Neorecormon Multidose Powder and Solvent for Solution for Injection (Roche Products Limited)

1. Name Of The Medicinal Product

NeoRecormon Multidose 50,000 IU Lyophilisate and solvent for solution for injection (5000 IU/ml)

2. Qualitative And Quantitative Composition

One vial contains 50,000 international units (IU) corresponding to 415 micrograms epoetin beta* (recombinant human erythropoietin).

One ampoule contains 10 ml solvent (water for injections with benzyl alcohol and benzalkonium chloride as preservatives).

One ml of reconstituted solution contains 5000 IU epoetin beta.

* produced in Chinese Hamster Ovary cells (CHO) by recombinant DNA technology

Excipients:

Phenylalanine (up to 5.0 mg/vial)

Sodium (less than 1 mmol per dose)

Benzyl alcohol (up to 40 mg per multidose solvent ampoule)

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Lyophilisate and solvent for solution for injection.

White lyophilisate and clear, colourless solvent.

4. Clinical Particulars

4.1 Therapeutic Indications

- Treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adult and paediatric patients.

- Treatment of symptomatic anaemia in adult patients with non-myeloid malignancies receiving chemotherapy.

- Increasing the yield of autologous blood from patients in a pre-donation programme.

Its use in this indication must be balanced against the reported increased risk of thromboembolic events. Treatment should only be given to patients with moderate anaemia (Hb 10 - 13 g/dl [6.21 - 8.07 mmol/l], no iron deficiency) if blood conserving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units of blood for females or 5 or more units for males).

4.2 Posology And Method Of Administration

Therapy with NeoRecormon should be initiated by physicians experienced in the above mentioned indications. As anaphylactoid reactions were observed in isolated cases, it is recommended that the first dose be administered under medical supervision.

This multidose preparation can be used for several patients. To avoid the risk of cross-infection always follow aseptic techniques and use disposable sterile syringes and needles for each administration. Please check that only one vial of NeoRecormon Multidose is in use (i.e. reconstituted) at any one time.

The reconstituted product is a colourless, clear to slightly opalescent solution.

For instructions on reconstitution of the product before administration, see section 6.6.

Treatment of symptomatic anaemia in adult and paediatric chronic renal failure patients:

Anaemia symptoms and sequelae may vary with age, gender, and overall burden of disease; a physician's evaluation of the individual patient's clinical course and condition is necessary. NeoRecormon should be administered either subcutaneously or intravenously in order to increase haemoglobin to not greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving haemodialysis to avoid puncture of peripheral veins. In case of intravenous administration, the solution should be injected over approx. 2 minutes, e.g. in haemodialysis patients via the arterio-venous fistula at the end of dialysis.

Due to intra-patient variability, occasional individual haemoglobin values for a patient above and below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed through dose management, with consideration for the haemoglobin target range of 10 g/dl (6.2 mmol/l) to 12 g/dl (7.5 mmol/l). A sustained haemoglobin level of greater than 12 g/dl (7.5 mmol/l) should be avoided; guidance for appropriate dose adjustment for when haemoglobin values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.

A rise in haemoglobin of greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided. If it occurs, appropriate dose adjustment should be made as provided. If the rate of rise in haemoglobin is greater than 2 g/dl (1.25 mmol/l) in one month or if the haemoglobin level is increasing and approaching 12 g/dl (7.45 mmol/l), the dose is to be reduced by approximately 25 %. If the haemoglobin level continues to increase, therapy should be interrupted until the haemoglobin level begins to decrease, at which point therapy should be restarted at a dose approximately 25 % below the previously administered dose.

Patients should be monitored closely to ensure that the lowest approved dose of NeoRecormon is used to provide adequate control of the symptoms of anaemia.

In the presence of hypertension or existing cardiovascular, cerebrovascular or peripheral vascular diseases, the weekly increase in Hb and the target Hb should be determined individually taking into account the clinical picture.

Treatment with NeoRecormon is divided into two stages.

1. Correction phase

- Subcutaneous administration:

- The initial dosage is 3 x 20 IU/kg body weight per week. The dosage may be increased every 4 weeks by 3 x 20 IU/kg and week if the increase of Hb is not adequate (< 0.25 g/dl per week).

- The weekly dose can also be divided into daily doses.

- Intravenous administration:

The initial dosage is 3 x 40 IU/kg per week. The dosage may be raised after 4 weeks to 80 IU/kg three times per week - and by further increments of 20 IU/kg if needed, three times per week, at monthly intervals.

For both routes of administration, the maximum dose should not exceed 720 IU/kg per week.

2. Maintenance phase

To maintain an Hb of between 10 and 12 g/dl, the dosage is initially reduced to half of the previously administered amount. Subsequently, the dose is adjusted at intervals of one or two weeks individually for the patient (maintenance dose).

In the case of subcutaneous administration, the weekly dose can be given as one injection per week or in divided doses three or seven times per week. Patients who are stable on a once weekly dosing regimen may be switched to once every two weeks administration. In this case dose increases may be necessary.

Results of clinical studies in children have shown that, on average, the younger the patients, the higher the NeoRecormon doses required. Nevertheless, the recommended dosing schedule should be followed as the individual response cannot be predicted.

Treatment with NeoRecormon is normally a long-term therapy. It can, however, be interrupted, if necessary, at any time. Data on the once weekly dosing schedule are based on clinical studies with a treatment duration of 24 weeks.

Treatment of symptomatic chemotherapy-induced anaemia in cancer patients:

NeoRecormon should be administered by the subcutaneous route to patients with anaemia (e.g. haemoglobin concentration

The weekly dose can be given as one injection per week or in divided doses 3 to 7 times per week.

The recommended initial dose is 30,000 IU per week (corresponding to approximately 450 IU/kg body weight per week, based on an average weighted patient).

Due to intra-patient variability, occasional individual haemoglobin values for a patient above and below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed through dose management, with consideration for the haemoglobin target range of 10 g/dl (6.2 mmol/l) to 12 g/dl (7.5 mmol/l). A sustained haemoglobin level of greater than 12 g/dl (7.5 mmol/l) should be avoided; guidance for appropriate dose adjustment for when haemoglobin values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.

If, after 4 weeks of therapy, the haemoglobin value has increased by at least 1 g/dl (0.62 mmol/l), the current dose should be continued. If the haemoglobin value has not increased by at least 1 g/dl (0.62 mmol/l), a doubling of the weekly dose should be considered. If, after 8 weeks of therapy, the haemoglobin value has not increased by at least 1 g/dl (0.62 mmol/l), response is unlikely and treatment should be discontinued.

The therapy should be continued up to 4 weeks after the end of chemotherapy.

The maximum dose should not exceed 60,000 IU per week.

Once the therapeutic objective for an individual patient has been achieved, the dose should be reduced by 25 to 50 % in order to maintain haemoglobin at that level. Appropriate dose titration should be considered.

If the haemoglobin exceeds 12 g/dl (7.5 mmol/l), the dose should be reduced by approximately 25 to 50 %. Treatment with NeoRecormon should be temporarily discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at approximately 25 % lower than the previous dose after haemoglobin levels fall to 12 g/dl (7.5 mmol/l) or below.

If the rise in haemoglobin is greater than 2 g/dl (1.3 mmol/l) in 4 weeks, the dose should be reduced by 25 to 50 %.

Patients should be monitored closely to ensure that the lowest approved dose of NeoRecormon is used to provide adequate control of the symptoms of anaemia.

Treatment for increasing the amount of autologous blood:

The reconstituted solution is administered intravenously over approx. 2 minutes or subcutaneously.

NeoRecormon is administered twice weekly over 4 weeks. On those occasions where the patient's PCV allows blood donation, i.e. PCV

During the entire treatment period, a PCV of 48 % should not be exceeded.

