Ondansetron 4 mg / 2 ml Solution for Injection (Hospira UK Ltd)

1. Name Of The Medicinal Product

Ondansetron 4 mg/2 ml Solution for Injection

2. Qualitative And Quantitative Composition

Each ampoule containing 2 ml solution contains 4 mg ondansetron (as ondansetron hydrochloride dihydrate). The strength of the solution is 2 mg/ml ondansetron.

For excipients, see 6.1.

3. Pharmaceutical Form

Solution for injection

The aqueous solution is clear and colourless.

4. Clinical Particulars

4.1 Therapeutic Indications

Ondansetron hydrochloride is indicated for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy, and for the prevention and treatment of post-operative nausea and vomiting (PONV).

4.2 Posology And Method Of Administration

Chemotherapy and radiotherapy:

Adults:

The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. The route of administration and dose of ondansetron hydrochloride should be flexible in the range of 8-32 mg a day and selected as shown below.

Emetogenic chemotherapy and radiotherapy:

Ondansetron hydrochloride can be given either by rectal, oral (tablets or syrup), intravenous or intramuscular administration.

For most patients receiving emetogenic chemotherapy or radiotherapy, ondansetron hydrochloride 8 mg should be administered as a slow intravenous or intramuscular injection immediately before treatment, followed by 8 mg orally twelve hourly.

To protect against delayed or prolonged emesis after the first 24 hours, oral or rectal treatment with ondansetron hydrochloride should be continued for up to 5 days after a course of treatment.

Highly emetogenic chemotherapy:

For patients receiving highly emetogenic chemotherapy, e.g. high-dose cisplatin, ondansetron hydrochloride can be given either by rectal, intravenous or intramuscular administration.

Ondansetron hydrochloride has been shown to be equally effective in the following dose schedules over the first 24 hours of chemotherapy:

- A single dose of 8 mg by slow intravenous or intramuscular injection immediately before chemotherapy

- A dose of 8 mg by slow intravenous or intramuscular injection immediately before chemotherapy, followed by two further intravenous or intramuscular doses of 8 mg two or four hours apart, or by a constant infusion of 1 mg/hour for up to 24 hours

- A single dose of 32 mg diluted in 50-100 ml of saline or other compatible infusion fluid (see Pharmaceutical Precautions) and infused over not less than 15 minutes immediately before chemotherapy

The selection of dose regimen should be determined by the severity of the emetogenic challenge.

The efficacy of ondansetron hydrochloride in highly emetogenic chemotherapy may be enhanced by the addition of a single intravenous dose of dexamethasone sodium phosphate, 20 mg administered prior to chemotherapy.

To protect against delayed or prolonged emesis after the first 24 hours, oral or rectal treatment with ondansetron hydrochloride should be continued for up to 5 days after a course of treatment.

Children:

Ondansetron hydrochloride may be administered as a single intravenous dose of 5 mg/m² immediately before chemotherapy, followed by 4 mg orally twelve hours later. 4 mg orally twice daily should be continued for up to 5 days after a course of treatment.

Elderly:

Ondansetron hydrochloride is well tolerated by patients over 65 years and no alteration of dosage, dosing frequency or route of administration are required.

Patients with renal impairment:

No alteration of daily dosage, frequency of dosing or route of administration are required.

Patients with hepatic impairment:

Clearance of ondansetron hydrochloride is significantly reduced and serum half-life significantly prolonged in subjects with moderate or severe impairment of hepatic function. In such patients a total daily dose of 8 mg should not be exceeded.

Post-operative nausea and vomiting (PONV):

Adults:

For the prevention of PONV ondansetron hydrochloride can be administered orally or by intravenous or intramuscular injection.

Ondansetron hydrochloride may be administered as a single dose of 4 mg given by intramuscular or slow intravenous injection at induction of anaesthesia.

For treatment of established PONV a single dose of 4 mg given by intramuscular or slow intravenous injection is recommended.

Children (aged 2 years and over):

For prevention of PONV in paediatric patients having surgery performed under general anaesthesia, ondansetron may be administered by slow intravenous injection at a dose of 0.1 mg/kg up to a maximum of 4 mg either prior to, at or after induction of anaesthesia.

For treatment of established PONV in paediatric patients, ondansetron may be administered by slow intravenous injection at a dose of 0.1 mg/kg up to a maximum of 4 mg.

There is limited data on the use of ondansetron hydrochloride in the prevention and treatment of PONV in children under 2 years of age.

Elderly:

There is limited experience in the use of ondansetron hydrochloride in the prevention and treatment of PONV in the elderly, however ondansetron hydrochloride is well tolerated in patients over 65 years receiving chemotherapy.

Patients with renal impairment:

No alteration of daily dosage, frequency of dosing or route of administration are required.

Patients with hepatic impairment:

Clearance of ondansetron hydrochloride is significantly reduced and serum half-life significantly prolonged in subjects with moderate or severe impairment of hepatic function. In such patients a total daily dose of 8 mg should not be exceeded.

Patients with poor sparteine / debrisoquine metabolism:

The elimination half-life of ondansetron is not altered in subjects classified as poor metabolisers of sparteine and debrisoquine. Consequently in such patients repeat dosing will give drug exposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing are required.

