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Wednesday, October 19, 2016

Navelbine 80mg Soft Capsule

1. Name Of The Medicinal Product

NAVELBINE® 80 mg soft capsule

2. Qualitative And Quantitative Composition

Each soft capsule contains 80mg vinorelbine as tartrate

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Soft capsule.

Pale yellow soft capsule printed N80.

4. Clinical Particulars

4.1 Therapeutic Indications

As a single agent or in combination for:

• The first line treatment of stage 3 or 4 non small cell lung cancer.

• The treatment of advanced breast cancer stage 3 and 4 relapsing after or refractory to an anthracycline containing regimen.

4.2 Posology And Method Of Administration

In adult patients

As a single agent, the recommended regimen is:

First three administrations

60mg/m² of body surface area, administered once weekly

Subsequent administrations

Beyond the third administration, it is recommended to increase the dose of Navelbine to 80mg/m² once weekly except in those patients for whom the neutrophil count dropped once below 500/mm³ or more than once between 500 and 1000/mm³ during the first three administrations at 60mg/m².

Neutrophil count during the first 3 administrations of 60 mg/m²/week

Neutrophils

> 1000

Neutrophils

(1 episode)

Neutrophils

(2 episodes)

Neutrophils

< 500

Recommended dose starting with the 4^th administration

Dose modification

For any administration planned to be given at 80mg/m², if the neutrophil count is below 500/mm³ or more than once between 500 and 1000 / mm³ the administration should be delayed until recovery and the dose reduced from 80 to 60mg/m² per week during the 3 following administrations.

If the neutrophil count is below 1500 /mm³ and/or the platelet count below 100000/mm³, then the treatment should be delayed until recovery.

Neutrophil countbeyond the 4^th administration of 80 mg/m²/week

Neutrophils

> 1000

Neutrophils

(1 episode)

Neutrophils

(2 episodes)

Neutrophils

< 500

Recommended dose starting with the next administration

It is possible to re-escalate the dose from 60 to 80 mg/m² per week if the neutrophil count did not drop below 500/mm³ or more than once between 500 and 1000/mm³ during 3 administrations given at 60 mg/m² according to the rules previously defined for the first 3 administrations.

For combination regimens, the dose and schedule will be adapted to the treatment protocol.

Based on clinical studies, the oral dose of 80 mg/m² was demonstrated to correspond to 30 mg/m² of the iv form and 60 mg/m² to 25 mg/m².

This has been the base for combination regimens alternating iv and oral forms improving patient convenience.

Capsules of different strengths (20, 30, 80 mg) are available in order to choose the adequate combination for the right dosage.

The following table gives the dose required for appropriate ranges of body surface area (BSA).

60 mg/m²

80 mg/m²

BSA (m²)

Dose (mg)

0.95 to 1.04

1.05 to 1.14

1.15 to 1.24

1.25 to 1.34

1.35 to 1.44

1.45 to 1.54

1.55 to 1.64

1.65 to 1.74

1.75 to 1.84

1.85 to 1.94

100

110

120

100

110

120

130

140

150

160

Even for patients with BSA > 2 m² the total dose should never exceed 120 mg per week at 60 mg /m² and 160 mg per week at 80 mg/m².

Administration

Navelbine must be given strictly by the oral route.

Navelbine must be swallowed whole with water, without chewing, sucking or dissolving the capsule.

It is recommended to administer the capsule with some food.

Administration in the elderly

Clinical experience has not detected any significant differences among elderly patients with regard to the response rate, although greater sensitivity in some of these patients cannot be excluded. Age does not modify the pharmacokinetics of vinorelbine: see section 5.2.

Administration in children

Safety and efficacy in children have not been established and administration is therefore not recommended.

Administration in patients with liver insufficiency

Navelbine can be administered at the standard dose of 60 mg/m²/week in patients with mild liver impairment (bilirubin < 1.5 x ULN, and ALAT and/or ASAT from 1.5 to 2.5 x ULN). In patients with moderate liver impairment (bilirubin from 1.5 to 3 x ULN, whatever the levels of ALAT and ASAT), Navelbine should be administered at a dose of 50 mg/m²/week. The administration of Navelbine in patients with severe hepatic impairment is contra-indicated: see sections 4.3, 4.4, 5.2.

Administration in patients with renal insufficiency

Given the minor renal excretion, there is no pharmacokinetic justification for reducing the dose of Navelbine in patients with serious renal insufficiency: see sections 4.4, 5.2.

Specific instructions must be observed for handling Navelbine: see section 6.6

4.3 Contraindications

- Known hypersensitivity to vinorelbine or other vinca-alkaloids or to any of the constituents.

- Disease significantly affecting absorption

- Previous significant surgical resection of stomach or small bowel.

- Neutrophil count < 1500/mm³ or severe infection current or recent (within 2 weeks).

- Platelet count < 100000/mm³

- Severe hepatic insufficiency

- Pregnancy: see section 4.6

- Lactation: see section 4.6

- Patients requiring long-term oxygen therapy

- In combination with yellow fever vaccine: see section 4.5

4.4 Special Warnings And Precautions For Use

Special warnings

Navelbine should be prescribed by a physician who is experienced in the use of chemotherapy with facilities for monitoring cytotoxic drugs.

If the patient chews or sucks the capsule by error, the liquid is an irritant. Proceed to mouth rinses with water or preferably a normal saline solution.

In the event of the capsule being cut or damaged, the liquid content is an irritant, and so may cause damage if in contact with skin, mucosa or eyes. Damaged capsules should not be swallowed and should be returned to the pharmacy or to the doctor in order to be properly destroyed. If any contact occurs, immediate thorough washing with water or preferably with normal saline solution should be undertaken.

In the case of vomiting within a few hours after drug intake, do not re-administer. Supportive treatment such as metoclopramide or 5HT₃ antagonists (e.g. ondansetron, granisetron) may reduce the occurrence of this: see section 4.5. Navelbine soft capsule is associated with a higher incidence of nausea/vomiting than the intravenous formulation. Primary prophylaxis with antiemetics and administration of the capsules with some food is recommended as this has also been shown to reduce the incidence of nausea and vomiting: see section 4.2.

Patients receiving concomitant morphine or opioid analgesics: laxatives and careful monitoring of bowel mobility are recommended. Prescription of laxatives may be appropriate in patients with prior history of constipation.

Due to sorbitol content, patients with rare hereditary problems with fructose intolerance should not take the capsules.

Close haematological monitoring must be undertaken during treatment (determination of haemoglobin level and the leucocyte, neutrophil and platelet counts on the day of each new administration).

Dosing should be determined by haematological status:

- If the neutrophil count is below 1500 /mm³ and/or the platelet count is below 100000/mm³, then the treatment should be delayed until recovery.

- For dose escalation from 60 to 80 mg/m² per week, after the third administration: see section 4.2.

- For the administrations given at 80mg/m², if the neutrophil count is below 500/mm³ or more than once between 500 and 1000 /mm³, then the treatment should be delayed until recovery. The administration should not only be delayed but also reduced to 60mg/m² per week. It is possible to reescalate the dose from 60 to 80 mg/m² per week: see section 4.2.

During clinical trials where treatments were initiated at 80 mg/m², a few patients developed excessive neutropenic complications including those with a poor performance status. Therefore it is recommended that the starting dose should be 60 mg/m² escalating to 80 mg/m² if the dose is tolerated as described in section 4.2.

If patients present signs or symptoms suggestive of infection, a prompt investigation should be carried out.

Special precautions for use

Special care should be taken when prescribing for patients with:

- history of ischemic heart disease: see section 4.8

- poor performance status

Navelbine should not be given concomitantly with radiotherapy if the treatment field includes the liver.

This product is specifically contra-indicated with yellow fever vaccine and its concomitant use with other live attenuated vaccines is not recommended: see section 4.3.

Caution must be exercised when combining Navelbine and strong inhibitors or inducers of CYP3A4 (see section 4.5), and its combination with phenytoin (like all cytotoxics) and with itraconazole (like all vinca alkaloids) is not recommended.

Oral Navelbine was studied in patients with liver impairment at the following doses:

- 60 mg/m² in 7 patients with mild liver impairment (bilirubin < 1.5 x ULN, and ALAT and/or ASAT from 1.5 to 2.5 x ULN);

- 50 mg/m² in 6 patients with moderate liver impairment (bilirubin from 1.5 to 3 x ULN, whatever the levels of ALAT and ASAT).

Total clearance of vinorelbine was neither modified between mild and moderate liver impairment nor was it altered in hepatically impaired patients when compared with clearance in patients with normal liver function.

Oral Navelbine was not studied in patients with severe hepatic impairment therefore its use is contra-indicated in these patients: see sections 4.2, 4.3, 5.2.

As there is a low level of renal excretion there is no pharmacokinetic rationale for reducing the dose of Navelbine in patients with impaired kidney function: see sections 4.2, 5.2.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use contraindicated

Yellow fever vaccine: as with all cytotoxics, risk of fatal generalised vaccine disease: see section 4.3.

Concomitant use not recommended

Live attenuated vaccines: (for yellow fever vaccine, see concomitant use contraindicated) as with all cytotoxics, risk of generalised vaccine disease, possibly fatal. This risk is increased in patients already immunodepressed by their underlying disease. It is recommended to use an inactivated vaccine when one exists (e.g. poliomyelitis): see section 4.4

Phenytoin: as with all cytotoxics, risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic drug or risk of toxicity enhancement or loss of efficacy of the cytotoxic drug due to increased hepatic metabolism by phenytoin.