The dosage must be determined by the surgical team individually for each patient as a function of the required amount of pre-donated blood and the endogenous red cell reserve:

1. The required amount of pre-donated blood depends on the anticipated blood loss, use of blood conserving procedures and the physical condition of the patient.

This amount should be that quantity which is expected to be sufficient to avoid homologous blood transfusions.

The required amount of pre-donated blood is expressed in units whereby one unit in the nomogram is equivalent to 180 ml red cells.

2. The ability to donate blood depends predominantly on the patient's blood volume and baseline PCV. Both variables determine the endogenous red cell reserve, which can be calculated according to the following formula.

Endogenous red cell reserve = blood volume [ml] x (PCV - 33) ÷ 100

Women: blood volume [ml] = 41 [ml/kg] x body weight [kg] + 1200 [ml]

Men: blood volume [ml] = 44 [ml/kg] x body weight [kg] + 1600 [ml] (body weight

The indication for NeoRecormon treatment and, if given, the single dose should be determined from the required amount of pre-donated blood and the endogenous red cell reserve according to the following graphs.

The single dose thus determined is administered twice weekly over 4 weeks. The maximum dose should not exceed 1600 IU/kg body weight per week for intravenous or 1200 IU/kg per week for subcutaneous administration.

4.3 Contraindications

Hypersensitivity to the active substance or any of the excipients.

Poorly controlled hypertension.

In the indication "increasing the yield of autologous blood": myocardial infarction or stroke in the month preceding treatment, unstable angina pectoris, increased risk of deep venous thrombosis such as history of venous thromboembolic disease.

NeoRecormon Multidose contains benzyl alcohol as a preservative and must therefore not be given to infants or young children up to three years old.

4.4 Special Warnings And Precautions For Use

NeoRecormon should be used with caution in the presence of refractory anaemia with excess blasts in transformation, epilepsy, thrombocytosis, and chronic liver failure. Folic acid and vitamin B₁₂ deficiencies should be ruled out as they reduce the effectiveness of NeoRecormon.

In order to ensure effective erythropoiesis, iron status should be evaluated for all patients prior to and during treatment and supplementary iron therapy may be necessary and conducted in accordance with therapeutic guidelines.

Severe aluminium overload due to treatment of renal failure may compromise the effectiveness of NeoRecormon.

The indication for NeoRecormon treatment of nephrosclerotic patients not yet undergoing dialysis should be defined individually, as a possible acceleration of progression of renal failure cannot be ruled out with certainty.

Pure red cell aplasia caused by neutralising anti-erythropoietin antibodies has been reported in association with erythropoietin therapy, including NeoRecormon. These antibodies have been shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have neutralising antibodies to erythropoietin should not be switched to NeoRecormon (see section 4.8).

A paradoxical decrease in haemoglobin and development of severe anaemia associated with low reticulocyte counts should prompt to discontinue treatment with epoetin and perform anti-erythropoietin antibody testing. Cases have been reported in patients with hepatitis C treated with interferon and ribavirin, when epoetins are used concomitantly. Epoetins are not approved in the management of anaemia associated with hepatitis C.

In chronic renal failure patients an increase in blood pressure or aggravation of existing hypertension, especially in cases of rapid PCV increase can occur. These increases in blood pressure can be treated with medicinal products. If blood pressure rises cannot be controlled by drug therapy, a transient interruption of NeoRecormon therapy is recommended. Particularly at beginning of therapy, regular monitoring of the blood pressure is recommended, including between dialyses. Hypertensive crisis with encephalopathy-like symptoms may occur and require the immediate attention of a physician and intensive medical care. Particular attention should be paid to sudden stabbing migraine like headaches as a possible warning sign.

In chronic renal failure patients there may be a moderate dose-dependent rise in the platelet count within the normal range during treatment with NeoRecormon, especially after intravenous administration. This regresses during the course of continued therapy. It is recommended that the platelet count be monitored regularly during the first 8 weeks of therapy.

Haemoglobin concentration

In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical trials, an increased risk of death and serious cardiovascular events or cerebrovascular events including stroke was observed when erythropoiesis stimulating agents (ESAs) were administered to target a haemoglobin of greater than 12 g/dl (7.5 mmol/l).

Controlled clinical trials have not shown significant benefits attributable to the administration of epoetins when haemoglobin concentration is increased beyond the level necessary to control symptoms of anaemia and to avoid blood transfusion.

Effect on tumour growth

Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, there is a concern that epoetins could stimulate the growth of tumours. In several controlled studies, epoetins have not been shown to improve overall survival or decrease the risk of tumour progression in patients with anaemia associated with cancer.

In controlled clinical studies, use of NeoRecormon and other erythropoiesis-stimulating agents (ESAs) have shown:

- shortened time to tumour progression in patients with advanced head and neck cancer receiving radiation therapy when administered to target a haemoglobin of greater than 14 g/dl (8.7 mmol/l),

- shortened overall survival and increased deaths attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to target a haemoglobin of 12-14 g/dl (7.5-8.7 mmol/l),

- increased risk of death when administered to target a haemoglobin of 12 g/dl (7.5 mmol/l) in patients with active malignant disease receiving neither chemotherapy nor radiation therapy. ESAs are not indicated for use in this patient population.

In view of the above, in some clinical situations blood transfusion should be the preferred treatment for the management of anaemia in patients with cancer. The decision to administer recombinant erythropoietins should be based on a benefit-risk assessment with the participation of the individual patient, which should take into account the specific clinical context. Factors that should be considered in this assessment should include the type of tumour and its stage; the degree of anaemia; life-expectancy; the environment in which the patient is being treated; and patient preference (see section 5.1)

There may be an increase in blood pressure which can be treated with drugs. It is therefore recommended to monitor blood pressure, in particular in the initial treatment phase in cancer patients.

Platelet counts and haemoglobin level should also be monitored at regular intervals in cancer patients.

In patients in an autologous blood predonation programme there may be an increase in platelet count, mostly within the normal range. Therefore, it is recommended that the platelet count be determined at least once a week in these patients. If there is an increase in platelets of more than 150 x 10⁹/l or if platelets rise above the normal range, treatment with NeoRecormon should be discontinued.

In chronic renal failure patients an increase in heparin dose during haemodialysis is frequently required during the course of therapy with NeoRecormon as a result of the increased packed cell volume. Occlusion of the dialysis system is possible if heparinisation is not optimum.

Early shunt revision and thrombosis prophylaxis by administration of acetylsalicylic acid, for example, should be considered in chronic renal failure patients at risk of shunt thrombosis.

Serum potassium and phosphate levels should be monitored regularly during NeoRecormon therapy. Potassium elevation has been reported in a few uraemic patients receiving NeoRecormon, though causality has not been established. If an elevated or rising potassium level is observed then consideration should be given to ceasing NeoRecormon administration until the level has been corrected.

For use of NeoRecormon in an autologous predonation programme, the official guidelines on principles of blood donation must be considered, in particular:

- only patients with a PCV

- special care should be taken with patients below 50 kg weight;

- the single volume drawn should not exceed approx. 12 % of the patient's estimated blood volume.

Treatment should be reserved for patients in whom it is considered of particular importance to avoid homologous blood transfusion taking into consideration the risk/benefit assessment for homologous transfusions.

Misuse by healthy persons may lead to an excessive increase in packed cell volume. This may be associated with life-threatening complications of the cardiovascular system.

NeoRecormon Multidose contains up to 5.0 mg phenylalanine/vial as an excipient. Therefore this should be taken into consideration in patients affected with severe forms of phenylketonuria.

NeoRecormon in reconstituted multidose solution contains benzyl alcohol which may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”.