4.3 Contraindications

Hypersensitivity to any component of the preparation.

4.4 Special Warnings And Precautions For Use

Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5HT₃ receptor antagonists.

As ondansetron is known to increase large bowel transit time, patients with signs of subacute intestinal obstruction should be monitored following administration.

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

There is no evidence that ondansetron either induces or inhibits the metabolism of other drugs commonly co-administered with it. Specific studies have shown that there are no pharmacokinetic interactions when ondansetron is administered with alcohol, temazepan, furosemide, tramadol or propofol.

Ondansetron is metabolised by multiple hepatic cytochrome P-450 enzymes: CYP3A4, CYP2D6 and CYP1A2. Due to the multiplicity of metabolic enzymes capable of metabolising ondansetron, enzyme inhibition or reduced activity of one enzyme (e.g. CYP2D6 genetic deficiency) is normally compensated by other enzymes and should result in little or no significant change in overall ondansetron clearance or dose requirement.

Phenytoin, Carbamazepine and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e. phenytoin, carbamazepine, and rifampicin), the oral clearance of ondansetron was increased and ondansetron blood concentrations were decreased.

Tramadol: Data from small studies indicate that ondansetron may reduce the analgesic effect of tramadol.

4.6 Pregnancy And Lactation

The safety of ondansetron for use in human pregnancy has not been established.

Evaluation of experimental animal studies does not indicate direct or indirect harmful effects with respect to the development of the embryo, or foetus, the course of gestation and peri- and post-natal development. However, as animal studies are not always predictive of human response, the use of ondansetron in pregnancy is not recommended.

Tests have shown that ondansetron passes into the milk of lactating animals. It is therefore recommended that mothers receiving ondansetron hydrochloride should not breast-feed their babies.

4.7 Effects On Ability To Drive And Use Machines

In psychomotor testing ondansetron does not impair performance nor cause sedation.

4.8 Undesirable Effects

Ondansetron is known to increase large bowel transit time and may cause constipation in some patients. The following side effects can occur: headache, a sensation of flushing or warmth, hiccups and occasional asymptomatic increases in liver function tests. There have been rare reports of immediate hypersensitivity reactions sometimes severe including anaphylaxis. Rare cases of transient visual disturbances (e.g. blurred vision) and dizziness have been reported during rapid intravenous administration of ondansetron. There have been rare reports suggestive of involuntary movement disorders such as extrapyramidal reactions e.g. oculogyric crisis/dystonic reactions without definitive evidence of persistent clinical sequelae and seizures have been rarely observed although no known pharmacological mechanism can account for ondansetron causing these effects. Chest pain with or without ST segment depression, cardiac arrhythmias, hypotension and bradycardia have been rarely reported.

Occasionally, hypersensitivity reactions around the injection site (e.g. rash, urticaria, itching) may occur, sometimes extending along the drug administration vein.

4.9 Overdose

Little is known at present about overdosage with ondansetron, however, a limited number of patients received overdoses. Manifestations that have been reported include visual disturbances, severe constipation, hypotension and a vasovagal episode with transient second degree AV block. In all instances, the events resolved completely. There is no specific antidote for ondansetron, therefore in all cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antiemetics and Antinauseants – Serotonin (5HT₃) antagonists, ATC code: A04A A01.

Ondansetron is a potent, highly selective 5HT₃ receptor-antagonist. Its precise mode of action in the control of nausea and vomiting is not known. Chemotherapeutic agents and radiotherapy may cause release of 5HT in the small intestine initiating a vomiting reflex by activating vagal afferents via 5HT₃ receptors. Ondansetron blocks the initiation of this reflex. Activation of vagal afferents may also cause a release of 5HT in the area postrema, located on the floor of the fourth ventricle, and this may also promote emesis through a central mechanism.

Thus, the effect of ondansetron in the management of the nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy is probably due to antagonism of 5HT₃ receptors on neurons located both in the peripheral and central nervous system. The mechanisms of action in post-operative nausea and vomiting are not known but there may be common pathways with cytotoxic induced nausea and vomiting.

Ondansetron does not alter plasma prolactin concentrations.

The role of ondansetron in opiate-induced emesis is not yet established.

5.2 Pharmacokinetic Properties

Following oral administration, ondansetron is passively and completely absorbed from the gastrointestinal tract and undergoes first pass metabolism. Peak plasma concentrations of about 30 ng/ml are attained approximately 1.5 hours after an 8 mg dose. For doses above 8 mg the increase in ondansetron systemic exposure with dose is greater than proportional; this may reflect some reduction in first pass metabolism at higher oral doses. Bioavailability, following oral administration, is slightly enhanced by the presence of food but unaffected by antacids. Studies in healthy elderly volunteers have shown slight, but clinically insignificant, age-related increases in both oral bioavailability (65%) and half-life (5 hours) of ondansetron. Gender differences were shown in the disposition of ondansetron, with females having a greater rate and extent of absorption following an oral dose and reduced systemic clearance and volume of distribution (adjusted for weight).

The disposition of ondansetron following oral, intramuscular (IM) and intravenous (IV) dosing is similar with a terminal half-life of about 3 hours and steady state volume of distribution of about 140 litres. Equivalent systemic exposure is achieved after IM and IV administration of ondansetron.

