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

Boots Skin Therapy Emollient Cream 300g

Boots Skin Therapy Emollient Cream

(Almond Oil, Lanolin)

Effective relief for dry skin conditions

Soothes

Moisturisers

Relieves

relieves dry skin conditions such as dry eczema, chapping, nappy soreness and sunburn

300 g e

Read all of this label for full instructions.

What this medicine is for

An emollient cream that relieves dry skin conditions such as dry eczema, chapping, nappy soreness and sunburn.

Before you use this medicine

X Do not use:

• 
  If you are allergic to any of the ingredients

You can use this medicine if you are pregnant or breastfeeding.

Cetyl alcohol may cause skin reactions (e.g. contact dermatitis).

How to use this medicine

Check the tub seal is not broken before first use. If it is, do not use the cream. To open, lift tear strip and pull around tub.

Apply to the skin only.

Adults and children: Use on the affected area 2 or 3 times a day.

If symptoms do not go away talk to your pharmacist or doctor.

If anyone accidentally swallows some: Talk to a pharmacist or doctor.

Possible side effects

Most people will not have problems.

If you get these side effects stop using the cream and see a doctor:

• Allergic reaction (e.g. skin rash, red or itchy skin)

If you notice any side effect not listed here, please tell your pharmacist or doctor.

Keep all medicines out of the sight and reach of children.

Use by the date on the base of the tub.

Active ingredients

This cream contains Almond Oil 5% w/w, Anhydrous Hypoallergenic Lanolin 1% w/w.

Also contains: purified water, cetyl alcohol, white soft paraffin, cetomacrogol 1000, benzyl alcohol, sorbitan sesquioleate, sodium citrate, anhydrous citric acid.

Skin Therapy Emollient Cream is a rich, soothing cream to relieve a wide variety of dry skin conditions such as dry eczema, chapping caused by the weather or water, nappy soreness and sunburn. It is non-perfumed and non-greasy.

PL 00014/0369

Text prepared 9/06

Manufactured by the Marketing Authorisation holder

The Boots Company PLC

Nottingham

NG2 3AA

If you need more advice ask your pharmacist.

BTC18973 vA 19-06-07

Levemir Cartridges

Pronunciation: IN-su-lin DE-te-mir
Generic Name: Insulin Detemir
Brand Name: Levemir

Levemir Cartridges are used for:

Treating diabetes mellitus.

Levemir Cartridges are a long-acting form of the hormone insulin. It works by helping your body to use sugar properly. This lowers the amount of glucose in the blood, which helps to treat diabetes.

Do NOT use Levemir Cartridges if:

• you are allergic to any ingredient in Levemir Cartridges


• you are having an episode of low blood sugar

Contact your doctor or health care provider right away if any of these apply to you.

Before using Levemir Cartridges:

Some medical conditions may interact with Levemir Cartridges. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you drink alcoholic beverages or smoke


• if you have kidney or liver problems; nerve problems; adrenal, pituitary, or thyroid problems; or diabetic ketoacidosis


• if you use 3 or more insulin injections per day


• if you are fasting, have high blood sodium levels, or are on a low-salt diet

Some MEDICINES MAY INTERACT with Levemir Cartridges. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Beta-blockers (eg, propranolol), clonidine, guanethidine, lithium, or reserpine because they may increase the risk of high or low blood sugar or may hide the signs and symptoms of low blood sugar, if it occurs


• Angiotensin-converting enzyme (ACE) inhibitors (eg, enalapril), disopyramide, fenfluramine, fibrates (eg, clofibrate, gemfibrozil), fluoxetine, monoamine oxidase inhibitors (MAOIs) (eg, phenelzine), oral medicines for diabetes (eg, glipizide, metformin, nateglinide), pentamidine, propoxyphene, salicylates (eg, aspirin), somatostatin analogs (eg, octreotide), or sulfonamide antibiotics (eg, sulfamethoxazole) because the risk of low blood sugar may be increased


• Corticosteroids (eg, prednisone), danazol, diuretics (eg, furosemide, hydrochlorothiazide), estrogen, hormonal contraceptives (eg, birth control pills), isoniazid, niacin, phenothiazines (eg, chlorpromazine), progesterones (eg, medroxyprogesterone), somatropin, sympathomimetics (eg, albuterol, epinephrine, terbutaline), or thyroid hormones (eg, levothyroxine) because they may decrease Levemir Cartridges's effectiveness, resulting in high blood sugar

This may not be a complete list of all interactions that may occur. Ask your health care provider if Levemir Cartridges may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Levemir Cartridges:

Use Levemir Cartridges as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Levemir Cartridges. Talk to your pharmacist if you have questions about this information.


• Use Levemir Cartridges at the same time each day, as directed by your doctor.


• If you will be using Levemir Cartridges at home, a health care provider will teach you how to use it. Be sure you understand how to use Levemir Cartridges. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions.