In order to improve the traceability of ESAs, the name of the prescribed ESA should be clearly recorded (or: stated) in the patient file.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The clinical results obtained so far do not indicate any interaction of NeoRecormon with other medicinal products.

Animal experiments revealed that epoetin beta does not increase the myelotoxicity of cytostatic medicinal products like etoposide, cisplatin, cyclophosphamide, and fluorouracil.

4.6 Pregnancy And Lactation

For epoetin beta no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see 5.3).

Caution should be exercised when prescribing to pregnant women.

4.7 Effects On Ability To Drive And Use Machines

NeoRecormon has no influence on the ability to drive and use machines.

4.8 Undesirable Effects

Based on results from clinical trials including 1725 patients approximately 8 % of patients treated with NeoRecormon are expected to experience adverse reactions.

- Anaemic patients with chronic renal failure

The most frequent adverse reaction during treatment with NeoRecormon is an increase in blood pressure or aggravation of existing hypertension, especially in cases of rapid PCV increase (see section 4.4). Hypertensive crisis with encephalopathy-like symptoms (e.g. headaches and confused state, sensorimotor disorders - such as speech disturbance or impaired gait - up to tonoclonic seizures) may also occur in individual patients with otherwise normal or low blood pressure (see section 4.4).

Shunt thromboses may occur, especially in patients who have a tendency to hypotension or whose arteriovenous fistulae exhibit complications (e.g. stenoses, aneurisms), see section 4.4. In most cases, a fall in serum ferritin values simultaneous with a rise in packed cell volume is observed (see section 4.4). In addition, transient increases in serum potassium and phosphate levels have been observed in isolated cases (see section 4.4).

In isolated cases, neutralising anti erythropoietin antibody-mediated pure red cell aplasia (PRCA) associated with NeoRecormon therapy has been reported. In case anti-erythropoietin antibody-mediated PRCA is diagnosed, therapy with NeoRecormon must be discontinued and patients should not be switched to another erythropoietic protein (see section 4.4).

The incidences of undesirable effects in clinical trials, considered related to treatment with NeoRecoromon are shown in the table below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class	Adverse Drug Reaction	Incidence
Vascular disorders	Hypertensive crisis Hypertension	Uncommon (>0.1%, <1%) Common (>1%, <10%)
Nervous system disorders	Headache	Common (>1%, <10%)
Blood and the lymphatic system disorders	Shunt thrombosis Thrombocytosis	Rare (>0.01%, <0.1%) Very rare (<0.01%)

- Patients with cancer

Epoetin beta treatment-related headache and hypertension which can be treated with drugs are common (>1 %, <10 %) (see section 4.4).

In some patients, a fall in serum iron parameters is observed (see section 4.4).

Clinical studies have shown a higher frequency of thromboembolic events in cancer patients treated with NeoRecormon compared to untreated controls or placebo. In patients treated with NeoRecormon, this incidence is 7 % compared to 4 % in controls; this is not associated with any increase in thromboembolic mortality compared with controls.

The incidences of undesirable effects in clinical trials, considered related to treatment with NeoRecoromon are shown in the table below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class	Adverse Drug Reaction	Incidence
Vascular disorders	Hypertension	Common (>1%, <10%)
Blood and the lymphatic system disorders	Thromboembolic event	Common (>1%, <10%)
Nervous system disorders	Headache	Common (>1%, <10%)

- Patients in an autologous blood predonation programme

Patients in an autologous blood predonation programme have been reported to show a slightly higher frequency of thromboembolic events. However, a causal relationship with treatment with NeoRecormon could not be established.

In placebo controlled trials temporary iron deficiency was more pronounced in patients treated with NeoRecormon than in controls (see section 4.4).

The incidences of undesirable effects in clinical trials, considered related to treatment with NeoRecoromon are shown in the table below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class	Adverse Drug Reaction	Incidence
Nervous system disorders	Headache	Common (>1%, <10%)

- All indications

Rarely (

In very rare cases (

Data from a controlled clinical trial with epoetin alfa or darbepoetin alfa, reported an incidence of stroke as common (

4.9 Overdose

The therapeutic margin of NeoRecormon is very wide. Even at very high serum levels no symptoms of poisoning have been observed.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antianaemic, ATC code: B03XA

Epoetin beta is identical in its amino acid and carbohydrate composition to erythropoietin that has been isolated from the urine of anaemic patients.

Erythropoietin is a glycoprotein that stimulates the formation of erythrocytes from its committed progenitors. It acts as a mitosis stimulating factor and differentiation hormone.

The biological efficacy of epoetin beta has been demonstrated after intravenous and subcutaneous administration in various animal models in vivo (normal and uraemic rats, polycythaemic mice, dogs). After administration of epoetin beta, the number of erythrocytes, the Hb values and reticulocyte counts increase as well as the ⁵⁹Fe-incorporation rate.

An increased ³H-thymidine incorporation in the erythroid nucleated spleen cells has been found in vitro (mouse spleen cell culture) after incubation with epoetin beta.

Investigations in cell cultures of human bone marrow cells showed that epoetin beta stimulates erythropoiesis specifically and does not affect leucopoiesis. Cytotoxic actions of epoetin beta on bone marrow or on human skin cells were not detected.

After single dose administration of epoetin beta no effects on behaviour or locomotor activity of mice and circulatory or respiratory function of dogs were observed.

In a randomised, double-blind, placebo-controlled study of 4,038 CRF patients not on dialysis with type 2 diabetes and haemoglobin levels

Erythropoietin is a growth factor that primarily stimulates red cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells.

Survival and tumour progression have been examined in five large controlled studies involving a total of 2833 patients, of which four were double-blind placebo-controlled studies and one was an open-label study. Two of the studies recruited patients who were being treated with chemotherapy. The target haemoglobin concentration in two studies was >13 g/dl; in the remaining three studies it was 12-14 g/dl. In the open-label study there was no difference in overall survival between patients treated with recombinant human erythropoietin and controls. In the four placebo-controlled studies the hazard ratios for overall survival ranged between 1.25 and 2.47 in favour of controls. These studies have shown a consistent unexplained statistically significant excess mortality in patients who have anaemia associated with various common cancers who received recombinant human erythropoietin compared to controls. Overall survival outcome in the trials could not be satisfactorily explained by differences in the incidence of thrombosis and related complications between those given recombinant human erythropoietin and those in the control group.

An individual patient data based meta-analysis, which included data from all 12 controlled clinical studies in anaemic cancer patients conducted with NeoRecormon (n=2301), showed an overall hazard ratio point estimate for survival of 1.13 in favour of controls (95 % CI 0.87, 1.46). In patients with baseline haemoglobin

A patient-level data analysis has also been performed on more than 13,900 cancer patients (chemo-, radio-, chemoradio- or no therapy) participating in 53 controlled clinical trials involving several epoetins. Meta-analysis of overall survival data produced a hazard ratio point estimate of 1.06 in favour of controls (95% CI: 1.00, 1.12; 53 trials and 13,933 patients) and for cancer patients receiving chemotherapy, the overall survival hazard ratio was 1.04 (95% CI: 0.97, 1.11; 38 trials and 10, 441 patients). Meta-analyses also indicate consistently a significantly increased relative risk of thromboembolic events in cancer patients receiving recombinant human erythropoietin (see Section 4.4).

In very rare cases, neutralising anti-erythropoietin antibodies with or without pure red cell aplasia (PRCA) occurred during rHuEPO therapy.

5.2 Pharmacokinetic Properties

Pharmacokinetic investigations in healthy volunteers and uraemic patients show that the half-life of intravenously administered epoetin beta is between 4 and 12 hours and that the distribution volume corresponds to one to two times the plasma volume. Analogous results have been found in animal experiments in uraemic and normal rats.