A 4 mg intravenous infusion of ondansetron given over 5 minutes results in peak plasma concentrations of about 65 ng/ml. Following intramuscular administration of ondansetron, peak plasma concentrations of about 25 ng/ml are attained within 10 minutes of injection.

Following administration of ondansetron suppository, plasma ondansetron concentrations become detectable between 15 and 60 minutes after dosing. Concentrations rise in an essentially linear fashion, until peak concentrations of 20-30 ng/ml are attained, typically 6 hours after dosing. Plasma concentrations then fall, but at a slower rate than observed following oral dosing due to continued absorption of ondansetron. The absolute bioavailability of ondansetron from the suppository is approximately 60% and is not affected by gender. The half-life of the elimination phase following suppository administration is determined by the rate of ondansetron absorption, not systemic clearance and is approximately 6 hours. Females show a small, clinically insignificant, increase in half-life in comparison with males.

Ondansetron is not highly protein bound (70-76%). Ondansetron is cleared from the systemic circulation predominantly by hepatic metabolism through multiple enzymatic pathways. Less than 5% of the absorbed dose is excreted unchanged in the urine. The absence of the enzyme CYP2D6 (the debrisoquine polymorphism) has no effect on ondansetron's pharmacokinetics. The pharmacokinetic properties of ondansetron are unchanged on repeat dosing.

In a study of 21 paediatric patients aged between 3 and 12 years undergoing elective surgery with general anaesthesia, the absolute values for both the clearance and volume of distribution of ondansetron following a single intravenous dose of 2 mg (3-7 years old) or 4 mg (8-12 years old) were reduced. The magnitude of the change was age-related, with clearance falling from about 300 ml/min at 12 years of age to 100 ml/min at 3 years. Volume of distribution fell from about 75 litres at 12 years to 17 litres at 3 years. Use of weight-based dosing (0.1 mg/kg up to 4 mg maximum) compensates for these changes and is effective in normalising systemic exposure in paediatric patients.

In patients with renal impairment (creatinine clearance 15-60 ml/min), both systemic clearance and volume of distribution are reduced following IV administration of ondansetron, resulting in a slight, but clinically insignificantly, increase in elimination half-life (5.4 h). A study in patients with severe renal impairment who required regular haemodialysis (studied between dialyses) showed ondansetron's pharmacokinetics to be essentially unchanged following IV administration.

Specific studies in the elderly or patients with renal impairment have been limited to IV and oral administration. However, it is anticipated that the half-life of ondansetron after rectal administration in these populations will be similar to that seen in healthy volunteers, since the rate of elimination of ondansetron following rectal administration is not determined by systemic clearance.

Following oral, intravenous or intramuscular dosing in patients with severe hepatic impairment, ondansetron's systemic clearance is markedly reduced with prolonged elimination half-lives (15-32 h) and oral bioavailability approaching 100% due to reduced pre-systemic metabolism. The pharmacokinetics of ondansetron following administration as a suppository have not been evaluated in patients with hepatic impairment.

5.3 Preclinical Safety Data

No additional data of relevance.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium chloride

Citric acid monohydrate

Sodium citrate

Water for injections

6.2 Incompatibilities

Ondansetron 4 mg/2 ml Solution for Injection should not be administered in the same syringe or infusion as any other medication.

6.3 Shelf Life

12 months (unopened). 24 hours (dilutions stored at 2-8°C).

6.4 Special Precautions For Storage

Do not store above 30°C. Keep ampoules in the outer carton.

Dilutions of Ondansetron 4 mg/2 ml Solution for Injection in compatible intravenous infusion fluids are stable under normal room lighting conditions or daylight for at least 24 hours, thus no protection from light is necessary while infusion takes place.

6.5 Nature And Contents Of Container

Ondansetron 4 mg/2 ml Solution for Injection, is contained in 2 ml Type I colourless ampoules with a green marking for the One-Point-Cut.

There are packs of 1, 2, 5, 6, 10, 25, 50 and 5x 50 ampoules.

6.6 Special Precautions For Disposal And Other Handling

Compatibility with intravenous fluids:

Ondansetron 4 mg/2 ml Solution for Injection should only be admixed with those infusion solutions, which are recommended:

- Sodium chloride intravenous infusion 0.9 %

- Glucose intravenous infusion 5 %

- Mannitol intravenous infusion 10 %

- Ringer's intravenous infusion

- Potassium chloride 0.3 % and sodium chloride 0.9 % intravenous infusion

- Potassium chloride 0.3 % and glucose 5 % intravenous infusion

In keeping with good pharmaceutical practice, dilutions of Ondansetron 4 mg/2 ml Solution for Injection in intravenous fluids should be prepared at the time of infusion or stored at 2-8°C for no more than 24 hours before the start of administration.

Compatibility studies have been undertaken in polyvinyl chloride infusion bags and polyvinyl chloride administration sets. It is considered that adequate stability would also be conferred by the use of polyethylene infusion bags or type I glass bottles.

Dilutions of Ondansetron 4 mg/2 ml Solution for Injection in sodium chloride 0.9 % or in glucose 5 % have been demonstrated to be stable in polypropylene syringes. It is considered that Ondansetron 4 mg/2 ml Solution for Injection diluted with other compatible infusion fluids would be stable in polypropylene syringes.