Itraconazole: as with all vinca-alkaloids, increased neurotoxicity of vinca-alkaloids due to the decrease of their hepatic metabolism.

Concomitant use to take into consideration

Cisplatin: There is no mutual pharmacokinetic interaction when combining Navelbine with cisplatin over several cycles of treatment. However, the incidence of granulocytopenia associated with Navelbine use in combination with cisplatin is higher than associated with Navelbine single agent.

Mitomycin C: risk of bronchospasm and dyspnoea are increased, in rare case an interstitial pneumonitis was observed.

Ciclosporin, tacrolimus: excessive immunodepression with risk of lymphoproliferation.

As vinca-alkaloids are known as substrates for P-glycoprotein, and in the absence of specific study, caution should be exercised when combining Navelbine with strong modulators of this membrane transporter.

The combination of NAVELBINE with other drugs with known bone marrow toxicity is likely to exacerbate the myelosuppressive adverse effects.

No clinically significant pharmacokinetic interaction was observed when combining Navelbine with several other chemotherapeutic agents (paclitaxel, docetaxel, capecitabine and oral cyclophosphamide).

As CYP3A4 is mainly involved in the metabolism of vinorelbine, combination with strong inhibitors of this isoenzyme (e.g. azole antifungals such as ketoconazole and itraconazole) could increase blood concentrations of vinorelbine and combination with strong inducers of this isoenzyme (e.g. rifampicin, phenytoin) could decrease blood concentrations of vinorelbine.

Anti-emetic drugs such as 5HT₃ antagonists (e.g. ondansetron, granisetron) do not modify the pharmacokinetics of Navelbine soft capsules (see section 4.4).

Anticoagulant treatment: as with all cytotoxics, the frequency of INR (International Normalised Ratio) monitoring should be increased due to the potential interaction with oral anticoagulants and increased variability of coagulation in patients with cancer.

Food does not modify the pharmacokinetics of vinorelbine.

4.6 Pregnancy And Lactation

Pregnancy

Navelbine is suspected to cause serious birth effects when administered during pregnancy: see section 5.3.

Navelbine is contra-indicated in pregnancy: see section 4.3.

In case of a vital indication for treatment with Navelbine during pregnancy a medical consultation concerning the risk of harmful effects for the child should be conducted. If pregnancy occurs during treatment genetic counseling should be offered.

Women of child-bearing potential

Women of child-bearing potential must use effective contraception during treatment and up to 3 months after treatment: see section 4.3

Lactation

It is unknown whether vinorelbine is excreted in human breast milk.

The excretion of vinorelbine in milk has not been studied in animal studies.

A risk to the suckling child cannot be excluded therefore breast feeding must be discontinued before starting treatment with Navelbine: see section 4.3.

Fertility

Men being treated with Navelbine are advised not to father a child during and minimally up to 3 months after treatment: see section 4.3.

Prior to treatment advice should be sought for conserving sperm due to the chance of irreversible infertility as a consequence of treatment with vinorelbine.

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 but on the basis of the pharmacodynamic profile vinorelbine does not affect the ability to drive and use machines. However, caution is necessary in patients treated with vinorelbine considering some adverse effects of the drug: see section 4.8.

4.8 Undesirable Effects

The overall reported frequency of undesirable effects was determined from clinical studies in 316 patients (132 patients with non small cell lung cancer and 184 patients with breast cancer) who received the recommended regimen of Navelbine (first three administrations at 60mg/m²/week followed by 80mg/m²/week).

Adverse reactions reported are listed below, by system organ and by frequency.

Additional Adverse reactions from Post Marketing experience has been added according to the MedDRA classification with the frequency Not known.

The reactions were described using the NCI common toxicity criteria

Very common
Common
Uncommon
Rare
Very rare	<1/10,000
Not known	Post marketing reports

Undesirable effects reported with Navelbine soft capsule:

Pre-marketing experience:

The most commonly reported adverse drug reactions are bone marrow depression with neutropenia, anaemia and thrombocytopenia, gastrointestinal toxicity with nausea, vomiting, diarrhoea, stomatitis and constipation. Fatigue and fever were also reported very commonly.

Post-marketing experience:

Navelbine soft capsule is used as single agent or in combination with other chemotherapeutic agents or targeted therapy agents such as cisplatin, capecitabine, carboplatin, epirubicin, trastuzumab, erlotinib, sorafenib.

The most commonly system organ classes involved during post-marketing experience are: 'Blood and lymphatic system disorders', 'Gastrointestinal disorders', 'Infections and infestations' and 'General disorders and administration site conditions'. This information is consistent with the pre-marketing experience.

Infections and infestations
Very common:	Bacterial, viral or fungal infections without neutropenia at different sites: G1-4: 12.7%; G3-4: 4.4%,
Common:	Bacterial, viral or fungal infections resulting from bone marrow depression and/or immune system compromise (neutropenic infections) are usually reversible with an appropriate treatment. Neutropenic infection: G3-4: 3.5%.
Not known:	Neutropenic sepsis.

Blood and lymphatic disorders

Very common:

Bone marrow depression resulting mainly in neutropenia G1-4: 71.5%; G3: 21.8%; G4: 25.9%, is reversible and is the dose limiting toxicity.

Leucopenia: G1-4: 70.6 %; G3: 24.7 %; G4: 6%.

Anaemia: G1-4: 67.4 %; G3-4: 3.8%.

Thrombocytopenia: G1-2: 10.8%.

Common:

G4 Neutropenia associated with fever over 38°C including febrile neutropenia 2.8%.

Metabolism and nutrition disorders
Not known:	Severe hyponatraemia.

Psychiatric disorders
Common:	Insomnia : G1-2: 2.8%.

Nervous system disorders
Very common:	Neurosensory disorders: G1-2: 11.1%, generally limited to loss of tendon reflexes and infrequently severe.
Common:	Neuromotor disorders: G1-4: 9.2%; G3-4:1.3%. Headache: G1-4: 4.1%, G3-4: 0.6%. Dizziness: G1-4: 6%; G3-4: 0.6%. Taste disorders: G1-2:3.8%.
Uncommon:	Ataxia grade 3: 0.3%.

Eye disorders
Common:	Visual disorders: G1-2: 1.3%.

Cardiac disorders
Not known:	Myocardial infarction in patients with cardiac medical history or cardiac risk factors.

Vascular disorders

Common:

Hypertension: G1-4: 2.5%; G3-4: 0.3%.

Hypotension: G1-4: 2.2%; G3-4: 0.6%.

Respiratory system, thoracic and mediastinal disorders

Common:

Dyspnoea: G1-4: 2.8%; G3-4: 0.3%.

Cough: G1-2: 2.8%.

Gastrointestinal disorders
Very Common:	Nausea: G1-4: 74.7% ; G3-4: 7.3%; Vomiting: G1-4: 54.7%; G 3-4: 6.3%, Supportive treatment such as 5HT₃ antagonists (ondansetron) may reduce the occurrence of nausea and vomiting: see section 4.4. Diarrhoea: G1-4: 49.7%; G3-4: 5.7%, Anorexia: G 1-4: 38.6%; G 3-4: 4.1%, Stomatitis: G1-4:10.4%; G3-4: 0.9%, Abdominal pain: G1-4: 14.2%, Constipation: G1-4: 19%; G3-4: 0.9%, Prescription of laxatives may be appropriate in patients with prior history of constipation and/or who receive concomitant treatment with opioid analgesics: see section 4.4. Gastric disorders: G1-4: 11.7%.
Common:	Oesophagitis: G1-3: 3.8%; G3: 0.3%, Dysphagia: G1-2: 2.3%.
Uncommon:	Paralytic ileus: G3-4: 0.9% [rarely fatal], treatment may be resumed after recovery of normal bowel mobility.
Not known:	Gastro-intestinal bleeding.

Hepatobiliary disorders
Common:	Hepatic disorders: G1-2: 1.3%.

Skin and subcutaneous tissue disorders
Very common:	Alopecia usually mild in nature G1-2: 29.4%, may occur.
Common:	Skin reactions: G1-2: 5.7%.

Musculoskeletal and connective tissue disorders
Common:	Arthralgia including jaw pain, Myalgia: G1-4: 7 %, G3-4: 0.3%.

Renal and urinary disorders

Common:

Dysuria: G1-2: 1.6%.

Other genitourinary disorders: G1-2: 1.9%.

General disorders and administration site conditions

Very common:

Fatigue/malaise: G1-4: 36.7%; G3-4: 8.5%.

Fever: G1-4: 13.0%, G3-4: 12.1%.

Common:

Pain including pain at the tumour site: G1-4: 3.8%, G3-4: 0.6%.

Chills: G1-2: 3.8%.

Investigations
Very common:	Weight loss: G1-4: 25%, G3-4: 0.3%.
Common:	Weight gain: G1-2: 1.3%.

Undesirable effects with Navelbine, concentrate for infusion:

Some undesirable effects were observed with Navelbine, concentrate for solution for infusion during pre- and post-marketing experience which were not reported with Navelbine soft capsule.

In order to provide the complete information and to further the safety of use of Navelbine soft capsule, these effects are presented below:

Infections and infestations
Uncommon:	Septicaemia [very rarely fatal]

Immune system disorders
Not known:	Systemic allergic reactions were reported as anaphylaxis, anaphylactic shock or anaphylactoïd type reaction.