After subcutaneous administration of epoetin beta to uraemic patients, the protracted absorption results in a serum concentration plateau, whereby the maximum concentration is reached after an average of 12 - 28 hours. The terminal half-life is higher than after intravenous administration, with an average of 13 - 28 hours.

Bioavailability of epoetin beta after subcutaneous administration is between 23 and 42 % as compared with intravenous administration.

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 toxicity to reproduction.

A carcinogenicity study with homologous erythropoietin in mice did not reveal any signs of proliferative or tumourigenic potential.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lyophilisate:

Urea,

Sodium chloride,

Polysorbate 20,

Sodium dihydrogen phosphate,

Disodium hydrogen phosphate,

Calcium chloride,

Glycine,

L-Leucine,

L-Isoleucine,

L-Threonine,

L-Glutamic acid,

L-Phenylalanine.

Solvent:

Benzyl alcohol,

Benzalkonium chloride,

Water for injections.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. (content of accompanying solvent ampoule).

6.3 Shelf Life

3 years.

Chemical and physical in-use stability of the reconstituted solution has been demonstrated for one month at 2°C - 8°C. From a microbiological point of view, once opened, the reconstituted solution may be stored for maximum of one month at 2°C - 8°C. Other in-use storage times and conditions are the responsibility of the user.

6.4 Special Precautions For Storage

Store in a refrigerator (2°C – 8°C).

Keep the vial in the outer carton, in order to protect from light.

For the purpose of ambulatory use, the patient may remove the unreconstituted product from the refrigerator and store it at room temperature (not above 25°C) for one single period of up to 5 days.

Leaving the reconstituted solution outside the refrigerator should be limited to the time necessary for preparing the injections.

For storage conditions of the reconstituted medicinal product see section 6.3.

6.5 Nature And Contents Of Container

Lyophilisate (50,000 IU) for solution for injection in a vial (type I glass) with a stopper (teflonised rubber) and 10 ml of solvent in an ampoule (type I glass), with one reconstitution and withdrawal device with one needle (21G2), and one disposable syringe (polypropylene and polyethylene) (10 ml).

6.6 Special Precautions For Disposal And Other Handling

NeoRecormon Multidose is supplied as a lyophilisate for solution for injection in vials. This is dissolved with the contents of the accompanying solvent ampoule by means of a reconstitution and withdrawal device according to the instructions given below. Only solutions which are clear or slightly opalescent, colourless and practically free of visible particles may be injected. Do not use glass materials for injection, use only plastic materials.

This is a multidose preparation from which different single doses can be withdrawn over a period of 1 month after dissolution. To avoid the risk of contamination of the contents always observe aseptic techniques (i.e. use disposable sterile syringes and needles to administer each dose) and strictly follow the handling instructions below. Before withdrawing each dose disinfect the rubber seal of the withdrawal device with alcohol to prevent contamination of the contents by repeated needle insertions.

Preparation of NeoRecormon Multidose solution

(1) Take the vial with the freeze-dried substance out of the package. Write the date of reconstitution and expiry on the label (expiry is 1 month after reconstitution).

(2) Remove the plastic cap from the vial.

(3) Disinfect the rubber seal with alcohol.

(4) Take the reconstitution and withdrawal device (which allows sterile air exchange) out of the blister and remove the protective cover from the spike.

(5) Attach the device to the vial until the snap lock clicks home.

(6) Put the green needle on the syringe contained in the package and remove the needle cover.

(7) Hold the OPC (One-Point-Cut) ampoule with the blue point upwards. Shake or tap the ampoule to get any fluid in the stem into the body of the ampoule. Take hold of the stem and snap off away from you. Withdraw all the solvent into the syringe. Disinfect the rubber seal of the device with alcohol.

(8) Penetrate the seal with the needle to a depth of about 1 cm and slowly inject the solvent into the vial. Then disconnect the syringe (with needle) from the device.

(9) Swirl the vial gently until the lyophilisate has dissolved. Do not shake. Check that the solution is clear, colourless and practically free from particles. Put the protective cap on the top of the device.

(10) Before and after reconstitution NeoRecormon Multidose must be stored at +2° to +8°C (refrigerator).

Preparation of a single injection

(1) Before withdrawing each dose disinfect the rubber seal of the device with alcohol.

(2) Place a 26G needle onto an appropriate single-use syringe (max.1 ml).

(3) Remove the needle cover and insert the needle through the rubber seal of the device. Withdraw NeoRecormon solution into the syringe, expel air from the syringe into the vial and adjust the amount of NeoRecormon solution in the syringe to the dose prescribed. Then disconnect the syringe (with needle) from the device.

(4) Replace the needle by a new one (the new needle should have the size which you normally use for injections).

(5) Remove the needle cover and carefully expel air from the needle by holding the syringe vertically and gently pressing the plunger upwards until a bead of liquid appears at the needle tip.

For subcutaneous injection, clean the skin at the site of injection using an alcohol wipe. Form a skin fold by pinching the skin between the thumb and the forefinger. Hold the syringe near to the needle and insert the needle into the skin with a quick, firm action. Inject NeoRecormon solution. Withdraw the needle quickly and apply pressure over the injection site with a dry, sterile pad.

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

7. Marketing Authorisation Holder

Roche Registration Limited

6 Falcon Way

Shire Park

Welwyn Garden City

AL7 1TW

United Kingdom

8. Marketing Authorisation Number(S)

EU/1/97/031/019

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of the first authorisation: 16 July 1997

Date of the last renewal: 16 July 2007

10. Date Of Revision Of The Text

6^th October 2011

LEGAL STATUS

POM

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

Nabilone 1mg Capsules

Nabilone 1 mg Capsules

(nabilone)

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 you experience any side effect and this becomes serious, tell your doctor or pharmacist.

In this leaflet:

• 1. What Nabilone is and what it is used for


• 2. Before you take Nabilone Capsules


• 3. How to take Nabilone Capsules


• 4. Possible side effects


• 5. How to store Nabilone Capsules


• 6. Further information

What Nabilone Is And What It Is Used For

Nabilone is a medicine that helps to reduce nausea and vomiting caused by many anticancer medicines.

Nabilone is often used when other medicines have not helped your nausea or vomiting.

Nabilone is a man-made chemical known as a cannabinoid. It is not made from the Cannabis plant but it is similar to some marijuana extracts and can cause similar effects.

Before You Take Nabilone Capsules

Do not take Nabilone

• If you are allergic (hypersensitive) to any of the other ingredients of Nabilone Capsules (these are listed in section 6, "Further Information").


• If your nausea / vomiting is not due to anticancer treatment.


• If you are under 18 years. Nabilone is not meant for children.

Take special care with Nabilone

It is best if you take Nabilone Capsules in hospital, as you may experience side effects.

Tell your doctor before you start treatment if you have any of the following problems or if you develop any of these during treatment:

• Any liver problems.


• High blood pressure or any other heart problem.


• Any mental illness, for example depression or schizophrenia.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

In particular, tell your doctor if you are taking any sleeping pills, pain killers or tranquillisers.

Taking Nabilone with alcohol

Do not drink alcohol while you are taking Nabilone.

Pregnancy and breast-feeding

Tell your doctor before you start treatment

• If you are pregnant, if you think that you are pregnant, or if you intend to become pregnant.


• If you are breast-feeding or planning to breast-feed.

Your doctor will then decide if you can take this medicine.

Driving and using machines

Nabilone Capsules may cause side effects such as sleepiness, confusion, hallucinations, a feeling of dizziness or spinning, poor muscle co-ordination, problems with your sight and problems with concentration. These side effects may occur up to 3 days after taking Nabilone. This may affect your ability to drive and operate machinery. Do not drive or operate machinery if you experience any of these side effects.