Compatibility with other drugs:

Ondansetron 4 mg/2 ml Solution for Injection may be administered by intravenous infusion at 1 mg/hour, e.g. from an infusion bag or syringe pump. The following drugs may be administered via the Y-site of the Ondansetron 4 mg/2 ml Solution for Injection giving set for ondansetron concentrations of 16 to 160 micrograms/ml (e.g. 8 mg/500 ml and 8 mg/50 ml, respectively):

Cisplatin:

Concentrations up to 0.48 mg/ml (e.g. 240 mg in 500 ml) administered over one to eight hours.

5 -Fluorouracil:

Concentrations up to 0.8 mg/ml (e.g. 2.4 g in 3 litres or 400 mg in 500 ml) administered at a rate of at least 20 ml per hour (500 ml per 24 hours). Higher concentrations of 5-fluorouracil may cause precipitation of ondansetron. The 5-flourouracil infusions may contain up to 0.045% (w/v) magnesium chloride in addition to other excipients shown to be compatible.

Carboplatin:

Concentrations in the range 0.18 mg/ml to 9.9 mg/ml (e.g. 90 mg in 500 ml to 990 mg in 100 ml), administered over ten minutes to one hour.

Etoposide:

Concentrations in the range 0.14 mg/ml to 0.25 mg/ml (e.g. 72 mg in 500 ml to 250 mg in 1 litre) administered over thirty minutes to one hour.

Ceftazidime:

Doses in the range 250 mg to 2000 mg, reconstituted with water for injections as recommended by the manufacturer (e.g. 2.5 ml for 250 mg and 10 ml for 2 g ceftazidime), and given as an intravenous bolus injection over approximately five minutes.

Cyclophosphamide:

Doses in the range 100 mg to 1 g, reconstituted with water for injections, 5 ml per 100 mg cyclophosphamide, as recommended by the manufacturer and given as an intravenous bolus injection over approximately five minutes.

Doxorubicin:

Doses in the range 10-100 mg reconstituted with water for injections, 5 ml per 10 mg doxorubicin, as recommended by the manufacturer and given as an intravenous bolus injection over approximately 5 minutes.

Dexamethasone:

Dexamethasone sodium phosphate 20 mg may be administered as a slow intravenous injection over 2-5 minutes via the Y-site of an infusion set delivering 8 or 32 mg of ondansetron diluted in 50-100 ml of a compatible infusion fluid over approximately 15 minutes. Compatibility between dexamethasone sodium phosphate and ondansetron has been demonstrated supporting administration of these drugs through the same giving set resulting in concentrations in line of 32 microgram – 2.5 mg/ml for dexamethasone sodium phosphate and 8 microgram – 1 mg/ml for ondansetron.

7. Marketing Authorisation Holder

Hospira Enterprises B.V.

Taurusavenue 19-21

2132LS Hoofddorp

The Netherlands

8. Marketing Authorisation Number(S)

PL 23061/0013

9. Date Of First Authorisation/Renewal Of The Authorisation

May 4^th, 2006

10. Date Of Revision Of The Text

May 29^th, 2006

Monofer 100mg / ml solution for injection / infusion

1. Name Of The Medicinal Product

Monofer 100mg/ml

2. Qualitative And Quantitative Composition

One millilitre of solution contains 100 mg iron as iron(III) isomaltoside 1000.

1 ml vial/ampoule contains 100 mg iron as iron(III) isomaltoside 1000

2 ml vial/ampoule contains 200 mg iron as iron(III) isomaltoside 1000

5 ml vial/ampoule contains 500 mg iron as iron(III) isomaltoside 1000

10 ml vial/ampoule contains 1,000 mg iron as iron(III) isomaltoside 1000

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection/infusion.

Dark brown, non transparent solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Monofer is indicated for the treatment of iron deficiency anaemia in the following conditions:

• When oral iron preparations are ineffective or cannot be used

• Where there is a clinical need to deliver iron rapidly

The diagnosis of iron deficiency anaemia should be based on appropriate laboratory tests (e.g. serum ferritin, serum iron, transferrin saturation or hypochromic red cells).

4.2 Posology And Method Of Administration

Calculation of the total iron dose:

Iron replacement in patients with iron deficiency anaemia:

The dose and dosage schedule for Monofer must be individually established for each patient based on a calculation of the total iron deficit. The optimal haemoglobin target level may vary in different patient groups. Please refer to official guidelines. The dose of Monofer is expressed in mg of elemental iron.

The total iron dose is calculated by the following Ganzoni formula, where haemoglobin is abbreviated Hb:

(A) It is recommended to use the patient's ideal body weight or pre-pregnancy weight

(B) To convert Hb [mM] to Hb [g/dl] you should multiply Hb [mM] by factor 1.61145

(C) Factor 2.4 = 0.0034 x 0.07 x 10,000

0.0034: Iron content of haemoglobin is 0.34%

0.07: Blood volume 70 ml/kg of body weight ≈ 7% of body weight

10,000: The conversion factor 1 g/dl = 10,000 mg/l

(D) For a person with a body weight above 35 kg, the iron stores are approximately 500 mg

Iron deficiency anaemia will not appear until essentially all iron stores have been depleted. Iron therapy should therefore replenish both haemoglobin iron and iron stores.