• Levemir Cartridges should be clear and colorless. Do not use Levemir Cartridges if it contains particles, is cloudy, discolored, or thickened, or if the container is cracked or damaged.


• Do NOT dilute Levemir Cartridges or mix it with other insulin. Do NOT use it in an insulin pump.


• Use the proper technique taught to you by your doctor. Inject deep under the skin, NOT into a vein or muscle.


• Injection sites within an injection area (eg, abdomen, thigh, upper arm) must be rotated from one injection to the next. Do not inject insulin into skin that is red, swollen, or itchy.


• Be sure you have purchased the correct insulin. Insulin comes in a variety of containers, including vials, cartridges, and pens. Make sure that you understand how to properly measure and prepare your dose. If you have any questions about measuring and preparing your dose, contact your doctor or pharmacist for information.


• The effect of Levemir Cartridges may last for up to 24 hours.


• Keep this product, as well as syringes and needles, out of the reach of children and away from pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.


• It is very important to follow your insulin regimen exactly. Do NOT miss any doses. Ask your doctor for specific instructions to follow in case you ever miss a dose of insulin.

Ask your health care provider any questions you may have about how to use Levemir Cartridges.

Important safety information:

• Drowsiness, dizziness, lightheadedness, or blurred vision may occur while you use Levemir Cartridges. These effects may be worse if you take it with alcohol or certain medicines. Use Levemir Cartridges with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Do not drink alcohol without discussing it with your doctor. Drinking alcohol may increase your risk of developing high or low blood sugar.


• Do NOT use more than the recommended dose, use more often than prescribed, or change the type or dose of insulin you are using without checking with your doctor.


• Any change of insulin should be made cautiously and only under medical supervision. Changes in purity, strength, brand (manufacturer), type (regular, NPH, lente), species (beef, pork, beef-pork, human), and/or method of manufacture may require a change in dose.


• Illness, especially with nausea and vomiting, may cause your insulin requirements to change. Even if you are not eating, you still require insulin. You and your doctor should establish a sick day plan to use in case of illness. When you are sick, test your blood/urine frequently and call your doctor as instructed.


• Tell your doctor or dentist that you take Levemir Cartridges before you receive any medical or dental care, emergency care, or surgery.


• If you will be traveling across time zones, consult your doctor concerning adjustments in your insulin schedule.


• Carry an ID card at all times that says you have diabetes.


• An insulin reaction resulting from low blood sugar levels (hypoglycemia) may occur if you take too much insulin, skip a meal, or exercise too much. Low blood sugar may make you anxious, sweaty, weak, dizzy, drowsy, or faint. It may also make your heart beat faster; make your vision change; give you a headache, chills, or tremors; or make you more hungry. It is a good idea to carry a reliable source of glucose (eg, tablets or gel) to treat low blood sugar. If this is not available, you should eat or drink a quick source of sugar like table sugar, honey, candy, orange juice, or non-diet soda. This will raise your blood sugar level quickly. Tell your doctor right away if this happens. To prevent low blood sugar, eat meals at the same time each day and do not skip meals.


• Developing a fever or infection, eating significantly more than prescribed, or missing your dose of insulin may cause high blood sugar (hyperglycemia). High blood sugar may make you feel confused, drowsy, or thirsty. It can also make you flush, breathe faster, or have a fruit-like breath odor. If these symptoms occur, tell your doctor right away.


• Check with your doctor if you notice a depression in the skin or skin thickening at the injection site. You may need to change your injection technique.


• Proper diet, regular exercise, and regular testing of blood sugar are important for best results when using Levemir Cartridges. Follow your doctor's instructions carefully. If your blood sugar level is often higher than it should be and you are taking Levemir Cartridges according to the directions, check with your doctor.


• Tell your doctor if you have had a recent change in diet or physical activity.


• Lab tests, including fasting blood glucose levels or hemoglobin A_1c, may be performed while you use Levemir Cartridges. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Use Levemir Cartridges with caution in the ELDERLY; if low blood sugar occurs, it may be more difficult to recognize in these patients.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Levemir Cartridges while you are pregnant. It is not known if Levemir Cartridges are found in breast milk. If you are or will be breast-feeding while you use Levemir Cartridges, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Levemir Cartridges:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Redness, swelling, itching, or mild pain at the injection site.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; wheezing); changes in vision; chills; confusion; dizziness; drowsiness; fainting; fast or irregular heartbeat; headache; loss of consciousness; mental or mood changes; muscle pain, weakness, or cramping; seizures; slurred speech; swelling; tremor; trouble breathing; trouble concentrating; unusual hunger; unusual sweating; weakness.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Levemir side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center or emergency room immediately. Symptoms may include chills; dizziness; drowsiness; fainting; headache; increased heartbeat; increased hunger; loss of consciousness; nervousness; seizures; shakiness; sweating; tremor; vision changes; weakness.