Endocrine disorders
Not known:	Inappropriate antidiuretic hormone secretion (SIADH).

Vascular disorders
Uncommon:	Flushing and peripheral coldness
Rare:	Severe hypotension, collapse.

Respiratory system, thoracic and mediastinal disorders
Uncommon:	Bronchospasm may occur as with other vinca alkaloids.
Rare:	Interstitial pneumonopathy has been reported in particular in patients treated with Navelbine in combination with mitomycin.

Gastrointestinal disorders
Rare:	Pancreatitis.

4.9 Overdose

Symptoms

Overdosage with Navelbine soft capsules could produce bone marrow hypoplasia sometimes associated with infection, fever, paralytic ileus and hepatic disorders.

Emergency procedure

General supportive measures together with blood transfusion, growth factors, and broad spectrum antibiotic therapy should be instituted as deemed necessary by the physician. A close monitoring of hepatic function recommended.

Antidote

There is no known antidote for overdosage of Navelbine.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Vinca alkaloïds and analogues (ATC Code: L01C A04)

Navelbine is a antineoplastic drug of the vinca alkaloid family but unlike all the other vinca alkaloids, the catharantine moiety of vinorelbine has been structurally modified. At the molecular level, it acts on the dynamic equilibrium of tubulin in the microtubular apparatus of the cell. It inhibits tubulin polymerization and binds preferentially to mitotic microtubules, affecting axonal microtubules at high concentrations only. The induction of tubulin spiralization is less than that produced by vincristine.

Navelbine blocks mitosis at G2-M, causing cell death in interphase or at the following mitosis.

Safety and efficacy of Navelbine in paediatric patients have not been established. Clinical data from two single-arm Phase II studies using intravenous vinorelbine in 33 and 46 paediatric patients with recurrent solid tumours, including rhabdomyosarcoma, other soft tissue sarcoma, Ewing sarcoma, liposarcoma, synovial sarcoma, fibrosarcoma, central nervous system cancer, osteosarcoma, neuroblastoma at doses of 30 to 33.75mg/m² D1 and D8 every 3 weeks or once weekly for 6 weeks every 8 weeks showed no meaningful clinical activity. The toxicity profile was similar to that reported in adult patients (see section 4.2).

5.2 Pharmacokinetic Properties

Pharmacokinetic parameters of vinorelbine were evaluated in blood.

Absorption

After oral administration, vinorelbine is rapidly absorbed and the T_max is reached between 1.5 to 3 h with a blood concentration peak (C_max) of approximately 130 ng/ml after a dose of 80 mg/m².

Absolute bioavailability is approximately 40% and a simultaneous intake of food does not alter the exposure to vinorelbine.

Oral vinorelbine at 60 and 80 mg/m² leads to blood exposure comparable to that achieved with intravenous vinorelbine at 25 and 30 mg/m², respectively.

The blood exposure to vinorelbine increases proportionally with the dose up to 100mg/m². Interindividual variability of the exposure is similar after administration by intravenous and oral routes.

Distribution

The steady-state volume of distribution is large, on average 21.2 l.kg^-1(range: 7.5 - 39.7 l.kg^-1), which indicates extensive tissue distribution.

Binding to plasma proteins is weak (13.5%), vinorelbine binds strongly to blood cells and especially to platelets (78%).

There is a significant uptake of vinorelbine in lungs, as assessed by pulmonary surgical biopsies which showed concentration up to a 300- fold higher concentration than in serum. Vinorelbine is not found in the central nervous system.

Biotransformation

All metabolites of vinorelbine are formed by CYP3A4 isoform of cytochromes P450, except 4-O-deacetylvinorelbine likely to be formed by carboxylesterases. 4-O-deacetylvinorelbine is the only active metabolite and the main one observed in blood.

Neither sulfate nor glucuronide conjugates are found.

Elimination

The mean terminal half-life of vinorelbine is around 40 hours. Blood clearance is high, approaching hepatic blood flow, and is 0.72 l.h^-1.kg^-1 (range: 0.32-1.26 l.h^-1.kg^-1).

Renal elimination is low (<5 % of the dose administered) and consists mostly in parent compound. Biliary excretion is the predominant elimination route of both unchanged vinorelbine, which is the main recovered compound, and its metabolites.

Special patients groups

Renal and liver impairment:

The effects of renal dysfunction on the pharmacokinetics of vinorelbine have not been studied. However, dose reduction in case of reduced renal function is not indicated with vinorelbine due to the low level of renal elimination.

Pharmacokinetics of orally administered vinorelbine were not modified after administration of 60 mg/m² in 7 patients with mild liver impairment (bilirubin < 1.5 x ULN, and ALAT and/or ASAT from 1.5 to 2.5 x ULN) and of 50 mg/m² in 6 patients with moderate liver impairment (bilirubin from 1.5 to 3 x ULN, whatever the levels of ALAT and ASAT). Total clearance of vinorelbine was neither modified between mild and moderate impairment nor was it altered in hepatically impaired patients when compared with clearance in patients with normal liver function.

No data is available for patients with severe liver impairment therefore Navelbine is contra-indicated in these patients: see sections 4.2, 4.3 and 4.4.

Elderly patients

A study with oral vinorelbine in elderly patients (

Pharmacokinetics/Pharmacodynamic relationships

A strong relationship has been demonstrated between blood exposure and depletion of leucocytes or PMNs.

5.3 Preclinical Safety Data

Pre-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity.

Vinorelbine induced chromosome changes but was not mutagenic in Ames test. It is assumed that vinorelbine can cause mutagenic effects (induction of aneuploidy of polyploidy) in man.

In animal reproductive studies, vinorelbine was embryo-feto-lethal and teratogenic.

No haemodynamic effects were found in dogs receiving vinorelbine at maximal tolerated dose; only some minor, non significant disturbances of repolarisation were observed as with other vinca alkaloids tested.

No effect on the cardiovascular system was observed in primates receiving repeated doses of vinorelbine over 39 weeks.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Fill solution:

Ethanol, anhydrous

Water, purified

Glycerol

Macrogol 400

Shell capsule:

Gelatin

Glycerol 85%

Sorbitol/Sorbitan Anidrisorb 85/70)

Yellow iron oxide E172

Titanium dioxide E171

Triglycerides, medium chain

Phosal 53 MCT (Phosphatidylcholine; Glycerides; Ethanol, anhydrous)

Edible printing ink:

Cochineal extract E120

Hypromellose

Propylene glycol

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Store at 2° C - 8° C (in a refrigerator). Store in the original container.

6.5 Nature And Contents Of Container

Peel-push PVC/PVDC/ aluminium blister.

Pack size: 1 capsule

Nexium 20mg, 40mg Tablets

Nexium 20 mg and 40 mg
gastro-resistant tablets

esomeprazole

Please read all of this leaflet carefully before you start taking this medicine.

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

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.

If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

1. What Nexium is and what it is used for

2. Before you take Nexium

3. How to take Nexium

4. Possible side effects

5. How to store Nexium

6. Further information

What Nexium is and what it is used for

Nexium contains a medicine called esomeprazole. This belongs to a group of medicines called ‘proton pump inhibitors’. They work by reducing the amount of acid that your stomach produces.

Nexium is used to treat the following conditions:

‘Gastro-oesophageal reflux disease’ (GORD). This is where acid from the stomach escapes into the gullet (the tube which connects your throat to your stomach) causing pain, inflammation and heartburn.

Ulcers in the stomach or upper part of the gut (intestine) that are infected with bacteria called ‘Helicobacter pylori’. If you have this condition, your doctor may also prescribe antibiotics to treat the infection and allow the ulcer to heal.

Stomach ulcers caused by medicines called NSAIDs (Non-Steroidal Anti-Inflammatory Drugs). Nexium can also be used to stop stomach ulcers from forming if you are taking NSAIDs.

Too much acid in the stomach caused by a growth in the pancreas (Zollinger-Ellison syndrome).

Prolonged treatment after prevention of rebleeding of ulcers with intravenous Nexium.

Before you take Nexium

Do not take Nexium if:

You are allergic (hypersensitive) to esomeprazole or any of the other ingredients of this medicine (listed in Section 6: Further information).

You are allergic to other proton pump inhibitor medicines.

You are taking a medicine containing nelfinavir (used to treat HIV).

Do not take Nexium if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist before taking Nexium.

Take special care with Nexium

Check with your doctor or pharmacist before taking Nexium if:

You have severe liver problems.

You have severe kidney problems.

Nexium may hide the symptoms of other diseases. Therefore, if any of the following happen to you before you start taking Nexium or while you are taking it, talk to your doctor straight away:

You lose a lot of weight for no reason and have problems swallowing.

You get stomach pain or indigestion.

You begin to vomit food or blood.

You pass black stools (blood-stained faeces).

If you have been prescribed Nexium "on demand" you should contact your doctor if your symptoms continue or change in character.

Using other medicines

Please tell your doctor or pharmacist if you are taking, or have recently taken, any other medicines. This includes medicines that you buy without a prescription. This is because Nexium can affect the way some medicines work and some medicines can have an effect on Nexium.

Do not take Nexium Tablets if you are taking a medicine containing nelfinavir (used to treat HIV).

Tell your doctor or pharmacist if you are taking any of the following medicines:

Atazanavir (used to treat HIV).

Ketoconazole, itraconazole or voriconazole (used to treat infections caused by a fungus).

Citalopram, imipramine or clomipramine (used to treat depression).

Diazepam (used to treat anxiety, relax muscles or in epilepsy).