How To Take Nabilone Capsules

Always take Nabilone exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure how to take it. Your doctor will usually start you on the lowest possible dose.

It is best if you take Nabilone Capsules in hospital, especially the first time that you take Nabilone. This is because you may experience side effects.

The hospital doctor or nurse may give you your first dose the night before you start chemotherapy and the second dose one to three hours before it begins.

Swallow the capsules with water.

Dose

• The usual dose is 1 or 2 capsules twice a day.


• You should never take more than 2 capsules three times a day. You can take Nabilone while you are having chemotherapy treatment and for up to 2 days after your last dose of chemotherapy.

The dosing recommendations for elderly patients are the same as for other adults.

If you take more Nabilone than you should

If you ever take too many capsules, tell your doctor or get someone to take you to the nearest hospital casualty department immediately together with your medicine to show to the doctor.

If you forget to take Nabilone

If you miss a dose, wait until it is time for the next dose, and then continue as before.

Do not take a double dose to make up for a forgotten dose.

Possible Side Effects

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

Side effects that you may experience are:

• Feeling sleepy, relaxed, or "high". A few patients have had hallucinations, felt confused, depressed, anxious or had other changes in their mood or mental state.


• A feeling of dizziness or spinning, especially when you stand up.


• Poor muscle co-ordination.


• Dry mouth, problems with your sight or concentration, difficulty sleeping, or headaches.


• Shaking, a faster heart beat than normal, low blood pressure, losing your appetite and stomach pains.

Any changes in your mood, such as feeling depressed, relaxed or "high", may last for 2 or 3 days after you stop taking Nabilone. You may find that you get used to these feelings.

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

How To Store Nabilone Capsules

• Keep Nabilone Capsules out of the reach and sight of children.


• Do not use Nabilone after the expiry date which is stated on the bottle and carton after "EXP". The expiry date refers to the last day of that month.


• Keep the container tightly closed.


• Store your capsules at room temperature (15-25°C) in a dry place.


• If your doctor tells you to stop taking the capsules, please take them back to the pharmacist. Medicines should not be disposed of via wastewater or household waste.


• Only keep the capsules if your doctor tells you to.

Further Information

What Nabilone contains

Active substance: Nabilone. Each capsule contains 1 mg of nabilone.
Other ingredients: Povidone, starch, gelatin and the colourants E132, E172 and E171.

What Nabilone looks like and contents of the pack

• Nabilone capsules are blue and white and have CL 3101 printed on them.


• Each bottle or blister pack of Nabilone contains 20 capsules.

Marketing Authorisation Holder

Meda Pharmaceuticals Ltd.

Skyway House

Parsonage Road

Takeley

Bishop's Stortford

CM22 6PU

UK

Manufacturer

Dales Pharmaceuticals Limited

Snaygill Industrial Estate

Keighley Road

Skipton

North Yorkshire

BD23 2RW

UK

For any information about this medicine, please contact the Marketing Authorisation Holder.

This leaflet was last approved in July 2009.

F687

Neupogen Vials

Neupogen 30 MU (0.3 mg/ml)

Neupogen 48 MU (0.3 mg/ml)

solution for injection

filgrastim

Read all of this leaflet carefully before you start using this medicine.

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


• If you have any further questions, ask your doctor, nurse 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 gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor, nurse or pharmacist.

In this leaflet:

1. What Neupogen is and what it is used for

2. Before you use Neupogen

3. How to use Neupogen

4. Possible side effects

5. How to store Neupogen

6. Further information

What Neupogen Is And What It Is Used For

Neupogen is a white blood cell growth factor (granulocyte colony stimulating factor) and belongs to a group of medicines called cytokines. Growth factors are proteins that are produced naturally in the body but they can also be made using biotechnology for use as a medicine. Neupogen works by encouraging the bone marrow to produce more white blood cells.

A reduction in the number of white blood cells (neutropenia) can occur for several reasons and makes your body less able to fight infection. Neupogen stimulates the bone marrow to produce new white cells quickly.

Neupogen can be used:

• to increase the number of white blood cells after treatment with chemotherapy to help prevent infections;


• to increase the number of white blood cells after a bone marrow transplant to help prevent infections;


• before high-dose chemotherapy to make the bone marrow produce more stem cells which can be collected and given back to you after your treatment. These can be taken from you or from a donor. The stem cells will then go back into the bone marrow and produce blood cells;


• to increase the number of white blood cells if you suffer from severe chronic neutropenia to help prevent infections;


• in patients with advanced HIV infection which will help reduce the risk of infections.

Before You Use Neupogen

Do not use Neupogen

• if you are allergic (hypersensitive) to filgrastim or any of the other ingredients of Neupogen;


• if you have Kostman’s Syndrome (severe condition acquired at birth), your doctor will discuss with you whether or not you should take Neupogen.

Take special care with Neupogen

Please tell your doctor before starting treatment:

• if you have sickle cell anaemia, as Neupogen may cause sickle cell crisis;


• if you have osteoporosis (bone disease).

If you are a stem cell donor, you must be aged between 16 and 60 years.

Take special care with other products that stimulate white blood cells.

Neupogen is one of a group of products that stimulate the production of white blood cells. Your healthcare professional should always record the exact product you are using.

Using other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription as they may affect the way Neupogen works.

Pregnancy and breast feeding

Neupogen has not been tested in pregnant women. It is important to tell your doctor if you are pregnant, think you may be pregnant or plan to get pregnant, as the doctor may decide that you should not use this medicine. Neupogen could affect your ability to become pregnant or stay pregnant.

You must not use this medicine if you are breast feeding.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Neupogen should not affect your ability to drive and use machines. However, it is advisable to wait and see how you feel after taking Neupogen and before driving or operating machinery.

Important information about some of the ingredients of Neupogen

Neupogen contains less than 1 mmol (23 mg) sodium per 0.3 mg/ml, i.e. essentially sodium free.

Neupogen contains sorbitol (E420), if you have been told by your doctor that you have a reaction to some sugars, contact your doctor before taking this medicinal product.

How To Use Neupogen

Always use Neupogen exactly as your doctor has told you. You should check with your doctor, nurse or pharmacist if you are not sure.

How is Neupogen given and how much should I take?

Neupogen is usually given as a daily injection into the tissue just under the skin (known as a subcutaneous injection). It can also be given as a daily slow injection into the vein (known as an intravenous infusion). The usual dose varies depending on your illness and weight. Your doctor will tell you how much Neupogen you should take.

How long will I have to take Neupogen?

You will need to take Neupogen until your white blood cell count is normal. Regular blood tests will be taken to monitor the number of white blood cells in your body. Your doctor will tell you how long you will need to take Neupogen.

Neupogen and children

Neupogen is used to treat children who are receiving chemotherapy or who suffer from severe low white blood cell count (neutropenia). The dosing in children is the same as for adults.

If you use more Neupogen than you should

If you think you have had more than you should, contact your doctor as soon as possible.

If you forget to use Neupogen

If you have missed an injection, contact your doctor as soon as possible.

If you have any further questions on the use of this product, ask your doctor, nurse or pharmacist.

Neupogen Vials Side Effects

Please tell your doctor immediately during treatment:

• if you experience an allergic reaction including weakness, drop in blood pressure, difficulty breathing, swelling of the face (anaphylaxis), skin rash, itchy rash (urticaria), swelling of the face lips, mouth, tongue or throat (angioedema) and shortness of breath (dyspnoea);


• if you experience a cough, fever and difficulty breathing (dyspnoea) as this can be a sign of Adult Respiratory Distress Syndrome (ARDS);


• if you get left upper belly (abdominal) pain or pain at the tip of your shoulder, as there may be a problem with your spleen.