Proper storage of Levemir Cartridges:

Store new (unopened) cartridge systems or prefilled syringes in the refrigerator, between 36 and 46 degrees F (2 and 8 degrees C). Do not freeze. Store used (open) cartridge systems and prefilled syringes at room temperature, below 86 degrees F (30 degrees C). Do NOT store used (open) cartridges or prefilled syringes in the refrigerator. Do NOT store used (open) cartridges or prefilled syringes with the needle in place. Store away from heat and light. Throw away unrefrigerated or used cartridge systems or prefilled syringes after 42 days, even if they still contain medicine. Do not use Levemir Cartridges if it has been frozen or overheated. Throw it away.

Do not leave Levemir Cartridges in a car on a warm or sunny day. If Levemir Cartridges has been frozen or overheated, throw it away. Do not use Levemir Cartridges after the expiration date stamped on the label. Keep Levemir Cartridges, as well as syringes and needles, out of the reach of children and away from pets.

General information:

• If you have any questions about Levemir Cartridges, please talk with your doctor, pharmacist, or other health care provider.


• Levemir Cartridges are to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Levemir Cartridges. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Levemir resources

• Levemir Side Effects (in more detail)
• Levemir Use in Pregnancy & Breastfeeding
• Levemir Drug Interactions
• Levemir Support Group
• 6 Reviews for Levemir - Add your own review/rating

Compare Levemir with other medications

• Diabetes, Type 1
• Diabetes, Type 2

PecFent

1. Name Of The Medicinal Product

PecFent 100 and 400 micrograms/spray nasal spray solution

2. Qualitative And Quantitative Composition

Each ml of solution contains 1,000 or 4,000 micrograms fentanyl (as citrate)

1 spray (100 microlitres) contains 100 or 400 micrograms fentanyl (as citrate)

Each bottle contains 1.55 ml (1.55 mg or 6.20 mg fentanyl) ensuring delivery of 8 sprays of 100 or 400 micrograms

Excipients

Each spray contains 0.02 mg propylhydroxybenzoate (E216).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Nasal spray, solution (nasal spray)

A clear to practically clear colourless aqueous solution.

4. Clinical Particulars

4.1 Therapeutic Indications

PecFent is indicated for the management of breakthrough pain (BTP) in adults who are already receiving maintenance opioid therapy for chronic cancer pain. Breakthrough pain is a transitory exacerbation of pain that occurs on a background of otherwise controlled persistent pain.

Patients receiving maintenance opioid therapy are those who are taking at least 60 mg of oral morphine daily, at least 25 micrograms of transdermal fentanyl per hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer.

4.2 Posology And Method Of Administration

Treatment should be initiated by and remain under the supervision of a physician experienced in the management of opioid therapy in cancer patients. Physicians should keep in mind the potential for abuse of fentanyl.

Posology

PecFent should be titrated to an “effective” dose that provides adequate analgesia and minimises adverse reactions without causing undue (or intolerable) adverse reactions, for two consecutively treated episodes of BTP. The efficacy of a given dose should be assessed over the ensuing 30 minute period.

Patients should be carefully monitored until an effective dose is reached.

One dose of PecFent may include administration of 1 spray (100 microgram or 400 microgram doses) or 2 sprays (200 microgram or 800 microgram doses) of the same dose strength (either 100 microgram or 400 microgram strength).

Patients should not take more than 4 doses per day. Patients should wait at least 4 hours after a dose before treating another BTP episode with PecFent.

Initial dose

• The initial dose of PecFent to treat episodes of BTP is always 100 micrograms (one spray), even in patients switching from other fentanyl containing products for their BTP.

• Patients must wait at least 4 hours before treating another episode of BTP with PecFent.

Method of titration

• Patients should be prescribed an initial titration supply of one bottle (8 sprays) of PecFent 100 micrograms/spray.

• Patients whose initial dose is 100 micrograms and who need to titrate to a higher dose due to a lack of effect can be instructed to use two 100 microgram sprays (one in each nostril) for their next BTP episode. If this dose is not successful, the patient may be prescribed a bottle of PecFent 400 micrograms/spray and instructed to change to one 400 microgram spray for their next episode of pain. If this dose is not successful, the patient may be instructed to increase to two 400 microgram sprays (one in each nostril).

• From treatment initiation, patients should be closely followed and the dose titrated until an effective dose is reached and confirmed for two consecutively treated episodes of BTP.

Titration in patients switching between immediate-release fentanyl containing products

Substantial differences may exist in the pharmacokinetic profile of immediate-release fentanyl products, which result in clinically important differences in the rate and extent of absorption of fentanyl. Therefore, when switching between fentanyl containing products indicated for treatment of breakthrough pain, including intranasal formulations, it is essential that patients are again titrated with the new product, and not switched on a dose-for-dose (microgram-for-microgram) basis.