Phenytoin (used in epilepsy). If you are taking phenytoin, your doctor will need to monitor you when you start or stop taking Nexium.

Medicines that are used to thin your blood, such as warfarin. Your doctor may need to monitor you when you start or stop taking Nexium.

Cisapride (used for indigestion and heartburn).

If your doctor has prescribed the antibiotics amoxicillin and clarithromycin as well as Nexium to treat ulcers caused by Helicobacter pylori infection, it is very important that you tell your doctor about any other medicines you are taking.

Pregnancy and breast-feeding

Before taking Nexium, tell your doctor if you are pregnant or trying to get pregnant. Ask your doctor or pharmacist for advice before taking any medicine. Your doctor will decide whether you can take Nexium during this time.

It is not known if Nexium passes into breast milk. Therefore, you should not take Nexium if you are breastfeeding.

Driving and using machines

Nexium is not likely to affect you being able to drive or use any tools or machines.

Important information about some of the ingredients of Nexium

Nexium gastro-resistant tablets contain sucrose, which is a type of sugar. If you have been told by your doctor that you have an intolerance to some sugars, talk to your doctor before taking this medicine.

How to take Nexium

Always take Nexium exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

Nexium gastro-resistant tablets are not recommended for children less than 12 years old.

If you are taking this medicine for a long time, your doctor will want to monitor you (particularly if you are taking it for more than a year).

If your doctor has told you to take this medicine as and when you need it, tell your doctor if your symptoms change.

Taking this medicine

You can take your tablets at any time of the day.

You can take your tablets with food or on an empty stomach.

Swallow your tablets whole with a drink of water. Do not chew or crush the tablets. This is because the tablets contain coated pellets which stop the medicine from being broken down by the acid in your stomach. It is important not to damage the pellets.

What to do if you have trouble swallowing the tablets

If you have trouble swallowing the tablets:
- Put them into a glass of still (non-fizzy) water. Do not use any other liquids.
- Stir until the tablets break up (the mixture will not be clear). Then drink the mixture straight away or within 30 minutes. Always stir the mixture just before drinking it.
- To make sure that you have drunk all of the medicine, rinse the glass very well with half a glass of water and drink it. The solid pieces contain the medicine - do not chew or crush them.

If you cannot swallow at all, the tablet can be mixed with some water and put into a syringe. It can then be given to you through a tube directly into your stomach (‘gastric tube’).

How much to take

Your doctor will tell you how many tablets to take and how long to take them for. This will depend on your condition, how old you are and how well your liver works.

The usual doses are given below.

To treat heartburn caused by gastro-oesophageal reflux disease (GORD):

Adults and children aged 12 or above:

If your doctor has found that your food pipe (gullet) has been slightly damaged, the usual dose is one Nexium 40 mg gastro-resistant tablet once a day for 4 weeks. Your doctor may tell you to take the same dose for a further 4 weeks if your gullet has not yet healed.

The usual dose once the gullet has healed is one Nexium 20 mg gastro-resistant tablet once a day

If your gullet has not been damaged, the usual dose is one Nexium 20 mg gastro-resistant tablet each day. Once the condition has been controlled, your doctor may tell you to take your medicine as and when you need it, up to a maximum of one Nexium 20 mg gastro-resistant tablet each day.

If you have severe liver problems, your doctor may give you a lower dose.

To treat ulcers caused by Helicobacter pylori infection and to stop them coming back:

Adults aged 18 or above: the usual dose is one Nexium 20 mg gastro-resistant tablet twice a day for one week.

Your doctor will also tell you to take antibiotics called amoxicillin and clarithromycin.

To treat stomach ulcers caused by NSAIDs (Non-Steroidal Anti-Inflammatory Drugs):

Adults aged 18 and above: the usual dose is one Nexium 20 mg gastro-resistant tablet once a day for 4 to 8 weeks.

To prevent stomach ulcers if you are taking NSAIDs (Non-Steroidal Anti-Inflammatory Drugs):

Adults aged 18 and above: the usual dose is one Nexium 20 mg gastro-resistant tablet once a day.

To treat too much acid in the stomach caused by a growth in the pancreas (Zollinger-Ellison syndrome):

Adults aged 18 and above: the usual dose is one Nexium 40 mg gastro-resistant tablet twice a day.

Your doctor will adjust the dose depending on your needs and will also decide how long you need to take the medicine for. The maximum dose is 80 mg twice a day.

To be used as prolonged treatment after prevention of rebleeding of ulcers with intravenous Nexium:

Adults aged 18 and above: the usual dose is one Nexium 40 mg tablet once a day for 4 weeks.

If you take more Nexium than you should

If you take more Nexium than prescribed by your doctor, talk to your doctor or pharmacist straight away.

If you forget to take Nexium

If you forget to take a dose, take it as soon as you remember it. However, if it is almost time for your next dose, skip the missed dose.

Do not take a double dose (two doses at the same time) to make up for a forgotten dose.

Possible side effects

Like all medicines, Nexium can cause side effects, although not everybody gets them.

If you notice any of the following serious side effects, stop taking Nexium and contact a doctor immediately:

Sudden wheezing, swelling of your lips, tongue and throat or body, rash, fainting or difficulties in swallowing (severe allergic reaction).

Reddening of the skin with blisters or peeling. There may also be severe blisters and bleeding in the lips, eyes, mouth, nose and genitals. This could be ‘Stevens-Johnson syndrome’ or ‘toxic epidermal necrolysis’.

Yellow skin, dark urine and tiredness which can be symptoms of liver problems.

These effects are rare, affecting less than 1 in 1,000 people.

Other side effects include:

Common (affects less than 1 in 10 people)

Headache.

Effects on your stomach or gut: diarrhoea, stomach pain, constipation, wind (flatulence).

Feeling sick (nausea) or being sick (vomiting).

Uncommon (affects less than 1 in 100 people)

Swelling of the feet and ankles.

Disturbed sleep (insomnia).

Dizziness, tingling feelings such as “pins and needles”, feeling sleepy.

Spinning feeling (vertigo).

Dry mouth.

Changes in blood tests that check how the liver is working.

Skin rash, lumpy rash (hives) and itchy skin.

Rare (affects less than 1 in 1,000 people)

Blood problems such as a reduced number of white cells or platelets. This can cause weakness, bruising or make infections more likely.

Low levels of sodium in the blood. This may cause weakness, being sick (vomiting) and cramps.

Feeling agitated, confused or depressed.

Taste changes.

Eyesight problems such as blurred vision.

Suddenly feeling wheezy or short of breath (bronchospasm).

An inflammation of the inside of the mouth.

An infection called “thrush” which can affect the gut and is caused by a fungus.

Liver problems, including jaundice which can cause yellow skin, dark urine, and tiredness.

Hair loss (alopecia).

Skin rash on exposure to sunshine.

Joint pains (arthralgia) or muscle pains (myalgia).

Generally feeling unwell and lacking energy.

Increased sweating.

Very rare (affects less than 1 in 10,000 people)

Changes in blood count including agranulocytosis (lack of white blood cells)

Aggression.

Seeing, feeling or hearing things that are not there (hallucinations).

Severe liver problems leading to liver failure and inflammation of the brain.

Sudden onset of a severe rash or blistering or peeling skin. This may be associated with a high fever and joint pains (Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis).

Muscle weakness.

Severe kidney problems.

Enlarged breasts in men.

Nexium may in very rare cases affect the white blood cells leading to immune deficiency. If you have an infection with symptoms such as fever with a severely reduced general condition or fever with symptoms of a local infection such as pain in the neck, throat or mouth or difficulties in urinating, you must consult your doctor as soon as possible so that a lack of white blood cells (agranulocytosis) can be ruled out by a blood test.

It is important for you to give information about your medication at this time.

Do not be concerned by this list of possible side effects. You may not get any of them. If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How to store Nexium

Keep out of the reach and sight of children.

Do not store above 30°C.

Keep this medicine in the original container (blister) or keep the container tightly closed (bottle) in order to protect from moisture.

Do not take your tablets after the expiry date (EXP) shown on the carton, wallet pack or blister foil. The expiry date refers to the last day of that month.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines that are no longer required. These measures will help to protect the environment.

Further information

What Nexium contains

The active substance is esomeprazole. Nexium gastro-resistant tablets come in two strengths containing 20 mg or 40 mg of esomeprazole (as magnesium trihydrate).

The other ingredients are glycerol monostearate 40-55, hyprolose, hypromellose, iron oxide (reddish-brown, yellow) (E172), magnesium stearate, methacrylic acid ethyl acrylate copolymer (1:1) dispersion 30 per cent, microcrystalline cellulose, synthetic paraffin, macrogol, polysorbate 80, crospovidone, sodium stearyl fumarate, sugar spheres (sucrose and maize starch), talc, titanium dioxide (E171), triethyl citrate.

What Nexium looks like and contents of the pack

Nexium 20 mg gastro-resistant tablets are light pink with an 'AEH' on one side and 20 mg on the other side.

Nexium 40 mg gastro-resistant tablets are pink with an 'AEI' on one side and 40 mg on the other side.

Your tablets will come in a blister pack in wallets and/or cartons containing

20 mg, 40 mg: Bottles of 2, 5, 7, 14, 15, 28, 30, 56, 60, 100, 140(5x28) tablets.

