective proton plump inhibitor, substituted benzimidazole.

ATC-CODE:A02B C01

Mechanism of action

Omeprazole, a racemic mixture of two enantiomers reduces gastric acid secretion through a highly targeted mechanism of action. It is a specific inhibitor of the acid pump in the parietal cell. It is rapidly acting and provides control through reversible inhibition of gastric acid secretion with once daily dosing.

Omeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the intracellular canaliculi within the parietal cell, where it inhibits the enzyme H+ K+-ATPase - the acid pump. This effect on the final step of the gastric acid formation process is dose-dependent and provides for highly effective inhibition of both basal acid secretion and stimulated acid secretion, irrespective of stimulus.

Pharmacodynamic effects

All pharmacodynamic effects observed can be explained by the effect of omeprazole on acid secretion.

Effect on gastric acid secretion

Oral dosing with omeprazole once daily provides for rapid and effective inhibition of daytime and night time gastric acid secretion with maximum effect being achieved within 4 days of treatment. With omeprazole 20 mg, a mean decrease of at least 80% in 24-hour intragastric acidity is then maintained in duodenal ulcer patients, with the mean decrease in peak acid output after pentagastrin stimulation being about 70% 24 hours after dosing.

Oral dosing with omeprazole 20 mg maintains an intragastric pH of

As a consequence of reduced acid secretion and intragastric acidity, omeprazole dose-dependently reduces/normalizes acid exposure of the esophagus in patients with gastro-esophageal reflux disease. The inhibition of acid secretion is related to the area under the plasma concentration-time curve (AUC) of omeprazole and not to the actual plasma concentration at a given time.

No tachyphylaxis has been observed during treatment with omeprazole.

Effect on H. pylori

H. pylori is associated with peptic ulcer disease, including duodenal and gastric ulcer disease. H. pylori is a major factor in the development of gastritis. H. pylori together with gastric acid are major factors in the development of peptic ulcer disease. H. pylori is a major factor in the development of atrophic gastritis which is associated with an increased risk of developing gastric cancer.

Eradication of H. pylori with omeprazole and antimicrobials is associated with, high rates of healing and long-term remission of peptic ulcers.

Dual therapies have been tested and found to be less effective than triple therapies. They could, however, be considered in cases where known hypersensitivity precludes use of any triple combination.

Other effects related to acid inhibition

During long-term treatment gastric glandular cysts have been reported in a somewhat increased frequency. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible.

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 drugs may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter.

Paediatric use

In a non-controlled study in children (1 to 16 years of age) with severe reflux esophagitis, omeprazole at doses of 0.7 to 1.4 mg/kg improved esophagitis level in 90% of the cases and significantly reduced reflux symptoms. In a single-blind study, children aged 0–24 months with clinically diagnosed gastroesophageal reflux disease were treated with 0.5, 1.0 or 1.5 mg omeprazole/kg. The frequency of vomiting/regurgitation episodes decreased by 50% after 8 weeks of treatment irrespective of the dose.

Eradication of H. pylori in children

A randomised, double blind clinical study (Héliot study) concluded that omeprazole in combination with two antibiotics (amoxicillin and clarithromycin), was safe and effective in the treatment of H. pylori infection in children age 4 years old and above with gastritis: H. pylori eradication rate: 74.2% (23/31 patients) with omeprazole + amoxicillin + clarithromycin versus 9.4% (3/32 patients) with amoxicillin + clarithromycin. However, there was no evidence of any clinical benefit with respect to dyspeptic symptoms. This study does not support any information for children aged less than 4 years.

5.2 Pharmacokinetic Properties

Absorption

Omeprazole and omeprazole magnesium are acid labile and are therefore administered orally as enteric-coated granules in capsules or tablets. Absorption of omeprazole is rapid, with peak plasma levels occurring approximately 1-2 hours after dose. Absorption of omeprazole takes place in the small intestine and is usually completed within 3-6 hours. Concomitant intake of food has no influence on the bioavailability. The systemic availability (bioavailability) from a single oral dose of omeprazole is approximately 40%. After repeated once-daily administration, the bioavailability increases to about 60%.

Distribution

The apparent volume of distribution in healthy subjects is approximately 0.3 l/kg body weight. Omeprazole is 97% plasma protein bound.