Maintenance therapy

Once an effective dose has been established during titration, patients should continue to take this dose up to a maximum of 4 doses per day.

Dose readjustment

Generally, the maintenance dose of PecFent should be increased only where the current dose fails to adequately treat the BTP for several consecutive episodes.

A review of the dose of the background opioid therapy may be required if patients consistently present with more than four BTP episodes per 24 hours.

If adverse reactions are intolerable or persistent, the dose should be reduced or treatment with PecFent replaced by another analgesic.

Discontinuation of therapy

PecFent should be discontinued immediately if the patient no longer experiences breakthrough pain episodes. The treatment for persistent backgound pain should be kept as prescribed.

If discontinuation of all opioid therapy is required, the patient must be closely followed by the doctor as gradual downward opioid titration therapy is necessary in order to avoid the possibility of abrupt withdrawal effects.

Paediatric population

The safety and efficacy of PecFent in children aged below 18 years have not yet been established.

No data are available.

Use in the elderly (older than 65 years)

In the PecFent clinical trial programme, 104 (26.1%) of patients were over 60 years of age, 67 (16.8%) over 65 years and 15 (3.8%) over 75 years. There was no indication that older patients tended to titrate to lower doses or experience more adverse reactions. Nevertheless, in view of the importance of renal and hepatic function in the metabolism and clearance of fentanyl, additional care should be exercised in the use of PecFent in the elderly. No data on the pharmacokinetics of PecFent in elderly patients are available.

Hepatic or renal impairment

PecFent should be administered with caution to patients with moderate or severe hepatic or renal impairment (see section 4.4).

Method of administration

PecFent is for administration via the nasal route only.

PecFent can deliver 100, 200, 400 and 800 microgram doses as follows:

Dose required (micrograms)	Product strength (micrograms)	Amount
100	100	One spray administered into one nostril
200	100	One spray administered into each nostril
400	400	One spray administered into one nostril
800	400	One spray administered into each nostril

The bottle should be removed from the child resistant container immediately prior to use and the protective cap removed. The bottle must be primed before first use by holding upright and simply pressing and releasing the finger grips either side of the nozzle until a green bar appears in the counting window (should occur after four sprays).

If the product has not been used for more than 5 days or if it is more than 14 days since the product was first used, the PecFent bottle should be discarded.

To administer PecFent the nozzle is placed a short distance (about 1 cm) into the nostril and pointed slightly towards the bridge of the nose. A spray is then administered by pressing and releasing the finger grips either side of the nozzle. An audible click will be heard and the number displayed on the counter will advance by one.

Patients must be advised that they may not feel the spray being administered, and that they should therefore rely on the audible click and the number on the counter advancing to confirm that a spray has been delivered.

The PecFent spray droplets form a gel in the nose. Patients should be advised not to blow their nose immediately after PecFent administration.

The protective cap should be replaced after each use and the bottle returned to the child resistant container for safe storage.

4.3 Contraindications

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

Use in opioid naïve patients.

Severe respiratory depression or severe obstructive lung conditions.

4.4 Special Warnings And Precautions For Use

Patients and their carers must be instructed that PecFent contains an active substance in an amount that can be fatal to a child, and therefore to keep PecFent out of the reach and sight of children.

In order to minimise the risks of opioid-related adverse reactions and to identify the effective dose, it is imperative that patients be monitored closely by health professionals during the titration process.

It is important that the long acting opioid treatment used to treat the patient's persistent pain has been stabilised before PecFent therapy begins.

Respiratory depression

There is a risk of clinically significant respiratory depression associated with the use of fentanyl. Patients with pain who receive chronic opioid therapy develop tolerance to respiratory depression and hence the risk of respiratory depression in these patients is reduced. The use of concomitant central nervous system depressants may increase the risk of respiratory depression (see section 4.5).

Chronic pulmonary disease

In patients with chronic obstructive pulmonary diseases, fentanyl may cause more serious adverse reactions. In these patients, opioids may decrease respiratory drive and increase airway resistance.

Increased intracranial pressure

PecFent should only be administered with extreme caution in patients who may be particularly susceptible to the intracranial effects of CO₂ retention, such as those with evidence of increased intracranial pressure or impaired consciousness. Opioids may obscure the clinical course of patients with a head injury and should be used only if clinically warranted.

Cardiac disease

Intravenous fentanyl may produce bradycardia. PecFent should therefore be used with caution in patients with pre-existing bradyarrhythmias.

Impaired hepatic or renal function

In addition, PecFent should be administered with caution to patients with hepatic or renal impairment. The influence of hepatic and renal impairment on the pharmacokinetics of the medicinal product has not been evaluated; however, when administered intravenously the clearance of fentanyl has been shown to be altered in hepatic and renal impairment due to alterations in metabolic clearance and plasma proteins. Therefore, special care should be taken during the titration process in patients with moderate or severe hepatic or renal impairment.