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

Very common side effects (seen in more than 1 in 10 people who take Neupogen):

in cancer patients

• nausea and vomiting


• pain in your bones (musculoskeletal pain), which can be helped by taking standard pain relief medicines (analgesics)


• changes in blood chemistry

in normal stem cell donors

• headache


• increase in white blood cells (leukocytosis), decrease of platelets which reduces the bloods ability to clot (thrombocytopenia)


• pain in your bones (musculoskeletal pain), which can be treated with standard pain relief tablets

in severe chronic neutropenia patients

• low red blood cell count (anaemia), enlargement of the spleen (splenomegaly)


• changes in blood chemistry


• pain in your bones (musculoskeletal pain)


• nose bleeds (epistaxis)

in HIV patients

• pain in your bones (musculoskeletal)

Common side effects (seen in more than 1 in 100 people taking Neupogen):

in cancer patients

• tiredness (fatigue), generalised weakness


• headache


• constipation, anorexia, diarrhoea, soreness and swelling of the digestive tract lining which runs from the mouth to the anus (mucositis)


• chest pain, pain in your bones (musculoskeletal pain)


• cough, sore throat


• unusual hair loss or thinning (alopecia), skin rash

in normal stem cell donors

• changes in blood chemistry

in severe chronic neutropenia patients

• headache


• diarrhoea


• decrease of platelets which reduces the bloods ability to clot (thrombocytopenia)


• enlargement of the liver (hepatomegaly)


• disease which causes bones to become less dense, making them weaker, more brittle and likely to break (osteoporosis)


• unusual hair loss or thinning (alopecia), injection site pain, rash

in HIV patients

• enlargement of the spleen (splenomegaly)

Uncommon side effects (seen in more than 1 in 1000 people taking Neupogen):

in cancer patients

• unspecified pain

in normal stem cell donors

• changes in blood chemistry


• enlargement of the spleen (splenomegaly)

in severe chronic neutropenia patients

• enlargement of the spleen (splenomegaly)


• blood in the urine (haematuria)


• excess protein in the urine (proteinuria)

Rare side effects (seen in more than 1 in 10,000 people taking Neupogen):

in cancer patients

• problems with your blood vessels (vascular disorders)

Very rare side effects (seen in less than 1 in 10,000 people taking Neupogen):

in cancer patients

• pain when passing urine (dysuria)

Frequency unknown

in cancer patients

• inflammation of the blood vessels in the skin (cutaneous vasculitis)


• plum-coloured, raised, painful sores on the limbs and sometimes the face and neck with a fever (Sweet’s syndrome)


• worsening of rheumatoid arthritis


• a cough, fever and difficulty breathing (dyspnoea)


• problems with your lungs (pulmonary) including serious lung infection (interstitial pneumonia), swelling and/or fluid in the lungs (pulmonary oedema)


• pain and swelling of the joints, similar to gout (pseudogout)

in normal stem cell donors

• cough, fever and difficulty breathing or coughing up blood.

Some changes may occur in your blood, but these will be detected by routine blood tests.

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

How To Store Neupogen

Keep out of the reach and sight of children.

Store in a refrigerator (2°C – 8°C).

Accidental freezing will not harm Neupogen.

Do not use Neupogen after the expiry date which is stated on the syringe label and carton after EXP. The expiry date refers to the last day of that month.

Do not use Neupogen if you notice discolouration, cloudiness or particles, it should be a clear, colourless liquid.

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

Further Information

What Neupogen contains

• The active substance is filgrastim 30 million units in a 1 ml vial (0.3 mg/ml) or 48 million units in a 1.6 ml vial (0.3 mg/ml).


• The other ingredients are sodium acetate, sorbitol (E420), polysorbate 80, water for injections.

What Neupogen looks like and contents of the pack

Neupogen is a clear colourless solution for injection (injection)/concentrate for solution for infusion (sterile concentrate) in a vial.

Neupogen is available in packs of one or five vials. Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Amgen Europe B.V.

Minervum 7061

4817 ZK Breda

The Netherlands

This medicine is marketed in the European Economic Area under the name Neupogen, except in Cyprus, Greece and Italy where it is called Granulokine.

This leaflet was last approved in July 2010.

Detailed information on this medicine can be found on the following web sites:

• For UK residents, the Medicines and Healthcare products Regulatory Agency (MHRA) www.mhra.gov.uk.

Local representative of the marketing authorisation holder:

United Kingdom

Amgen Limited

240 Cambridge Science Park

Cambridge

CB4 0WD

United Kingdom

Tel:01223 420305

Neupogen is available on the Royal National Institute of the Blind (RNIB) Medicines Information Line who can provide this leaflet in a number of physical formats including large/clear print, Braille and audio CD.

You can also listen to this leaflet when you call the Medicines Information Line.

The RNIB Medicines Information Line is free to use and available 24 hours a day, 7 days a week. Please call them on 0800 198 5000.

Nalidixic Acid 300mg / 5ml Oral Suspension

1. Name Of The Medicinal Product

Nalidixic Acid 300mg/5ml Oral Suspension

2. Qualitative And Quantitative Composition

Nalidixic Acid BP 300mg/5ml

3. Pharmaceutical Form

Suspension for oral administration

4. Clinical Particulars

4.1 Therapeutic Indications

Nalidixic Acid Oral Suspension is recommended for the treatment of acute or chronic infections, especially those of the urinary tract caused by Gram-negative organisms, other than Pseudomonas species, sensitive to nalidixic acid. It may also be used for the treatment of selective cases of gastro-intestinal Gram-negative infections sensitive to nalidixic acid.

4.2 Posology And Method Of Administration

For oral administration only.

Adults including the elderly: Three 5ml spoonfuls four times daily for at least seven days reducing to two 5ml spoonfuls four times daily for chronic infections.

Children: For those over the age of three months, the recommended dose is 1ml of suspension per Kilogram body weight daily. The neonate does not tolerate nalidixic acid suspension well owing to immaturity of the liver enzymes.

4.3 Contraindications

Nalidixic acid is contra-indicated for patients with a history of convulsive disorder, porphyria and severe renal impairment. It should be used with caution in patients with liver disease.

Contra-indicated for those with a hypersensitivity to hydroxybenzoate esters or nalidixic acid.

Use in infants under the age of three months is not recommended.

4.4 Special Warnings And Precautions For Use

Nalidixic acid may precipitate a haemolytic reaction in Glucose-6-phosphate dehydrogenase deficient individuals. Toxicological studies have shown that high doses of oxyquinoline antibacterial agents can produce erosion of the cartilage in weight – bearing joints in immature animals of some species. No such lesions have been reported in man to date, nevertheless, until significance of this finding is clarified, care should be exercised when prescribing nalidixic acid for children.

Prescribe with caution in patients with hepatic impairment, moderate renal impairment or severe cerebral arteriosclerosis (risk of seizures).

Monitor full blood count, renal function and hepatic function in long-term therapy (more than 2 weeks).

Although care should be exercised when treating patients with renal failure, the full dosage of nalidixic acid may be administered in patients with creatinine clearance of more than 20ml/min.

Nalidixic acid in therapeutic doses can interfere with the estimation of urinary 17-ketosteroids and may cause high results in the assay of urinary vanilmandelic acid (Pisano method).

Active proliferation of the organisms is a necessary condition for the antibacterial action of nalidixic acid and the action of the suspension may therefore be inhibited by the presence of other antibacterial substances.

When testing for glycosuria in patients receiving nalidixic acid, “Clinistix” or “Tes-tape” should be used since other reagents give a false positive result.