20 mg, 40 mg: Blister packs in wallet and/or carton of 3, 7, 7x1, 14, 15, 25x1, 28, 30, 50x1, 56, 60, 90, 98, 100x1, 140 tablets

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

The Marketing Authorisations for Nexium are held by

AstraZeneca UK Ltd

600 Capability Green

Luton

LU1 3LU

United Kingdom

Nexium is released by

AstraZeneca UK Ltd

Silk Road Business Park

Macclesfield

Cheshire

SK10 2NA

United Kingdom

AstraZeneca AB

S-151 85

Södertälje

Sweden

AstraZeneca AB

Umeå

Sweden

AstraZeneca GmbH

Wedel

Germany

Corden Pharma GmbH

Plankstadt

Germany

AstraZeneca Reims

Reims

France

Recipharm Monts

Monts

France

To listen to or request a copy of this leaflet in Braille, large print or audio please call, free of charge:

0800 198 5000 (UK only)

Please be ready to give the following information:

Product name: Reference number

Nexium 20 mg Tablets: 17901/0068

Nexium 40 mg Tablets: 17901/0069

This is a service provided by the Royal National Institute of Blind People.

This leaflet was prepared in September 2009.

Nexium is a trade mark of the AstraZeneca group of companies.

GI 08 0051a

P026334

Neoral Soft Gelatin Capsules, Neoral Oral Solution

1. Name Of The Medicinal Product

NEORAL® Soft Gelatin Capsules and NEORAL® Oral Solution (ciclosporin*, also known as ciclosporin A) - Immunosuppressive agent

*INN rec.

2. Qualitative And Quantitative Composition

NEORAL Soft Gelatin Capsules containing 10, 25, 50, or 100mg ciclosporin.

For a full list of excipients see section 6.1 List of excipients.

NEORAL Oral Solution containing 100mg ciclosporin/mL

3. Pharmaceutical Form

Neoral Soft Gelatin Capsules 10mg: Yellow-white, oval soft gelatin capsules marked 'NVR 10'.

Neoral Soft Gelatin Capsules 25mg: Blue-grey, oval soft gelatin capsules marked 'NVR 25mg'.

Neoral Soft Gelatin Capsule 50mg: Yellow-white, oblong soft gelatin capsules marked 'NVR 50mg'.

Neoral Soft Gelatin Capsules 100mg: Blue-grey, oblong soft gelatin capsules marked 'NVR 100mg'.

NEORAL Soft Gelatin Capsules and NEORAL Oral Solution are for oral administration.

NEORAL is an improved pharmaceutical form of the active ingredient ciclosporin. NEORAL is a pre-concentrate formulation of ciclosporin which undergoes a microemulsification process in the presence of water, either in the form of a beverage or in the form of the gastrointestinal fluid. NEORAL reduces the intra-patient variability of pharmacokinetic parameters, with a more consistent absorption profile and less influence of concomitant food intake and the presence of bile. In pharmacokinetic and clinical studies it has been demonstrated that the correlation between trough concentration (Cmin) and total exposure (AUC) is significantly stronger when ciclosporin is given as NEORAL than when it is given as SANDIMMUN. NEORAL therefore allows greater predictability and consistency of ciclosporin exposure.

4. Clinical Particulars

4.1 Therapeutic Indications

Transplantation indications

Organ transplantation

Prevention of graft rejection following kidney, liver, heart, combined heart-lung, lung or pancreas transplants.

Treatment of transplant rejection in patients previously receiving other immunosuppressive agents.

Bone marrow transplantation

Prevention of graft rejection following bone marrow transplantation and prophylaxis of graft-versus-host disease (GVHD).

Treatment of established graft-versus-host disease (GVHD).

Non-transplantation indications

Psoriasis

NEORAL Soft Gelatin Capsules and NEORAL Oral Solution are indicated in patients with severe psoriasis in whom conventional therapy is ineffective or inappropriate.

Atopic dermatitis

NEORAL Soft Gelatin Capsules and NEORAL Oral Solution are indicated for the short term treatment (8 weeks) of patients with severe atopic dermatitis in whom conventional therapy is ineffective or inappropriate.

Rheumatoid arthritis

NEORAL Soft Gelatin Capsules and NEORAL Oral Solution are indicated for the treatment of severe, active rheumatoid arthritis in patients in whom classical, slow-acting anti-rheumatic agents are inappropriate or ineffective.

Nephrotic syndrome

NEORAL Soft Gelatin Capsules and NEORAL Oral Solution are indicated for the treatment of steroid dependent or steroid resistant nephrotic syndrome (associated with adverse prognostic features) due to minimal change glomerulonephritis, focal segmental glomerulosclerosis or membranous glomerulonephritis in both adults and children.

4.2 Posology And Method Of Administration

Dosage

Following initiation of treatment with NEORAL, due to the different bioavailabilities of the different oral ciclosporin formulations, patients should not be transferred to any other oral formulation of ciclosporin without appropriate monitoring of ciclosporin blood concentrations, serum creatinine levels and blood pressure. This does not apply to the conversion between NEORAL Soft Gelatin Capsules and NEORAL Oral Solution as these two forms are bioequivalent.

Due to the differences in bioavailability between different oral formulations of ciclosporin, it is important that prescribers, pharmacists and patients be aware that substitution of NEORAL with any other oral formulation of ciclosporin is not recommended as this may lead to alterations in ciclosporin blood levels. For this reason it may be appropriate to prescribe by brand.

Transplantation indications

Organ transplantation

Treatment with NEORAL Soft Gelatin Capsules or NEORAL Oral Solution should be initiated within 12 hours before transplantation at a dose of 10 to 15mg/kg body weight given in two divided doses.

As a general rule, treatment should continue at a dose of 10 to 15mg/kg per day given in two divided doses for one to two weeks post-operatively. Dosage should then be gradually reduced until a maintenance dose of about 2 to 6mg/kg per day is reached. This total daily dose should be given in two divided doses. Dosage should be adjusted by monitoring ciclosporin trough levels and kidney function (see Section 4.2 and 4.4).

When NEORAL is given with other immunosuppressants (e.g. with corticosteroids or as part of a triple or quadruple drug therapy), lower doses (e.g. 3 to 6mg/kg per day given orally in two divided doses) may be used for the initial treatment. For trough level monitoring, whole blood is preferred, measured by a specific analytical method. Target trough concentration ranges depend on organ type, time after transplantation and immunosuppressive regimen.

The use of SANDIMMUN Concentrate for Solution for Infusion is recommended only in organ transplant patients who are unable to take SANDIMMUN/NEORAL orally (e.g. shortly after surgery) or in whom the absorption of the oral forms might be impaired such as during episodes of gastrointestinal disturbances. It is recommended, however, that patients be transferred to NEORAL therapy as soon as the given circumstances allow (please refer to SANDIMMUN data sheet/SmPC for prescribing information on SANDIMMUN Concentrate for Solution for Infusion).

Bone marrow transplantation/prevention and treatment of graft-versus-host-disease (GVHD)

SANDIMMUN Concentrate for Solution for Infusion is usually preferred for initiation of therapy, although NEORAL Soft Gelatin Capsules or NEORAL Oral Solution may be used (please refer to SANDIMMUN data sheet/SmPC for prescribing information on SANDIMMUN Concentrate for Solution for Infusion).

Maintenance treatment should continue using NEORAL Soft Gelatin Capsules or NEORAL Oral Solution at a dosage of 12.5mg/kg per day, given in two divided doses, for at least three and preferably six months before tailing off to zero. In some cases it may not be possible to withdraw NEORAL until a year after bone marrow transplantation. Higher doses of NEORAL or the use of SANDIMMUN Concentrate for Solution for Infusion may be necessary in the presence of gastro-intestinal disturbances which might decrease absorption.

If NEORAL Soft Gelatin Capsules or NEORAL Oral Solution are used to initiate therapy, the recommended dose is 12.5 to 15mg/kg per day, given in two divided doses, starting on the day before transplantation.

If GVHD develops after NEORAL is withdrawn it should respond to reinstitution of therapy. Low doses of NEORAL should be used for mild, chronic GVHD.

Non-transplantation indications

Psoriasis

(Refer also to Section 4.4 Additional precautions in psoriasis and atopic dermatitis section)

Due to the variability of this condition, treatment must be individualised. To induce remission, the recommended initial dose of NEORAL is 2.5mg/kg a day given orally in two divided doses. If there is no improvement after 1 month, the daily dose may be gradually increased, but should not exceed 5mg/kg. Treatment should be discontinued if sufficient response is not achieved within 6 weeks on a daily basis of 5mg/kg per day, or if the effective dose is not compatible with the safety guidelines given below (see Section 4.4). Initial doses of 5mg/kg per day of NEORAL are justified in patients whose condition requires rapid improvement.

For maintenance treatment, NEORAL dosage must be individually titrated to the lowest effective level, and the dosage should not exceed 5mg/kg per day, given orally in two divided doses.

Some clinical data are available which provide evidence that once satisfactory response is achieved, NEORAL may be discontinued and subsequent relapse managed with re-introduction of NEORAL at the previous effective dose. In some patients continuous maintenance therapy may be necessary.

Atopic dermatitis

(Refer also to Section 4.4 Additional precautions in atopic dermatitis section)

The recommended dose range for NEORAL is 2.5-5mg/kg per day given orally in two divided doses for a maximum of 8 weeks. If a starting dose of 2.5mg/kg/day does not achieve a good initial response within 2 weeks the dose may be rapidly increased to a maximum of 5mg/kg per day. In very severe cases rapid and adequate control of disease is more likely with a starting dose of 5mg/kg per day, given orally in two divided doses.