Careful consideration should be given to patients with hypovolaemia and hypotension.

Abuse potential and tolerance

Tolerance and physical and/or psychological dependence may develop upon repeated administration of opioids such as fentanyl. However, iatrogenic addiction following therapeutic use of opioids is rare.

Athletes should be informed that treatment with fentanyl could lead to positive doping tests.

Route of administration

PecFent is only intended for intranasal administration, and must not be administered by any other route. Due to physico-chemical properties of excipients included in the formulation, intravenous or intra-arterial injection must be avoided in particular.

Nasal conditions

If the patient experiences recurrent episodes of epistaxis or nasal discomfort while taking PecFent, an alternative method of administration for treatment of breakthrough pain should be considered.

PecFent excipients

PecFent contains propylhydroxybenzoate (E216). In some patients this may cause allergic reactions (possibly delayed) and, exceptionally, bronchospasm (if the product is not correctly administered).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Fentanyl is metabolised mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4), therefore potential interactions may occur when PecFent is given concurrently with agents that affect CYP3A4 activity. Coadministration with agents that induce 3A4 activity may reduce the efficacy of PecFent. The concomitant use of PecFent with strong CYP3A4 inhibitors (e.g. ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, and nelfinavir) or moderate CYP3A4 inhibitors (e.g. amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in increased fentanyl plasma concentrations, potentially causing serious adverse drug reactions including fatal respiratory depression. Patients receiving PecFent concomitantly with moderate or strong CYP3A4 inhibitors should be carefully monitored for an extended period of time. Dose increase should be undertaken with caution.

The concomitant use of other central nervous system depressants, including other opioids, sedatives or hypnotics, general anaesthetics, phenothiazines, tranquillisers, skeletal muscle relaxants, sedating antihistamines and alcohol may produce additive depressant effects.

PecFent is not recommended for use in patients who have received monoamine oxidase (MAO) inhibitors within the previous 14 days because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.

The concomitant use of partial opioid agonists/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) is not recommended. They have high affinity to opioid receptors with relatively low intrinsic activity and therefore partially antagonise the analgesic effect of fentanyl and may induce withdrawal symptoms in opioid dependant patients.

Concomitant use of nasally administered oxymetazoline has been shown to decrease the absorption of PecFent (see section 5.2). The concomitant use of nasally administered vasoconstrictive decongestants during titration is therefore not recommended as this may lead to patients titrating to a dose that is higher than required. PecFent maintenance treatment may also be less effective in patients with rhinitis when administered concomitantly with a nasal vasoconstrictive decongestant. If this occurs, patients should be advised to discontinue their decongestant.

Concomitant use of PecFent and other medicinal products (other than oxymetazoline) administered via the nose has not been evaluated in the clinical trials. Other nasally administered treatments should be avoided within 15 minutes of dosing with PecFent.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of fentanyl in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. PecFent should not be used during pregnancy unless clearly necessary.

Following long-term treatment, fentanyl may cause withdrawal in the new-born infant. It is advised not to use fentanyl during labour and delivery (including caesarean section) because fentanyl passes through the placenta and may cause respiratory depression in the foetus. If PecFent is administered, an antidote for the child should be readily available.

Breastfeeding

Fentanyl passes into breast milk and may cause sedation and respiratory depression in the breast-fed child. Fentanyl should not be used by breastfeeding women and breast-feeding should not be restarted until at least 48 hours after the last administration of fentanyl.

Fertility

There are no clinical data on the effects of fentanyl on fertility.

4.7 Effects On Ability To Drive And Use Machines

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

However, opioid analgesics may impair the mental and/or physical ability required for driving or operating machinery.

Patients should be advised not to drive or operate machinery if they experience somnolence, dizziness, or visual disturbance or other adverse reactions which can impair their ability to drive or operate machinery.

4.8 Undesirable Effects

Typical opioid adverse reactions are to be expected with PecFent. Frequently, these will cease or decrease in intensity with continued use of the medicinal product, as the patient is titrated to the most appropriate dose. However, the most serious adverse reactions are respiratory depression (potentially leading to apnoea or respiratory arrest), circulatory depression, hypotension and shock and all patients should be monitored for these.

The clinical studies of PecFent were designed to evaluate safety and efficacy in treating BTP and all patients were also on background opioid therapies, such as sustained-release morphine or transdermal fentanyl, for their persistent pain. Therefore it is not possible to definitively separate the effects of PecFent alone.