Patients should avoid excessive exposure to sunlight.

Discontinue treatment if symptoms of neuropathy or arthropathy occur.

Tendon damage or rupture may occur rarely. Discontinue treatment if patients experience tendon pain, inflammation or tendon rupture.

Excipient warnings

This product contains the following:

• Parahydroxybenzoates: may cause allergic reactions (possibly delayed).

• Sucrose: contains 0.45g sucrose per 5ml. This should be taken into account in patients with diabetes mellitus. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. May be harmful to teeth.

• Sorbitol: patients with rare hereditary problems of fructose intolerance should not take this medicine.

• Ponceau 4R E124: may cause allergic reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

1. Anticoagulants (coumarin-or-indandione-derivative):

Due to competition for protein binding sites between nalidixic acid and anti-coagulants, it may be necessary to reduce the anti-coagulant dosage and monitor the prothrombin time until a satisfactory prothrombin ratio is achieved.

2. Probenecid:

May be associated with reduced efficacy against urinary pathogens and an increased incidence of side effects.

3. NSAID's:

An increased likelihood of convulsions has been reported.

4. Melphalan:

Serious GI toxicity has been reported.

5. Ciclosporin:

Increased nephrotoxicity may result.

6. Other antibacterials:

Chloramphenicol, nitrofurantoin and tetracycline may inhibit the action of nalidixic acid.

7. Oestrogens:

Theoretical risk of contraceptive failure with oestrogen containing preparations.

8. Oral typhoid vaccination:

Live vaccines can be inactivated by antibiotics.

9. Strontium ranelate, sucralfate and products containing divalent or trivalent cations such as iron, aluminium, zinc, magnesium and calcium can inhibit nalidixic acid absorption.

4.6 Pregnancy And Lactation

Nalidixic acid crosses the placenta. Particular consideration should be given before prescribing Nalidixic Acid Oral Suspension for pregnant women, especially during the first trimester. Nalidixic acid is excreted in breast milk and therefore consideration should be given when treating women who are breast feeding.

4.7 Effects On Ability To Drive And Use Machines

None

4.8 Undesirable Effects

Blood disorders, including eosinophilia, leucopenia, thrombocytopenia, haemolytic anemia and altered prothrombin concentrations have been reported.

Metabolic acidosis has been reported.

Gastro intestinal effects including nausea, diarrhoea, abdominal pain and cholestasis have been reported. Visual disturbances may occur but are readily reversible on reduction of or discontinuation of therapy.

Skin reactions including allergic reactions (urticaria and pruritus) photosensitivity reactions (erythema, bullous eruptions) have been reported. Other reported skin reactions include Stevens Johnson syndrome, erythema multiforme, eosinophilia, angioedema and anaphylaxis.

Arthralgia, myalgia and muscular weakness occur occasionally. Tendon damage or rupture has also been reported (discontinue treatment if tendon pain or inflammation.

Headache, dizziness, vertigo, sleep disorders, depression, hallucinations, drowsiness, confusion, excitement and disorders of taste and smell have been reported. Raised intra-cranial pressure may occur in infants. Toxic psychoses and convulsions have been reported, sometimes associated with overdosage. Patients with a post history of convulsions or cerebral arteriosclerosis are at increased risk of convulsions when taking nalidixic acid.

Reports of peripheral neuropathy, sixth cranial nerve palsy and intracranial hypertension (especially in infants/children).

4.9 Overdose

In adults, symptoms of overdosage have been noted following single doses of 20g and 25g. These have included toxic psychosis convulsions and metabolic acidosis.

In an emergency, it is suggested that the stomach should be emptied and symptomatic treatment applied as necessary, a particular watch being kept for central respiratory depression.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Nalidixic acid appears to act by inhibiting DNA synthesis, probably by interfering with DNA polymerisation. Resistance may develop rapidly during treatment.

5.2 Pharmacokinetic Properties

Almost all orally administered nalidixic acid is absorbed. Plasma concentrations of 20µg to 50µg may be achieved, but it is 93% to 97% bound to plasma proteins. In the body, some nalidixic acid is converted to an active hydroxynalidixic acid and both are excreted in the urine. Very high concentrations of nalidixic acid plus its active metabolite are achieved in the urine – 100µg to 500µg/ml. Antibacterial activity is not found in prostatic fluid. The plasma half life is normally about 8 hours, but it may be as long as 21 hours in the presence of renal failure.

5.3 Preclinical Safety Data

-

6. Pharmaceutical Particulars

6.1 List Of Excipients

Propylene glycol, methyl hydroxybenzoate, propyl hydroxybenzoate, sorbic acid, sodium carboxymethylcellulose, sucrose, sorbitol solution 70%, colloidal silicon dioxide, polysorbate 80, antifoam, ponceau 4R, raspberry flavour (containing propylene glycol), strawberry flavour (containing propylene glycol), dill water and purified water.

6.2 Incompatibilities

None stated

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Protect from light. Store below 25°C, avoid freezing.

6.5 Nature And Contents Of Container

Amber (type III) glass bottle with capacity of 150ml, 200ml and 500ml

Closure:	1. Aluminium, wadded, ROPP closure
	2. HDPE, child resistant, tamper evident, EPE wadded closure
	3. HDPE, tamper evident, EPE wadded closure.

6.6 Special Precautions For Disposal And Other Handling

Shake the bottle well before use

7. Marketing Authorisation Holder

Rosemont Pharmaceuticals Ltd

Rosemont House

Yorkdale Industrial Park

Braithwaite Street

Leeds

LS11 9XE

8. Marketing Authorisation Number(S)

PL 00427/0059

9. Date Of First Authorisation/Renewal Of The Authorisation

16.1.95

10. Date Of Revision Of The Text

26^th January 2010

Navispare Tablets (Goldshield plc)

1. Name Of The Medicinal Product

Navispare tablets

Cyclopenthiazide 0.25mg and Amiloride Hydrochloride 2.5mg Tablets

2. Qualitative And Quantitative Composition

6-Chloro-3-(cyclopentylmethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide1,1-dioxide (Cyclopenthiazide B.P.) 0.25mg.

N-amindino-3,5-diamino-6-chloropyrazine-2-carboxamide hydrochloride dihydrate (Amiloride Hydrochloride Ph.Eur.) 2.5mg

3. Pharmaceutical Form

Coated tablets

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment of mild to moderate hypertension.

4.2 Posology And Method Of Administration

Adults: Usually 1 or 2 Navispare tablets taken once a day in the morning.

Use in the Elderly: Although no special dosage regime is necessary in the elderly, particular caution should be exercised in the elderly, since they are more susceptible to electrolyte imbalances.

Use in children: Navispare is not suitable for use in children.

4.3 Contraindications

Hypersensitivity to cyclopenthiazide or other sulphonamide derivatives;

Addison's disease;

Hyperkalaemia;

In the presence of other potassium conserving agents or potassium supplements;

Anuria;

Severe renal and hepatic failure;

Diabetic Nephropathy;

Concurrent lithium therapy;

Refractory hypokalaemia and hyponatraemia;

Hypercalcaemia;

Symptomatic hyperuricaemia.

4.4 Special Warnings And Precautions For Use

4.4.1 Warnings

None known.

4.4.2 Precautions

Diabetes mellitus:

Hyperkalaemia has occurred in diabetic patients receiving amiloride hydrochloride, especially those with chronic renal disease or pre-renal azotaemia. The status of renal function should therefore be determine before use in a known or suspected diabetic patient. Navispare should be discontinued for at least three days before a glucose tolerance test.

Prolonged doses may bring about a decrease in glucose tolerance and precipitate a diabetic condition. In known diabetics the addition of a thiazide to the treatment regime may alter their antidiabetic requirement.