After the total iron deficit has been corrected, patients may require continued therapy with Monofer to maintain target levels of haemoglobin and acceptable limits of other iron parameters.

Iron replacement for blood loss:

Iron therapy in patients with blood loss should supply an amount of iron equivalent to the amount of iron represented in the blood loss.

• If the Hb level is reduced: Use the previous formula considering that the depot iron does not need to be restored:

• If the volume of blood lost is unknown: The administration of 200 mg Monofer results in an increase of haemoglobin which is equivalent to 1 unit blood:

Administration:

Anaphylactoid reactions to parenteral iron are usually evident within a few minutes, and close observation is necessary to ensure recognition. If at any time during the intravenous administration of Monofer, any signs of a hypersensitivity reaction or intolerance are detected, administration must be stopped immediately.

Resuscitative medication and personnel trained to evaluate and handle anaphylactoid reactions should be available whenever a dose of parenteral iron is administered.

Children and adolescents:

Monofer is not recommended for use in children and adolescents < 18 years due to insufficient data on safety and efficacy.

Adults and the elderly:

Monofer can be administered either as an intravenous bolus injection, as a total dose infusion (TDI), as an intravenous drip infusion or as a direct injection into the venous limb of the dialyser.

Monofer should not be administered concomitantly with oral iron preparations, since the absorption of oral iron might be decreased (see section 4.5).

Intravenous bolus injection:

Monofer may be administered as a 100-200 mg intravenous bolus injection up to three times a week at an administration rate of up to 50 mg iron/minute. It may be diluted in 10-20 ml sterile 0.9% sodium chloride.

Total dose infusion (TDI):

Monofer may be administered as a total dose infusion in which the total iron dose is given in a single infusion.

Monofer given as total dose infusion is administered as a single dose of up to 20 mg iron/kg body weight as an intravenous drip infusion.

Doses of 0-10 mg iron/kg body weight must be infused over 30 min.

Doses of 11-20 mg iron/kg body weight must be infused over 60 min.

If the total iron dose exceeds 20 mg iron/kg body weight, the dose must be split in two administrations with an interval of at least one week.

Monofer should be added to 100-500 ml sterile 0.9% sodium chloride. Please refer to section 6.3 and 6.6.

Total dose infusion (TDI) has been associated with an increased incidence of adverse reactions, in particular delayed hypersensitivity-like reactions. The intravenous administration of Monofer by the total dose infusion method should be restricted to hospital use only.

Intravenous drip infusion:

Monofer may be administered in doses of 200-1,000 mg once every week until the total iron dose has been administered.

Doses of 0-5 mg iron/kg body weight must be infused over 15 min.

Doses of 6-10 mg iron/kg body weight must be infused over 30 min.

Doses of 11-20 mg iron/kg body weight must be infused over 60 min.

Monofer should be added to 100-500 ml sterile 0.9% sodium chloride. Please refer to section 6.3 and 6.6.

Injection into dialyser:

Monofer may be administered during a haemodialysis session directly into the venous limb of the dialyser under the same procedures as outlined for intravenous bolus injection.

4.3 Contraindications

• Non-iron deficiency anaemia (e.g. haemolytic anaemia)

• Iron overload or disturbances in utilisation of iron (e.g. haemochromatosis, haemosiderosis)

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

• Patients with a history of asthma, allergic eczema or other atopic allergy

• Decompensated liver cirrhosis and hepatitis

• Rheumatoid arthritis with symptoms or signs of active inflammation

4.4 Special Warnings And Precautions For Use

Parenteral administration of all iron complexes may cause immediate severe and potentially lethal hypersensitivity reactions. The risk is enhanced for patients with known (medical) allergies. Resuscitative medication and personnel trained to evaluate and handle anaphylactoid reactions should therefore be available. There is particularly increased risk of allergic reactions to parenteral iron complexes in patients with immune or inflammatory conditions (e.g. systemic lupus erythematosus, rheumathoid arthritis).

Parenteral iron should be used with caution in case of acute or chronic infection.

Monofer should not be used in patients with ongoing bacteraemia.

Hypotensive episodes may occur if intravenous injection is administered too rapidly.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

As with all parenteral iron preparations the absorption of oral iron is reduced when administered concomitantly. Oral iron therapy should not be started earlier than 5 days after the last injection of Monofer.

Large doses of parenteral iron (5 ml or more) have been reported to give a brown colour to serum from a blood sample drawn four hours after administration.

Parenteral iron may cause falsely elevated values of serum bilirubin and falsely decreased values of serum calcium.

4.6 Pregnancy And Lactation

There are no adequate and well-controlled trials of Monofer in pregnant women. A careful risk/benefit evaluation is therefore required before use during pregnancy and Monofer should not be used during pregnancy unless clearly necessary.

Iron deficiency anaemia occurring in the first trimester of pregnancy can in many cases be treated with oral iron. If the benefit of Monofer treatment is judged to outweigh the potential risk to the foetus, the treatment should be confined to second and third trimester.

There is no information available on the excretion of Monofer in the human breast milk.