Metabolism

Omeprazole is completely metabolised by the cytochrome P450 system (CYP). The major part of its metabolism is dependent on the polymorphically expressed CYP2C19, responsible for the formation of hydroxyomeprazole, the major metabolite in plasma. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of omeprazole sulphone. As a consequence of high affinity of omeprazole to CYP2C19, there is a potential for competitive inhibition and metabolic drugdrug interactions with other substrates for CYP2C19. However, due to low affinity to CYP3A4, omeprazole has no potential to inhibit the metabolism of other CYP3A4 substrates. In addition, omeprazole lacks an inhibitory effect on the main CYP enzymes.

Approximately 3% of the Caucasian population and 15-20% of Asian populations lack a functional CYP2C19 enzyme and are called poor metabolisers. In such individuals the metabolism of omeprazole is probably mainly catalysed by CYP3A4. After repeated once-daily administration of 20 mg omeprazole, the mean AUC was 5 to 10 times higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were also higher, by 3 to 5 times. These findings have no implications for the posology of omeprazole.

Excretion

The plasma elimination half-life of omeprazole is usually shorter than one hour both after single and repeated oral once-daily dosing. Omeprazole is completely eliminated from plasma between doses with no tendency for accumulation during once-daily administration. Almost 80% of an oral dose of omeprazole is excreted as metabolites in the urine, the remainder in the faeces, primarily originating from bile secretion.

The AUC of omeprazole increases with repeated administration. This increase is dose-dependent and results in a non-linear dose-AUC relationship after repeated administration. This time- and dosedependency is due to a decrease of first pass metabolism and systemic clearance probably caused by an inhibition of the CYP2C19 enzyme by omeprazole and/or its metabolites (e.g. the sulphone). No metabolite has been found to have any effect on gastric acid secretion.

Special populations

Impaired hepatic function

The metabolism of omeprazole in patients with liver dysfunction is impaired, resulting in an increased AUC. Omeprazole has not shown any tendency to accumulate with once daily dosing.

Impaired renal function

The pharmacokinetics of omeprazole, including systemic bioavailability and elimination rate, are unchanged in patients with reduced renal function.

Elderly

The metabolism rate of omeprazole is somewhat reduced in elderly subjects (75-79 years of age).

Paediatric patients

During treatment with the recommended doses to children from the age of 1 year, similar plasma concentrations were obtained as compared to adults. In children younger than 6 months, clearance of omeprazole is low due to low capacity to metabolise omeprazole.

5.3 Preclinical Safety Data

Gastric ECL-cell hyperplasia and carcinoids, have been observed in life-long studies in rats treated with omeprazole. These changes are the result of sustained hypergastrinaemia secondary to acid inhibition. Similar findings have been made after treatment with H2-receptor antagonists, proton pump inhibitors and after partial fundectomy. Thus, these changes are not from a direct effect of any individual active substance.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sugar spheres (consisting of corn starch and sucrose), sodium lauryl sulphate, disodium phosphate, mannitol, hypromellose, polyethylene glycol 6000, talc, polysorbate 80, titanium dioxide, Eudragit L30-D55 (poly(methacrylic acid, ethyl acrylate)). Capsules consist of gelatin and contain the colours quinoline yellow (E104) and titanium dioxide (E171).

6.2 Incompatibilities

None known

6.3 Shelf Life

Aluminium-aluminium blister

3 years

HDPE tablet containers with a PP closure incorporating a LDPE capsule containing silica gel dessicant

3 years. Use within 3 months of opening.

6.4 Special Precautions For Storage

Store below 25°C.

Aluminium/Aluminium blister pack: Store in the original package to protect from moisture.

HDPE tablet container: Keep the bottle tightly closed to protect from moisture.

6.5 Nature And Contents Of Container

OPA/Aluminium/PVC: Aluminium blister; OPA/Aluminium/PVC: PET/Aluminium blister

Pack sizes: 7's ,10's, 14's,15's, 20's, 21's, 28's, 30's, 50's, 56's, 60's ,84's, 90's, 98's, 100's

HDPE tablet containers with a PP closure incorporating a LDPE capsule containing silica gel dessicant

Pack size: 30

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Actavis UK Limited (Trading style: Actavis)

Whiddon Valley

BARNSTAPLE

N Devon EX32 8NS

8. Marketing Authorisation Number(S)

PL 00142/0516

9. Date Of First Authorisation/Renewal Of The Authorisation

22/03/2002

10. Date Of Revision Of The Text

28/09/2011

11 DOSIMETRY

IF APPLICABLE

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

IF APPLICABLE