Metabolic or respiratory acidosis:

Potassium conserving therapy should be initiated with caution in patients in whom metabolic or respiratory acidosis may occur e.g. patients with cardiopulmonary disease or decompensated diabetes. Shifts in acid-base balance of extracellular potassium and the development of acidosis may be associated with rapid increase in plasma potassium.

Electrolyte considerations:

In patients with renal impairment, a rise in blood urea can occur. In such cases, either the dose should be reduced or the treatment interrupted temporarily. Thiazides may precipitate an attack of gout in patients predisposed to this condition.

The elderly, especially those suffering from chronic disease and patients with hepatic cirrhosis are more susceptible to a lack of electrolyte and fluid balance homeostatis. During treatment with thiazides hyponatraemia accompanied by neurological symptoms has been observed in isolated cases. In the elderly and patients with hepatic cirrhosis, the serum electrolytes should be monitored at more frequent intervals.

Patients receiving relatively high doses of thiazides may develop hypomagnesaemia accompanied by signs and symptoms such as nervousness, muscle spasms and cardiac arrhythmias.

Miscellaneous:

In patients with hyperlipidaemia, the serum lipids should be regularly monitored. In the event of a rise in serum lipids, withdrawal of the thiazide medication should be considered. Lupus erythematosus may possibly become activated under treatment with thiazides.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The concomitant administration of thiazides with other antihypertensive agents (e.g. beta-blockers, vasodilators, calcium antagonists) may necessitate adjustment of the dosage of those drugs.

The concomitant administration of potassium-sparing agents such as amiloride and ACE inhibitors may increase serum potassium levels and is not to be recommended. However, if the concomitant use of these agents is deemed appropriate, they should be used with caution and with frequent monitoring of plasma potassium.

NSAIDs may attenuate the antihypertensive effect of thiazide diuretics.

Thiazide containing drugs may increase the responsiveness to tubocurarine.

Orthostatic hypotension may occur and may be potentiated by alcohol, barbiturates and narcotics.

4.6 Pregnancy And Lactation

Diuretics are best avoided for the management of oedema or hypertension in pregnancy as their use may be associated with hypovolaemia, increased blood viscosity and reduced placental perfusion.

There is inadequate evidence of safety in human pregnancy and there have been reports of foetal bone marrow depression, thrombocytopenia, and foetal and neonatal jaundice reported with the use of thiazide diuretics.

As cyclopenthiazide passes into breast milk, Navispare should be avoided in mothers who wish to breast-feed. It is not known whether amiloride hydrochloride passes into breast milk.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

Navispare is generally well tolerated. Reported side-effects of the combination include rare cases of dizziness, headache, lightheadedness, tiredness, nausea and vomiting, discomfort/pain in the chest. However, the following side-effects of cyclopenthiazide and amiloride as single agents have been reported:

Cyclopenthiazide:

Skin:

Occasional: allergic urticaria (nettle rash) and other forms of skin rash.

Rare: photosensitisation. Isolated cases: necrotising vasculitis.

Gastro-intestintal tract:

Occasional: loss of appetite, mild nausea, vomiting.

Rare: gastrospasm, diarrhoea or possibly constipation. Isolated cases: pancreatitis.

Central nervous system:

Rare: headache, muzziness, dizziness, sleep disturbances, depression and paraesthesiae.

Blood:

Rare: thrombocytopenia sometimes with purpura. In isolated cases: leucopenia, agranulocytosis, anaemia and bone marrow depression.

Electrolytes:

Frequent: hypokalaemia.

Occasional: hyponatraemia, hypomagnesaemia.

Rare: hypercalcaemia. If hypercalcaemia occurs, further diagnostic clarification is necessary (e.g. possibility of hyperparathyroidism).

In isolated cases: hypochloraemic alkalosis.

Liver:

Rare: intrahepatic cholestasis or jaundice.

Miscellaneous:

Occasional: impotence.

Metabolic:

Occasional: hyperuricaemia. Rare: hyperglycaemia, glycosuria. Gout or diabetes may be precipitated or aggravated. Increased blood lipid levels in response to higher doses.

Cardiovascular system:

Occasional: postural hypotension, which may be aggravated by alcohol, anaesthetics or sedatives.

Rare: cardiac arrhythmias.

Amiloride:

Gastro-intestinal tract:

Rare: anorexia, nausea, vomiting, abdominal pain.

In isolated cases: diarrhoea, constipation, GI bleeding, jaundice, thirst, dyspepsia, heartburn, flatulence.

Central nervous system:

Rare: dizziness, paraesthesiae, tremors, mental confusion.

In isolated cases: encephalopathy, nervousness, insomnia, decreased libido, depression, somnolence, vertigo.

Cardiovascular system:

Rare: palpitation.

In isolated cases: angina pectoris, orthostatic hypotension, arrhythmias.

Respiratory:

Rare: cough, dyspnoea.

Urogenital:

Rare: frequency or micturition.

In isolated cases: impotence, polyuria, dysuria.

Musculoskeletal:

Rare: joint pain.

In isolated cases: muscle cramps.

Skin and appendages:

Rare: pruritus, rash, alopecia.

In isolated cases: dryness of mouth.

4.9 Overdose

Signs and Symptoms

Signs: In cases of overdosage the following signs and symptoms may occur. Dizziness, nausea, somnolence, hypovolaemia, hypotension and electrolyte disturbances associated with cardiac arrhythmias and muscle spasms.

Treatment:

Emesis should be induced or gastric lavage performed. Intravenous fluid and electrolyte replacement may be indicated.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC code: C03E A07

Mode of action:

Cyclopenthiazide is a benzothiadiazine (thiazide) diuretic.

Cyclopenthiazide is a thiazide diuretic which exerts diuretic effect by inhibiting the reabsorption of sodium chloride and water probably at the distal renal tubules.

Amiloride hydrochloride is a mild potassium-sparing diuretic, belonging to the pyrazine carboxamide class, which acts mainly on the distal part of the renal tubule. It increases the excretion of sodium and chloride and reduces the excretion of potassium.

5.2 Pharmacokinetic Properties

The lipophilic thiazides - such as cyclopenthiazide - attain higher concentration in the cells and thus have a larger distribution volume than the hydrophilic derivatives. Their protein binding rate is also greater, amounting to approximately 92%. They therefore exert a more prolonged action than the more hydrophilic thiazides.

Amiloride is completely absorbed from the GI tract; peak serum concentrations are achieved about 3 and 4 hours after oral administration. It is excreted unchanged in the urine and has been estimated to have a serum half life of about 6 hours.

5.3 Preclinical Safety Data

Cyclopenthiazide: In reproduction toxicity studies with mice, rats, and rabbis, no teratogenic effects were observed.

6. Pharmaceutical Particulars

6.1 List Of Excipients

The coated tablets contain lactose, wheat starch, polyvinylpyrrolidone (K90), stearic acid, talc, sodium starch glycollate, titanium dioxide (E171), yellow iron oxide (E172), polyethoxylated hydrogenated castor oil, hydroxypropylmethylcellulose and water.

6.2 Incompatibilities

None known.

6.3 Shelf Life

Three years.

6.4 Special Precautions For Storage

Protect from moisture. Store below 25°C.

Medicines should be kept out of reach of children.

6.5 Nature And Contents Of Container

All tablets are packed in PVC/PVDC packs of 28 tablets.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Goldshield Pharmaceuticals Limited

NLA Tower

12-16 Addiscombe Road

Croydon

Surrey

CR0 0XT

UK

8. Marketing Authorisation Number(S)

PL 12762/0216

9. Date Of First Authorisation/Renewal Of The Authorisation

30/01/2006

10. Date Of Revision Of The Text

27/07/2007