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.

4.8 Undesirable Effects

Due to limited clinical data on Monofer the mentioned undesirable effects are primarily based on safety data for other parenteral iron solutions.

More than 1% of patients may be expected to experience adverse reactions.

Acute, severe anaphylactoid reactions may occur with parenteral iron preparations, although they are uncommon. They usually occur within the first few minutes of administration and are generally characterised by the sudden onset of respiratory difficulty and / or cardiovascular collapse; fatalities have been reported. Other less severe manifestations of immediate hypersensitivity are also uncommon and include urticaria, rashes, itching, nausea and shivering. Administration must be stopped immediately if signs of an anaphylactoid reaction are observed.

Delayed reactions may also occur with parenteral iron preparations and can be severe. They are characterised by arthralgia, myalgia and sometimes fever. The onset varies from several hours up to four days after administration. Symptoms usually last two to four days and settle spontaneously or following the use of simple analgesics. In addition, exacerbation of joint pain in rheumatoid arthritis can occur and local reactions may cause pain and inflammation at or near injection site and a local phlebitic reaction.

Very common (

Common (

Uncommon (

Rare (

Very Rare (<1/10,000)

Not known (cannot be estimated with the available data)

Cardiac disorders

Rare: Arrhythmia, tachycardia

Very rare: Foetal bradycardia, palpitations

Blood and lymphatic system disorders

Very rare: Haemolysis

Nervous system disorders

Uncommon: Blurred vision, numbness, dysphonia

Rare: Loss of consciousness, seizure, dizziness, restlessness, tremor, fatigue, altered mental status

Very rare: Headache, paresthesia

Ear and labyrinth disorders

Very rare: Transient deafness

Respiratory, thoracic and mediastinal disorders

Uncommon: Dyspnoea

Rare: Chest pain

Gastrointestinal disorders

Uncommon: Nausea, emesis, abdominal pain, constipation

Rare: Diarrhoea

Skin and subcutaneous tissue disorders

Uncommon: Flushing, pruritus, rash

Rare: Angioedema, sweating

Musculoskeletal and connective tissue disorders

Uncommon: Cramps

Rare: Myalgias, arthralgia

Vascular disorders

Rare: Hypotension

Very rare: Hypertension

General disorders and administration site conditions

Uncommon: Anaphylactoid reactions, feeling hot, fever, soreness, inflammation near the injection site, local phlebitic reaction

Rare: Fatigue

Very rare: Acute severe anaphylactic reactions

4.9 Overdose

The iron(III) isomaltoside 1000 in Monofer has a low toxicity. The preparation is well tolerated and has a minimal risk of accidental overdosing.

Overdose may lead to accumulation of iron in storage sites eventually leading to haemosiderosis. Monitoring of iron parameters such as serum ferritin may assist in recognising iron accumulation. Supportive measures such as chelating agents can be used.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Iron trivalent parenteral preparation, ATC code: B03A C06

Monofer solution for injection is a colloid with strongly bound iron in spheroidal iron-carbohydrate particles. Each particle consists of an iron(III) core and a carbohydrate shell of isomaltosides that surrounds and stabilises the core. The chelation of iron(III) with a carbohydrate shell confers to the particles a structure resembling ferritin that is suggested to protect against the toxicity of unbound inorganic iron(III).

The iron is available in a non-ionic water-soluble form in an aqueous solution with pH between 5.0 and 7.0. The toxicity is low and Monofer can therefore be administered in large doses.

Evidence of a therapeutic response can be seen within a few days of administration of Monofer as an increase in the reticulocyte count.

Serum ferritin peaks approximately 7 to 9 days after an intravenous dose of Monofer and slowly returns to baseline after about 3 weeks.

5.2 Pharmacokinetic Properties

The Monofer formulation contains iron in a strongly bound complex that enables a controlled and slow release of bioavailable iron to iron-binding proteins with little risk of free iron.

Following intravenous administration, iron isomaltoside 1000 is rapidly taken up by the cells in the reticuloendothelial system (RES), particularly in the liver and spleen from where iron is slowly released. The plasma half life is 5 hours for circulating iron and 20 hours for total iron (bound and circulating).

Circulating iron is removed from the plasma by cells of the reticuloendothelial system which split the complex into its components of iron and isomaltoside 1000. The iron is immediately bound to the available protein moieties to form hemosiderin or ferritin, the physiological storage forms of iron, or to a lesser extent, to the transport molecule transferrin. This iron, which is subject to physiological control, replenishes haemoglobin and depleted iron stores.

Iron is not easily eliminated from the body and accumulation can be toxic. Due to the size of the complex, Monofer is not eliminated via the kidneys. Small quantities of iron are eliminated in urine and faeces.

Isomaltoside 1000 is either metabolised or excreted.

5.3 Preclinical Safety Data

Iron complexes have been reported to be teratogenic and embryocidal in non-anaemic pregnant animals at high single doses above 125 mg iron/kg body weight. The highest recommended dose in clinical use is 20 mg iron/kg body weight.