Rheumatoid arthritis

(Refer also to Section 4.4 Additional precautions in rheumatoid arthritis section)

It is recommended that initiation of NEORAL therapy should take place over a period of 12 weeks. For the first 6 weeks of treatment, the recommended dose is 2.5mg/kg per day, given orally in two divided doses. If the clinical effect is considered insufficient, the daily dose may be increased gradually as tolerability permits, but should not exceed 4mg/kg per day.

If, after 3 months of treatment at the maximum permitted or tolerable dose the response is considered inadequate, treatment should be discontinued.

For maintenance treatment the dose has to be titrated individually according to tolerability.

NEORAL can be given in combination with low-dose corticosteroids. Pharmacodynamic interactions can occur between ciclosporin and NSAIDs and therefore this combination should be used with care (see Section 4.4 Additional precautions in rheumatoid arthritis section and Section 4.5).

Long-term data on the use of ciclosporin in the treatment of rheumatoid arthritis are still limited. Therefore, it is recommended that patients are re-evaluated after 6 months of maintenance treatment and therapy only continued if the benefits of treatment outweigh the risks.

Nephrotic syndrome

(Refer also to Section 4.4 Additional precautions in nephrotic syndrome section)

To induce remission, the recommended dose is 5mg/kg per day given orally in two divided doses for adults and 6mg/kg per day given orally in two divided doses for children if, with the exception of proteinuria, renal function is normal. In patients with impaired renal function, the initial dose should not exceed 2.5mg/kg per day orally.

In focal segmental glomerulosclerosis, the combination of NEORAL and low dose corticosteroids may be of benefit.

In the absence of efficacy after 3 months treatment for minimal change glomerulonephritis and focal segmental glomerulosclerosis or 6 months treatment for membranous glomerulonephritis, NEORAL therapy should be discontinued.

For maintenance treatment the maximum recommended dose is 5mg/kg per day orally in adults or 6mg/kg per day orally in children. The doses need to be slowly reduced individually according to efficacy (proteinuria) and safety (primarily serum creatinine), to the lowest effective level.

Long-term data of ciclosporin in the treatment of nephrotic syndrome are limited. However, in clinical trials patients have received treatment for 1 to 2 years. Long-term treatment may be considered if there has been a significant reduction in proteinuria with preservation of creatinine clearance and provided adequate precautions are taken (see Section 4.4 Additional precautions in nephrotic syndrome section).

Conversion of transplant patients from SANDIMMUN Soft Gelatin Capsules or Oral Solution to NEORAL

Ciclosporin absorption from SANDIMMUN oral formulations is highly variable and the relationship between SANDIMMUN dose and ciclosporin exposure (AUC) is non-linear. In contrast with NEORAL the absorption of ciclosporin is less variable and the correlation between ciclosporin trough concentrations and exposure is much stronger than with SANDIMMUN.

For converting patients from SANDIMMUN to NEORAL an initial mg for mg conversion from SANDIMMUN to NEORAL is recommended with subsequent dose titration if required. Available data confirm that following this initial mg for mg conversion, comparable trough concentrations of ciclosporin in whole blood are achieved, maintaining adequate immunosuppression. In many patients, higher peak concentrations (Cmax) and an increased exposure to the drug (AUC) may occur. In a small proportion of patients headache and paraesthesia may occur during transfer from SANDIMMUN to NEORAL, presumably related to higher exposure to ciclosporin. No additional adverse events, including renal dysfunction, however, were observed due to these changes in pharmacokinetic parameters during long-term treatment. In a small percentage of patients, these changes may be more marked and of clinical significance. Their magnitude depends largely on the individual ability to absorb ciclosporin from the originally used SANDIMMUN. In these patients, dose reduction should be undertaken to achieve the appropriate trough concentration range.

Long-term clinical data in renal transplant patients have demonstrated that a large proportion of patients previously on SANDIMMUN therapy can be maintained at the same dose of NEORAL as with SANDIMMUN.

All patients should be monitored according to the following recommendations:

a) Preconversion (i.e. on SANDIMMUN): Measure ciclosporin trough concentration, serum creatinine and blood pressure.

b) Day 1: Convert the patient to the same daily dose of NEORAL as was previously used with oral SANDIMMUN (i.e. on a mg to mg basis).

c) Day 4-7 post conversion: Follow-up visit to measure ciclosporin trough concentration, serum creatinine and blood pressure.

d) Subsequent follow-up: Depending on the findings on review at day 4-7, subsequent follow-up visits may need to be arranged (e.g. week 2 and week 4) in the first 12 week period after conversion to NEORAL. During these visits, ciclosporin trough concentrations, serum creatinine and blood pressure should be measured and dependent on these measurements the dose of NEORAL adjusted accordingly.

Further information on conversion can be obtained via the NEORAL Helpline (01276 698494)

Conversion of non-transplant (i.e. psoriasis, atopic dermatitis, rheumatoid arthritis, nephrotic syndrome) patients from SANDIMMUN Soft Gelatin Capsules or Oral Solution to NEORAL

With equivalent doses following conversion from SANDIMMUN to NEORAL, higher peak concentrations (Cmax) and an increased exposure to the drug (AUC) may occur. In a small percentage of patients, these changes may be more marked and of clinical significance. Their magnitude depends largely on the individual ability to absorb ciclosporin from the originally used SANDIMMUN. Therefore, the clinical status of each patient should be assessed prior to initiating NEORAL therapy.

It is recommended that where any potential loss of efficacy results in considerable risk to the patients (e.g. rheumatoid arthritis), conversion from SANDIMMUN to NEORAL is on a mg for mg basis. In other patients, the lowest recommended starting dose of NEORAL is recommended initially with appropriate dose titration according to clinical response, serum creatinine and blood pressure levels.

All patients converting on a mg for mg basis should be monitored according to the following recommendations:-

a) Preconversion (i.e. on SANDIMMUN): Measure serum creatinine and blood pressure.

b) Day 1: Start the patient with the same daily dose of NEORAL as was previously used with oral SANDIMMUN (i.e. on a mg for mg basis).

c) Week 2: Measure serum creatinine and blood pressure and consider reducing the dose of NEORAL if either parameter significantly exceeds the preconversion level.

d) Week 4: Measure serum creatinine and blood pressure and consider reducing the dose of NEORAL if either parameter significantly exceeds the preconversion level.

e) Week 8: Measure serum creatinine and blood pressure and consider reducing the dose of NEORAL if either parameter significantly exceeds the preconversion level.

f) Week 12: Measure serum creatinine and blood pressure and consider reducing the dose of NEORAL if either parameter significantly exceeds the preconversion level.

If, on more than one measurement, the serum creatinine increases more than 30% above the pre-SANDIMMUN baseline, the dose of NEORAL should be decreased (see Section 4.4 Additional precautions for psoriasis, atopic dermatitis, rheumatoid arthritis and nephrotic syndrome sections).

Conversion between oral ciclosporin formulations

Switching from one oral ciclosporin formulation to another should be made with caution and under specialist supervision. The introduction of the new formulation must be made with monitoring of blood levels of ciclosporin to ensure that pre-conversion levels are attained.

Administration

The total daily dosage of NEORAL Soft Gelatin Capsules or NEORAL Oral Solution should always be given in two divided doses. NEORAL Soft Gelatin Capsules should be taken with a mouthful of water and should then be swallowed whole.

NEORAL Oral Solution should be diluted immediately before being taken. For improved taste the solution can be diluted with orange juice or squash or apple juice. However, it may also be taken with water if preferred. It should be stirred well.

NEORAL Oral Solution has a characteristic taste which is distinct to that of SANDIMMUN Oral Solution.

The measuring device should not come into contact with the diluent. The measuring device should not be rinsed with water, alcohol or any other liquid. If it is necessary to clean the measuring device, the outside should be wiped with a dry tissue.

Owing to its possible interference with the P450-dependent enzyme system, grapefruit or grapefruit juice should not be ingested for 1 hour prior to dose administration, and grapefruit juice should not be used as a diluent for the Oral Solution.

Use in the Elderly

Experience with NEORAL in the elderly is limited. However, no particular problems have been reported following the use of ciclosporin at the recommended dose. Factors sometimes associated with ageing, in particular impaired renal function, make careful supervision essential and may necessitate dosage adjustment.

In rheumatoid arthritis clinical trials with ciclosporin, 17.5% of patients were aged 65 or older. These patients were more likely to develop systolic hypertension on therapy, and more likely to show serum creatinine rises

Clinical studies of NEORAL in transplant and psoriasis patients did not include a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experiences have not identified differences in response between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Use in Children

There is currently no experience with NEORAL in young children. However, transplant recipients from three months of age have received ciclosporin at the recommended dosage with no particular problems although at dosages above the upper end of the recommended range children seem to be more susceptible to fluid retention, convulsions and hypertension. This responds to dosage reduction.

4.3 Contraindications

Hypersensitivity to ciclosporin or to any of the other excipients of NEORAL.

NEORAL is contraindicated in psoriatic and atopic dermatitis patients with abnormal renal function, uncontrolled hypertension, uncontrolled infections or any kind of malignancy other than that of the skin (see section 4.4).

NEORAL is contraindicated in rheumatoid arthritis patients with abnormal renal function, uncontrolled hypertension, uncontrolled infections or any kind of malignancy.

NEORAL should not be used to treat rheumatoid arthritis in patients under the age of 18 years.