The adverse reactions considered to be at least possibly-related to treatment, from Phase II and III clinical studies were as follows (frequencies defined as very common (

	Common	Uncommon
Infections and infestations		Pneumonia Nasopharyngitis Pharyngitis Rhinitis
Blood and lymphatic system disorders		Neutropenia
Immune system disorders		Hypersensitivity
Metabolism and nutrition disorders		Dehydration Hyperglycaemia Decreased appetite Increased appetite
Psychiatric disorders	Disorientation	Drug abuse Delirium Hallucination Confusional state Depression Attention deficit/hyperactivity disorder Anxiety Euphoric mood Nervousness
Nervous system disorders	Dysgeusia Dizziness Somnolence Headache	Loss of consciousness Depressed level of consciousness Convulsion Ageusia Anosmia Memory impairment Parosmia Speech disorder Sedation Lethargy Tremor
Ear and labyrinth disorders		Vertigo
Cardiac disorders		Cyanosis
Vascular disorders		Cardiovascular insufficiency Lymphoedema Hypotension Hot flush
Respiratory, thoracic and mediastinal disorders	Epistaxis Rhinorrhoea Nasal discomfort	Upper airway obstruction Pharyngolaryngeal pain Rhinalgia Nasal mucosal disorder Cough Dyspnoea Sneezing Upper respiratory tract congestion Nasal congestion Intranasal hypoaesthesia Throat irritiation Postnasal drip Nasal dryness
Gastrointestinal disorders	Vomiting Nausea Constipation	Intestinal perforation Peritonitis Oral hypoaesthesia Oral paraesthesia Diarrhoea Retching Abdominal pain Tongue disorder Mouth ulceration Dyspepsia Dry mouth
Skin and subcutaneous tissue disorders	Pruritus	Hyperhydrosis Urticaria
Musculoskeletal and connective tissue disorders		Arthralgia Muscle twitching
Renal and urinary disorders		Anuria Dysuria Proteinuria Urinary hesitation
Reproductive system and breast disorders		Vaginal haemorrhage
General disorders and administration site conditions		Non-cardiac chest pain Asthenia Chills Face oedema Peripheral oedema Gait disturbance Pyrexia Fatigue Malaise Thirst
Investigations		Platelet count decreased Weight increased
Injury, poisoning and procedural complications		Fall Intentional drug misuse Medication error

4.9 Overdose

The symptoms of fentanyl overdose via the nasal route are expected to be similar in nature to those of intravenous fentanyl and other opioids, and are an extension of its pharmacological actions, with the most serious significant effect being respiratory depression.

Immediate management of opioid overdose includes ensuring a patent airway, physical and verbal stimulation of the patient, assessment of the level of consciousness, ventilatory and circulatory status, and assisted ventilation (ventilatory support) if necessary.

For treatment of overdose (accidental ingestion) in the opioid-naïve person, intravenous access should be obtained and naloxone or other opioid antagonists should be employed as clinically indicated. The duration of respiratory depression following overdose may be longer than the effects of the opioid antagonist's action (e.g. the half life of naloxone ranges from 30 to 81 minutes) and repeated administration may be necessary. Consult the Summary of Product Characteristics of the individual opioid antagonist for details about such use.

For treatment of overdose in opioid-maintained patients, intravenous access should be obtained. The judicious use of naloxone or another opioid antagonist may be warranted in some instances, but it is associated with the risk of precipitating an acute withdrawal syndrome.

It should be noted that although statistically significant increases in C_max levels were seen following a second dose of PecFent given either one or two hours after the initial dose, this increase is not considered to be large enough to suggest that clinically concerning accumulation or over-exposure would occur, providing a wide safety margin for the recommended dose interval of four hours.

Although muscle rigidity interfering with respiration has not been seen following the use of PecFent, this is possible with fentanyl and other opioids. If it occurs, it should be managed by the use of assisted ventilation, by an opioid antagonist, and as a final alternative, by a neuromuscular blocking agent.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Analgesics; phenylpiperidine derivatives; ATC code: N02A-B03.

Mechanism of action

Fentanyl is an opioid analgesic, interacting predominantly with the opioid µ-receptor. Its primary therapeutic actions are analgesia and sedation. Secondary pharmacological effects are respiratory depression, bradycardia, hypothermia, constipation, miosis, physical dependence and euphoria.

Pharmacodynamic effects

A double-blind, randomised, placebo-controlled crossover study has been conducted in which 114 patients who experienced on average 1 to 4 episodes of break through pain (BTP) per day while taking maintenance opioid therapy were entered into an initial open-label titration phase in order to identify an effective dose of PecFent (Study CP043). The patients entering the double-blind phase treated up to 10 episodes of BTP with either PecFent (7 episodes) or placebo (3 episodes) in a random order.

Of the patients entering the titration phase, only 7 (6.1 %) were unable to be titrated to an effective dose due to lack of efficacy and 6 (5.3 %) withdrew due to adverse events.

The primary endpoint was the comparison between the summed pain intensity difference at 30 minutes after dosing (SPID₃₀), which was 6.57 in the PecFent-treated episodes compared to 4.45 for placebo (p<0.0001 ). The SPID for PecFent-treated episodes was also significantly different to placebo at 10 15, 45 and 60 minutes after administration.