There are no other additional preclinical data of relevance to the prescriber than those already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Water for injections

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6

6.3 Shelf Life

Shelf life of ampoules as packaged for sale

3 years

Shelf life of vials as packaged for sale

2 years

Shelf life after first opening of the container (undiluted):

From a microbiological point of view, unless the method of opening precludes the risk of microbial contamination, the product should be used immediately.

If not used immediately, in-use storage times and conditions are the responsibility of the user.

Shelf life after dilution with sterile 0.9% sodium chloride:

Chemical and physical in-use stability has been demonstrated for 48 hours at 30°C in dilutions up to 1:250 with sterile 0.9% sodium chloride.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

For storage conditions of the reconstituted and diluted solution see 6.3.

6.5 Nature And Contents Of Container

Type 1 glass ampoule.

Pack sizes: 5 x 1 ml, 10 x 1 ml, 5 x 2 ml, 10 x 2 ml, 2 x 5 ml, 5 x 5 ml, 2 x 10 ml, 5 x 10 ml

Type 1 glass vial with chlorobutyle rubber stopper and aluminium cap.

Pack sizes: 5 x 1 ml, 10 x 1 ml, 5 x 2 ml, 10 x 2 ml, 2 x 5 ml, 5 x 5 ml, 2 x 10 ml, 5 x 10 ml

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Inspect vials/ampoules visually for sediment and damage before use. Use only those containing sediment-free, homogeneous solution.

Monofer is for single use only and any unused solution should be disposed of in accordance with local requirements.

Monofer must only be mixed with sterile 0.9% sodium chloride. No other intravenous dilution solutions should be used. No other therapeutic agents should be added. For dilution instructions, see section 4.2.

The reconstituted solution for injection should be visually inspected prior to use. Use only clear solutions without sediment.

7. Marketing Authorisation Holder

Pharmacosmos A/S

Roervangsvej 30

DK-4300 Holbaek

Denmark

8. Marketing Authorisation Number(S)

PL 18380/001

9. Date Of First Authorisation/Renewal Of The Authorisation

18/01/2010

10. Date Of Revision Of The Text

18/01/2010

Viroptic

Generic Name: Trifluridine
Class: Antivirals
CAS Number: 70-00-8

Introduction

Antiviral; fluorinated pyrimidine nucleoside.

Uses for Viroptic

Herpes Simplex Virus Keratitis and Keratoconjunctivitis

Treatment of primary keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus types 1 and 2 (HSV-1 and HSV-2).^{104 105}

Vaccinia Virus Ophthalmic Infections

Treatment of ocular vaccinia infections† (i.e., to minimize progression and begin resolution of vaccinia infection in the cornea and conjunctiva) that occur as a complication of smallpox vaccinations.^{101 103}

Used for prophylaxis to prevent extension of vaccinia infection to the conjunctiva and cornea† in patients with blepharitis or vaccinia lesions on or near the eyelid.^{101 103}

Recommended by the CDC and other experts for prophylaxis following possible inadvertent inoculation with vaccinia virus in or near the eye (e.g., splash to the eye) involving smallpox vaccine or a laboratory strain of the virus†.^{102 103}

Viroptic Dosage and Administration

Administration

Ophthalmic Administration

Apply topically onto the cornea of the eye as an ophthalmic solution.¹⁰⁴

Dosage

Adults

Herpes Simplex Virus Keratitis and Keratoconjunctivitis

Ophthalmic

1 drop of a 1% solution in the affected eye(s) every 2 hours while awake until reepithelialization has occurred.^{104 105}

Following reepithelialization, may decrease dosage to 1 drop every 4 hours while awake (i.e., minimum 5 drops daily) for an additional 7 days to prevent recurrence of the infection.^{104 105}

If there are no signs of improvement after 7 days or if complete reepithelialization has not occurred after 14 days of therapy, other forms of therapy should be considered.¹⁰⁴

Use of trifluridine for >21 days should be avoided.¹⁰⁴

Vaccinia Virus Ophthalmic Infections†

Treatment

Ophthalmic

1 drop of a 1% solution in the affected eye(s) every 2 hours while awake (i.e., 9 times daily) for up to 14 days or until all lesions have healed.¹⁰¹

Prophylaxis in Patients with Blepharitis or Vaccinia Lesions On or Near the Eyelid

Ophthalmic

1 drop of a 1% solution in the affected eye(s) every 4 hours while awake (i.e., 5 times daily) for up to 14 days or until all periocular and/or lid lesions have healed and scabs have fallen off.¹⁰¹

If there is are no signs of improvement or manifestations worsen after 24–48 hours of therapy, may increase dosage to 1 drop instilled into the affected eye(s) every 2 hours while awake (i.e., 9 times daily).¹⁰¹

Prophylaxis Following Inadvertent Exposure to Vaccinia

Ophthalmic

1 drop of a 1% solution in the affected eye(s) every 4 hours while awake (i.e., 5 times daily) for up to 5 days.¹⁰¹

Discontinue therapy if there is no evidence of vaccinia infection after 5 days.¹⁰²

Prescribing Limits

Adults

Herpes Simplex Virus Keratitis and Keratoconjunctivitis

Ophthalmic

Maximum 9 drops daily.^{104 105}

Use for >21 days should be avoided.¹⁰⁴

Vaccinia Virus Ophthalmic Infections

Treatment

Ophthalmic

Maximum 9 drops daily for up to 14 days.¹⁰¹

Vaccinia Virus Ophthalmic Infections† (Prophylaxis in Patients with Blepharitis or Vaccinia Lesions On or Near the Eyelid)