NEORAL is contraindicated in nephrotic syndrome patients with uncontrolled hypertension, uncontrolled infections, or any kind of malignancy.

Concomitant use of tacrolimus is specifically contraindicated.

Concomitant use of rosuvastatin is specifically contraindicated (see section 4.5).

4.4 Special Warnings And Precautions For Use

NEORAL should be prescribed only by physicians who are experienced in immunosuppressive therapy, and can provide adequate follow-up, including regular full physical examination, measurement of blood pressure, and control of laboratory safety parameters. Transplantation patients receiving the drug should be managed in facilities with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should receive complete information for the follow-up of the patient.

Like other immunosuppressants, ciclosporin increases the risk of developing lymphomas and other malignancies, particularly those of the skin. The increased risk appears to be related to the degree and duration of immunosuppression rather than to the use of specific agents.

Hence a treatment regimen containing multiple immunosuppressants (including ciclosporin) should be used with caution as this could lead to lymphoproliferative disorders and solid organ tumours, some with reported fatalities.

In view of the potential risk of skin malignancy, patients on NEORAL, in particular those treated for psoriasis or atopic dermatitis, should be warned to avoid excess unprotected sun exposure and should not receive concomitant ultraviolet B irradiation or PUVA photochemotherapy.

Like other immunosuppressants, ciclosporin predisposes patients to the development of a variety of bacterial, fungal, parasitic and viral infections often with opportunistic pathogens.

Activation of latent Polyomavirus infections that may lead to Polyomavirus associated nephropathy (PVAN), especially to BK virus nephropathy (BKVN), or to JC virus associated progressive multifocal leukoencephalopathy (PML) have been observed in patients receiving ciclosporin. These conditions are often related to a high total immunosuppressive burden and should be considered in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms. Serious and/or fatal outcomes have been reported. Effective pre-emptive and therapeutic strategies should be employed particularly in patients on multiple long-term immunosuppressive therapy.

A frequent and potentially serious complication, an increase in serum creatinine and urea may occur during the first few weeks of NEORAL therapy. These functional changes are dose-dependent and reversible, usually responding to dose reduction. During long-term treatment, some patients may develop structural changes in the kidney (e.g. interstitial fibrosis) which, in renal transplant patients, must be differentiated from changes due to chronic rejection. NEORAL may also cause dose-dependent, reversible increases in serum bilirubin and, occassionally, in liver enzymes (see section 4.8). There have been solicited and spontaneous reports of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver failure in patients treated with ciclosporin. Most reports included patients with significant co-morbidities, underlying conditions and other confounding factors including infectious complications and comedications with hepatotoxic potential. In some cases, mainly in transplant patients, fatal outcomes have been reported (see section 4.8). Close monitoring of parameters that assess renal and hepatic function is required. Abnormal values may necessitate dose reduction.

In elderly patients, renal function should be monitored with particular care.

For monitoring ciclosporin levels in whole blood, a specific monoclonal antibody (measurement of parent drug) is preferred; a HPLC method, which also measures the parent drug, can be used as well. If plasma or serum is used, a standard separation protocol (time and temperature) should be followed. For the initial monitoring of liver transplant patients, either the specific monoclonal antibody should be used, or parallel measurements using both the specific monoclonal antibody and the nonspecific monoclonal antibody should be performed, to ensure a dosage that provides adequate immunosuppression.

It must be remembered that the ciclosporin concentration in blood, plasma, or serum is only one of many factors contributing to the clinical status of the patient. Results should therefore serve only as a guide to dosage in relationship to other clinical and laboratory parameters.

Regular monitoring of blood pressure is required during NEORAL therapy; if hypertension develops, appropriate antihypertensive treatment must be instituted.

Since, on rare occasions, NEORAL has been reported to induce a reversible slight increase in blood lipids, it is advisable to perform lipid determinations before treatment andafter the first month of therapy. In the event of increased lipids being found, restriction of dietary fat and, if appropriate, a dose reduction, should be considered.

Ciclosporin enhances the risk of hyperkalaemia, especially in patients with renal dysfunction. Caution is also required when ciclosporin is co-administered with potassium sparing drugs (e.g. potassium sparing diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists) and potassium containing drugs as well as in patients on a potassium rich diet. Control of potassium levels in these situations is advisable.

Ciclosporin enhances the clearance of magnesium. This can lead to symptomatic hypomagnesaemia, especially in the peri-transplant period. Control of serum magnesium levels is therefore recommended in the peri-transplant period, particularly in the presence of neurological symptom/signs. If considered necessary, magnesium supplementation should be given.

Caution is required in treating patients with hyperuricaemia.

During treatment with ciclosporin, vaccination may be less effective; the use of live attenuated vaccines should be avoided.

Caution should be observed while co-administering lercanidipine with ciclosporin (see section 4.5).

Ciclosporin may increase blood levels of concomitant medications that are substrates of P-glycoprotein (Pgp) such as aliskiren (see section 4.5).

Ciclosporin may increase the risk of Benign Intracranial Hypertension. Patients presenting with signs of raised intracranial pressure should be investigated and if Benign Intracranial Hypertension is diagnosed, ciclosporin should be withdrawn due to the possible risk of permanent visual loss.

NEORAL contains Polyoxyl 40 hydrogenated castor oil which may cause stomach upsets and diarrhoea.

NEORAL oral formulations contain around 12% vol. ethanol. A 500 mg dose of NEORAL contains 500 mg of ethanol equivalent to nearly 15 ml of beer or 5 ml of wine. This may be harmful in alcoholic patients and should be taken into account in pregnant or breast feeding women, in patients presenting with liver disease or epilepsy, or if the medicine is being given to a child.

There are differences in bioavailability between different oral formulations of ciclosporin, however NEORAL Soft Gelatin Capsules are bioequivalent to NEORAL Oral Solution.

Additional precautions in non-transplant indications

Patients with impaired renal function (except in nephrotic syndrome patients with a permissible degree of renal impairment), uncontrolled hypertension, uncontrolled infections, or any kind of malignancy should not receive ciclosporin.

Additional precautions in nephrotic syndrome:

Since NEORAL can impair renal function, it is necessary to assess renal function frequently and if the serum creatinine remains increased by more than 30% above baseline at more than one measurement, to reduce the dosage of NEORAL by 25 to 50%.

Patients with abnormal baseline renal function should initially be treated with 2.5mg/kg per day and must be monitored very carefully.

In some patients it may be difficult to detect NEORAL-induced renal dysfunction because of changes in renal function related to the nephrotic syndrome itself. This explains why, in rare cases, NEORAL-associated structural kidney alterations have been observed without increases in serum creatinine. Renal biopsy should be considered for patients with steroid-dependent minimal-change nephropathy, in whom NEORAL therapy has been maintained for more than 1 year.

In patients with nephrotic syndrome treated with immunosuppressants (including ciclosporin), the occurrence of malignancies (including Hodgkin's lymphoma) has occasionally been reported.

The use of NEORAL therapy for the treatment of patients with nephrotic syndrome requires careful monitoring and follow-up. NEORAL should only be used provided that the necessary expertise and adequate equipment, laboratory and supporting medical resources are available.

Additional precautions in rheumatoid arthritis

Since NEORAL can impair renal function, a reliable baseline level of serum creatinine should be established by at least two measurements prior to treatment, and serum creatinine should be monitored at 2-weekly intervals during the first 3 months of therapy and thereafter once a month. After 6 months of therapy, serum creatinine needs to be measured every 4 to 8 weeks depending on the stability of the disease, its comedication, and concomitant diseases. More frequent checks are necessary when the NEORAL dose is increased, or concomitant treatment with a non-steroidal anti-inflammatory drug is initiated or its dosage increased. Because the pharmacodynamic interaction between ciclosporin and NSAIDs may adversely affect renal function, caution should be exercised if NSAID therapy is to be continued.

If the serum creatinine remains increased by more than 30% above baseline at more than one measurement, the dosage of NEORAL should be reduced. If the serum creatinine increases by more than 50%, a dosage reduction by 50% is mandatory. These recommendations apply even if the patient's values still lie within the laboratory normal range. If dose reduction is not successful in reducing levels within one month, NEORAL treatment should be discontinued.

Discontinuation of the drug may also become necessary if hypertension developing during NEORAL therapy cannot be controlled by appropriate antihypertensive therapy.

The combination of non-steroidal anti-inflammatory drugs and ciclosporin should be used with caution in patients with rheumatoid arthritis and should be accompanied by particularly close monitoring of renal function as detailed above. (Please also see section 4.5 ).

As hepatotoxicity is a potential side effect of non-steroidal anti-inflammatory drugs, regular monitoring of hepatic function is advised when NEORAL is co-administered with these drugs in rheumatoid arthritis patients.

The use of ciclosporin therapy for the treatment of patients with rheumatoid arthritis requires careful monitoring and follow-up. NEORAL should only be used provided that the necessary expertise and adequate equipment, laboratory and supportive medical resources are available.

Patients with rheumatoid arthritis have an increased incidence of malignancies compared to the general population. Use of disease modifying drugs increases the risk of malignancy further. The use of ciclosporin in the treatment of rheumatoid arthritis has not been shown to increase the incidence of malignancies more than other disease-modifying drugs.

As with other long-term immunosuppressive treatments (including ciclosporin), an increased risk of lymphoproliferative disorders must be borne in mind. Special caution should be observed if NEORAL is used in combination with methotrexate.