The mean pain intensity scores (73 patients) for all PecFent-treated episodes (459 episodes) compared to those treated with placebo (200 episodes) were significantly lower at 5, 10, 15, 30, 45 and 60 minutes following administration (see Figure 1).

Figure 1: Mean (± SE) Pain Intensity Scores at Each Time Point (mITT Population)

The superior efficacy of PecFent over placebo was supported by data from secondary endpoints including the number of BTP episodes with clinically meaningful pain relief, defined as a reduction in pain intensity score of at least 2 (Figure 2).

Figure 2: Clinically Meaningful Pain Relief – PecFent vs placebo: % Patients' Episodes With

In a double-blind, randomized comparator-controlled study (Study 044) of similar design to Study 043 conducted in opioid-tolerant patients with breakthrough cancer pain on stable doses of regularly scheduled opioids, PecFent was shown to be superior to immediate-release morphine sulfate (IRMS). Superiority was demonstrated by the primary endpoint, Pain Intensity Difference within 15 minutes, which was 3.02 in patients treated with PecFent compared to 2.69 in patients treated with IRMS (p=0.0396).

In a long-term, open-label, safety study (Study 045), 355 patients entered the 16-week treatment phase, during which 42,227 episodes of breakthrough cancer pain (BTP) were treated with PecFent. One hundred of these patients continued treatment for up to 26 months in an extension phase. Of the 355 patients treated in the open-label treatment phase, 90 % required no increase in dose.

In the randomised, placebo-controlled study (CP043) 9.4% of 459 PecFent-treated BTP episodes in 73 patients required use of any further (rescue) medicinal products within 60 minutes of dosing. During the longer-term, open-label study (CP045) this was 6.0 % of 42,227 episodes in 355 patients treated with PecFent during up to 159 days of treatment.

5.2 Pharmacokinetic Properties

General introduction

Fentanyl is highly lipophilic and can be absorbed very rapidly through the nasal mucosa and more slowly by the gastrointestinal route. It is subject to first pass hepatic and intestinal metabolism and the metabolites do not contribute to fentanyl's therapeutic effects.

PecFent utilises the PecSys nasal drug delivery system to modulate the delivery and absorption of fentanyl. The PecSys system allows the product to be sprayed into the front area of the nasal cavity as a fine mist of droplets, which gel on contact with the calcium ions present in the nasal mucosa. Fentanyl diffuses from the gel and is absorbed through the nasal mucosa; this gel-modulated absorption of fentanyl restrains the peak in plasma concentration (C_max) whilst allowing the attainment of an early time to that peak (T_max).

The effect of renal or hepatic impairment on the pharmacokinetics of PecFent has not been studied.

Absorption

In a pharmacokinetic study comparing PecFent (100, 200, 400 and 800 micrograms) with oral transmucosal fentanyl citrate (OTFC, 200 micrograms), fentanyl was shown to be rapidly absorbed following single dose intranasal administration of PecFent, with median T_max ranging from 15 to 21 minutes (T_max for OTFC was approximately 90 minutes). The variability of the pharmacokinetics of fentanyl was considerable following treatment with both PecFent and OTFC. Relative bioavailability of fentanyl from the PecFent treatment compared to the 200 microgram OTFC was approximately 120 %.

The main pharmacokinetic parameters are shown in the following table.

Pharmacokinetic parameters in adult subjects receiving PecFent and OTFC

Pharmacokinetic parameters (mean (%CV))	PecFent	OTFC
100 micrograms	200 micrograms	400 micrograms	800 micrograms	200 micrograms
Tmax (hours)*	0.33 (0.08-1.50)	0.25 (0.17-1.60)	0.35 (0.25-0.75)	0.34 (0.17-3.00)	1.50 (0.50-8.00)
Cmax (pg/ml)	351.5 (51.3)	780.8 (48.4)	1552.1 (26.2)	2844.0 (56.0)	317.4 (29.9)
AUC (pg.hour/ml)	2460.5 (17.9	4359.9 (29.8)	7513.4 (26.7)	17272 (48.9)	3735.0 (32.8)
t1/2 (hour)	21.9 (13.6)	24.9 (51.3)	15.0 (24.7)	24.9 (92.5)	18.6 (31.4)

*Data for T_max presented as median (range).

The curves for each dose level are similar in shape with increasing dose levels producing increasing plasma fentanyl levels. Dose-proportionality was demonstrated for C_max and area under the curve (AUC) in the dose range 100 micrograms to 800 micrograms (see Figure 3). If switching to PecFent from another fentanyl product for BTP, independent dose titration with PecFent is required as the bioavailability between products differs significantly.