Additional precautions in psoriasis

Careful dermatological and physical examinations, including measurements of blood pressure and renal function on at least two occasions prior to starting therapy should be performed to establish an accurate baseline status.

Thereafter, if creatinine remains stable, measurements should be made at monthly intervals. If serum creatinine increases and remains increased to more than 30% above baseline at more than one measurement, the dosage of NEORAL must be reduced by 25 to 50%. These recommendations apply even if the patient's values still lie within the laboratory's normal range. If dose reduction is not successful in reducing levels within one month, NEORAL treatment should be discontinued.

Discontinuation of NEORAL therapy is also recommended if hypertension developing during NEORAL treatment cannot be controlled with appropriate therapy.

Elderly patients should be treated only in the presence of disabling psoriasis, and renal function should be monitored with particular care.

There is only limited experience with the use of NEORAL in children with psoriasis.

In psoriatic patients on ciclosporin, as in those on conventional immunosuppressive therapy, development of malignancies (in particular of the skin) has been reported. Skin lesions not typical for psoriasis, but suspected to be malignant or pre-malignant should be biopsied before NEORAL treatment is started. Patients with malignant or pre-malignant alterations of the skin should be treated with NEORAL only after appropriate treatment of such lesions, and if no other option for successful therapy exists.

In a few psoriatic patients treated with NEORAL, lymphoproliferative disorders have occurred. These were responsive to prompt drug discontinuation.

Patients on NEORAL should not receive concomitant ultraviolet B irradiation or PUVA photochemotherapy.

NEORAL treatment and its monitoring should be carried out under the supervision of a dermatologist experienced in the management of severe skin diseases.

Additional precautions in atopic dermatitis

Discontinuation of NEORAL therapy is also recommended if hypertension developing during NEORAL treatment cannot be controlled with appropriate therapy.

The experience with NEORAL in children with atopic dermatitis is limited.

Elderly patients should be treated only in the presence of disabling atopic dermatitis and renal function should be monitored with particular care.

Benign lymphadenopathy is commonly associated with flares in atopic dermatitis, and invariably disappears spontaneously or with general improvement in the disease.

Lymphadenopathy observed on treatment with ciclosporin should be regularly monitored.

Lymphadenopathy which persists despite improvement in disease activity should be examined by biopsy as a precautionary measure to ensure the absence of lymphoma.

Active Herpes simplex infections should be allowed to clear before treatment with NEORAL is initiated, but is not necessarily a reason for drug withdrawal if they occur during treatment unless infection is severe.

Skin infections with Staphylococcus aureus are not an absolute contraindication for NEORAL therapy but should be controlled with appropriate antibacterial agents. Oral erythromycin, known to have the potential to increase the blood concentration of ciclosporin (see section 4.5) should be avoided or, if there is no alternative, it is recommended to closely monitor blood levels of ciclosporin, renal function, and for side effects of ciclosporin.

Patients on NEORAL should not receive concomitant ultraviolet B irradiation or PUVA photochemotherapy.

NEORAL treatment and its monitoring should be carried out under the supervision of a dermatologist experienced in the management of severe skin diseases.

Paediatric use in non-transplant indications

Except for the treatment of nephrotic syndrome, there is no adequate experience available with NEORAL; its use in children under 16 years of age for nontransplant indications other than nephrotic syndrome cannot be recommended.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Food interactions

The concomitant intake of grapefruit juice has been reported to increase the bioavailability of ciclosporin.

Drug interactions

Of the many drugs reported to interact with ciclosporin, those for which the interactions are adequately substantiated and considered to have clinical implications are listed below.

Various agents are known to either increase or decrease plasma or whole blood ciclosporin levels usually by inhibition or induction of enzymes involved in the metabolism of ciclosporin, in particular CYP3A4. Ciclosporin is also an inhibitor of CYP3A4 and of the multidrug efflux transporter P-glycoprotein and may increase plasma levels of comedications that are substrates of this enzyme and/or transporter.

Drugs that decrease ciclosporin levels:

Barbiturates, carbamazepine, oxcarbazepine, phenytoin; nafcillin, sulfadimidine i.v.; rifampicin, octreotide, probucol, orlistat, hypericum perforatum (St John's Wort), ticlopidine, sulfinpyrazone, terbinafine, bosentan.

Drugs that increase ciclosporin levels:

Macrolide antibiotics (e.g. erythromycin, azithromycin and clarithromycin); ketoconazole, fluconazole, itraconazole, voriconazole; diltiazem, nicardipine, verapamil; metoclopramide; oral contraceptives; danazol; methylprednisolone (high dose); allopurinol; amiodarone; cholic acid and derivatives; protease inhibitors, imatinib; colchicines; nefazodone.

Other relevant drug interactions

Care should be taken when using ciclosporin together with other drugs that exhibit nephrotoxic synergy such as: aminoglycosides (including gentamicin, tobramycin), amphotericin B, ciprofloxacin, vancomycin, trimethoprim (+ sulfamethoxazole); non-steroidal anti-inflammatory drugs (including diclofenac, naproxen, sulindac); melphalan, histamine H2-receptorantagonists (e.g. cimetidine, ranitidine); methotrexate (see section 4.4).

Concomitant use with tacrolimus should be avoided due to increased potential for nephrotoxicity.

The concurrent administration of nifedipine with ciclosporin may result in an increased rate of gingival hyperplasia compared with that observed when ciclosporin is given alone.

Following concomitant administration of ciclosporin and lercanidipine, the AUC of lercanidipine was increased threefold and the AUC of ciclosporin was increased 21%. Therefore caution is recommended when co-administering ciclosporin together with lercanidipine (see section 4.4).

Ciclosporin is a highly potent Pgp inhibitor and may increase blood levels of concomitant medications that are substrates of Pgp such as aliskiren. Following concomitant administration of ciclosporin and aliskiren, the Cmax of aliskiren was increased by approximately 2.5 fold and the AUC by approximately 5 fold. However, the pharmacokinetic profile of ciclosporin was not significantly altered. Caution is recommended when co-administering ciclosporin together with aliskiren (see section 4.4).

The concomitant use of diclofenac and ciclosporin has been found to result in a significant increase in the bioavailability of diclofenac, with the possible consequence of reversible renal function impairment. The increase in the bioavailability of diclofenac is most probably caused by a reduction of its first-pass effect. If non-steroidal anti-inflammatory drugs with a low first-pass effect (e.g. acetylsalicylic acid) are given together with ciclosporin, no increase in their bioavailability is to be expected.

Ciclosporin may reduce the clearance of digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors (statins) and etoposide.

Severe digitalis toxicity has been seen within days of starting ciclosporin in several patients taking digoxin. There are also reports on the potential of ciclosporin to enhance the toxic effects of colchicine such as myopathy and neuropathy, especially in patients with renal dysfunction. If digoxin or colchicine is used concurrently with ciclosporin, close clinical observation is required in order to enable early detection of toxic manifestations of digoxin or colchicine, followed by reduction of dosage or its withdrawal.

Literature and post marketing cases of myotoxicity, including muscle pain and weakness, myositis, and rhabdomyolysis, have been reported with concomitant administration of ciclosporin with lovastatin, simvastatin, atorvastatin, pravastatin, and rarely, fluvastatin. When concurrently administered with ciclosporin, the dosage of these statins should be reduced according to label recommendations. Statin therapy needs to be temporarily withheld or discontinued in patients with signs and symptoms of myopathy or those with risk factors predisposing to severe renal injury, including renal failure, secondary to rhabdomyolysis.

Rosuvastatin is specifically contraindicated with ciclosporin (see Section 4.3).

Elevations in serum creatinine were observed in the studies using everolimus or sirolimus in combination with full-dose ciclosporin for microemulsion. This effect is often reversible with ciclosporin dose reduction. Everolimus and sirolimus had only a minor influence on ciclosporin pharmacokinetics. Co-administration of ciclosporin significantly increases blood levels of everolimus and sirolimus.

Caution is required for concomitant use of potassium sparing drugs (e.g. potassium sparing diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists) or potassium containing drugs since they may lead to significant increases in serum potassium (see section 4.4).

Ciclosporin may increase the plasma concentrations of repaglinide and thereby increase the risk of hypoglycaemia.

Recommendations

If the concomitant use of drug known to interact with ciclosporin cannot be avoided, the following basic recommendations should be observed.

During the concomitant use of a drug that may exhibit nephrotoxic synergy, close monitoring of renal function (in particular serum creatinine) should be performed. If a significant impairment of renal function occurs, the dosage of the co-administered drug should be reduced or alternative treatment considered.

In graft recipients there have been isolated reports of considerable but reversible impairment of kidney function (with corresponding increase in serum creatinine) following concomitant administration of fibric acid derivatives (e.g. bezafibrate, fenofibrate). Kidney function must therefore be closely monitored in these patients. In the event of significant impairment of kidney function the co-medication should be withdrawn.

Drugs known to reduce or increase the bioavailability of ciclosporin: in transplant patients frequent measurement of ciclosporin levels and, if necessary, ciclosporin dosage adjustment is required, particularly during the introduction or withdrawal of the co-administered drug. In non-transplant patients the value of ciclosporin blood level monitoring is questionable, as in these patients the relationship between blood level and clinical effect is less well established. If drugs known to increase ciclosporin levels are given concomitantly, frequent assessment of renal function and careful monitoring for ciclosporin related side-effects may be more appropriate than blood level measurement.

The concomitant use of nifedipine should be avoided in patients in whom gingival h