Figure 3: Mean plasma fentanyl concentrations following single doses of PecFent and OTFC in healthy subjects

A pharmacokinetic study was conducted to evaluate the absorption and tolerability of a single dose of PecFent in patients with pollen-induced seasonal allergic rhinitis, comparing the un-challenged, acutely challenged (rhinitic) and acutely challenged and then treated with oxymetazoline, states.

There was no clinically significant effect of acute rhinitis on C_max, T_max or overall exposure to fentanyl, comparing the unchallenged with the acutely challenged states. Following treatment of the acute rhinitic state with oxymetazoline, there were reductions in C_max and exposure, and increases in T_max that were statistically, and possibly clinically, significant.

Distribution

Fentanyl is highly lipophilic and is well distributed beyond the vascular system, with a large apparent volume of distribution. Animal data have shown that, following absorption, fentanyl is rapidly distributed to the brain, heart, lungs, kidneys and spleen followed by a slower redistribution to muscles and fat.

The plasma protein binding of fentanyl is 80 – 85 %. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The free fraction of fentanyl increases with acidosis.

Biotransformation

The metabolic pathways following nasal administration of PecFent have not been characterised in clinical studies. Fentanyl is metabolised in the liver to norfentanyl by cytochrome CYP3A4 isoform. Norfentanyl is not pharmacologically active in animal studies. It is more than 90 % eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites.

Elimination

Disposition of fentanyl following intranasal administration of PecFent has not been characterised in a mass balance study. Less than 7 % of an administered dose of fentanyl is excreted unchanged in the urine and only about 1 % is excreted unchanged in the faeces. The metabolites are mainly excreted in the urine, while faecal excretion is less important.

The total plasma clearance of fentanyl following intravenous administration is approximately 42 L/h.

Linearity/non-linearity

Dose-proportionality was demonstrated for C_max and AUC in the dose range 100 micrograms to 800 micrograms.

5.3 Preclinical Safety Data

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

Embryo-foetal developmental toxicity studies conducted in rats and rabbits revealed no compound-induced malformations or developmental variations when administered during the period of organogenesis.

In a fertility and early embryonic development study in rats, a male-mediated effect was observed at high doses (300 mcg/kg/day, s.c.) and is consistent with the sedative effects of fentanyl in animal studies.

In studies on pre and postnatal development in rats the survival rate of offspring was significantly reduced at doses causing severe maternal toxicity. Further findings at maternally toxic doses in F1 pups were delayed physical development, sensory functions, reflexes and behaviour. These effects could either be indirect effects due to altered maternal care and/or decreased lactation rate or a direct effect of fentanyl on the pups.

Carcinogenicity studies (26-week dermal alternative bioassay in Tg.AC transgenic mice; two-year subcutaneous carcinogenicity study in rats) did not induce any findings indicative of oncogenic potential.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Pectin (E440)

Mannitol (E421)

Phenylethyl alcohol

Propyl hydroxybenzoate (E216)

Sucrose

Hydrochloric acid (0.36%) or sodium hydroxide (for pH adjustment)

Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years

After first use: 14 days

After last actuation of the pump: 5 days

The patient should be advised to write the date of first use in the space provided on the label of the child resistant container

6.4 Special Precautions For Storage

Do not store above 25 °C.

Do not freeze.

Keep the bottle in the child resistant container in order to protect from light.

Store the bottle in the child resistant container at all times, even when finished.

6.5 Nature And Contents Of Container

Bottle (clear Type I glass) with an attached metering pump incorporating an audible dose and a protective cap. Packed in a clam-shell-like child resistant container.

Each bottle contains 1.55 ml ensuring delivery of 8 full sprays.

Bottles in their child resistant containers are supplied in cartons containing 1, 4 or 12 bottles.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Partially used PecFent bottles may contain enough medicine to be harmful or life-threatening to a child. Even if there is little or no medicine left in the bottle, PecFent must be disposed of properly, according to the following steps:

• Patients and caregivers must be instructed to properly dispose of all unused, partially used and used PecFent bottles. The patient should be instructed how to do this correctly.

• If there are any unwanted therapeutic sprays remaining in the bottle, instruct the patient to expel these by aiming the spray away from themselves (and any other people or animals) until the red number “8” appears in the counting window and there are no more full therapeutic sprays obtainable from the bottle.

• After the counter has advanced to “8”, the patient should continue to push down on the finger grips (there will be some increased resistance) a total of four times in order to expel any residual medicine from the bottle.

• After the 8 therapeutic sprays have been emitted, the patient will not hear a click and the counter will not advance beyond “8”; further sprays emitted will not be full sprays and should not be used therapeutically.

As soon as PecFent is no longer needed, patients and members of their household must be advised to systematically dispose of any bottles remaining from a prescription as soon as possible by returning them to their child-resistant container and discarding them, according to local requirements or by returning them to the pharmacy.

7. Marketing Authorisation Holder