Ophthalmic

Maximum 9 drops daily.¹⁰¹ Therapy may be administered for up to 14 days.¹⁰¹

Vaccinia Virus Ophthalmic Infections† (Prophylaxis Following Inadvertent Exposure to Vaccinia)

Ophthalmic

Maximum 5 drops daily for up to 5 days.¹⁰¹

Cautions for Viroptic

Contraindications

• 
  

  Known hypersensitivity to trifluridine or any ingredient in the formulation or chemical intolerance to trifluridine.¹⁰⁴

  
  

Warnings/Precautions

Warnings

Ocular Toxicity

Potential ocular toxicity if recommended dosage and frequency are exceeded.¹⁰⁴ (See Prescribing Limits under Dosage and Administration.)

General Precautions

Mutagenic and Carcinogenic Effects

Mutagenic, DNA damaging, and cell-transforming effects reported in vitro; possible heritable genetic damage.¹⁰⁴

Malignancies (e.g., adenocarcinomas of the GI tract and mammary glands, hemangiosarcomas of the spleen and liver, carcinosarcomas of the prostate gland, granulosathecal cell tumors of the ovary) reported in rats.¹⁰⁴

Viral Resistance

Possible development of viral resistance.^a

Specific Populations

Pregnancy

Category C.^a

Lactation

It is unlikely that trifluridine is distributed into milk following topical application to the eye.^a Use not recommended unless the possible benefits outweigh the potential risks.^a

Pediatric Use

Safety and efficacy not established in children <6 years of age .^a

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.^a

Common Adverse Effects

Mild, usually transient burning, stinging, or local irritation upon instillation, palpebral edema.^a

Stability

Storage

Ophthalmic

Solution

2–8°C.^a

ActionsActions

• 
  

  Exact mechanism of antiviral activity not completely known; appears to interfere with DNA synthesis.^a

  
  


• 
  

  Incorporates into viral DNA during replication, which results in the formation of defective proteins and an increased mutation rate.^b

  
  


• 
  

  Reversibly inhibits thymidylate synthetase, an enzyme required for DNA synthesis.^b

  
  

Advice to Patients

• 
  

  Importance of not contaminating the tip of the solution container.^b

  
  


• 
  

  Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^a

  
  


• 
  

  Importance of informing patients of other important precautionary information.^a (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Trifluridine

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Ophthalmic	Solution	1%*	Trifluridine Ophthalmic Solution (with thimerosal 0.001%)	Falcon
			Viroptic (with thimerosal 0.001%)	Monarch

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions July 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

101. Centers for Disease Control and Prevention. Clinical evaluation tool for smallpox vaccine adverse reactions; ophthalmologic reactions/inadvertent inoculation in a vaccinee (or close contact). (03-12-2003 version). From the CDC website (). Accessed 2003 Apr 11.

102. Centers for Disease Control and Prevention. Clinical evaluation tool for smallpox vaccine adverse reactions; ophthalmologic reactions/eye splash or other potential exposure to vaccinia virus. (03-25-2003 version). From the CDC web site (). Accessed 2003 Apr 11.

103. Centers for Disease Control and Prevention. Smallpox vaccination and adverse reactions: guidance for clinicians. MMWR Morb Mortal Wkly Rep. 2003; 52(No. RR-4):1-28.

104. Monarch Pharmaceuticals. Viroptic (trifluridine) 1% ophthalmic solution prescribing information. Bristol, TN; 2000 Oct.

105. Anon. Drugs for non-HIV viral infections. Med Lett Drugs Ther. 2002; 44:9-16. [PubMed 11828264]

106. Lennette DA, Eiferman RA. Inhibition of adenovirus replication in vitro by trifluridine. Arch Ophthalmol. 1978; 96:1662-3. [PubMed 99133]

107. Hyndiuk RA, Seideman S, Leibsohn JM. Treatment of vaccinial keratitis with trifluorothymidine. Arch Ophthalmol. 1976; 94:1785-6. [PubMed 823931]

108. Allen C (US Centers for Disease Control and Prevention, Atlanta, GA): Personal communication. 2003 May 13.

a. Falcon Pharmaceuticals. Trifluridine 1% ophthalmic solution prescribing information. Fort Worth, TX; 2664-5.

b. AHFS drug information 2006. McEvoy GK, ed. Trifluridine. Bethesda, MD: American Society of Health-System Pharmacists; 2006:2751-3

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• Herpetic Keratitis

Sodium Valproate 500mg Enteric Coated Tablets

1. Name Of The Medicinal Product

Sodium Valproate 500mg Gastro-resistant Tablets

2. Qualitative And Quantitative Composition

Sodium Valproate 500mg.

3. Pharmaceutical Form

Gastro-resistant Tablet.

4. Clinical Particulars

4.1 Therapeutic Indications

In the treatment of generalised, partial or other epilepsy.

4.2 Posology And Method Of Administration

Sodium Valproate 500mg Gastro-resistant Tablets are for oral administration.

Daily dosage requirements vary according to age and body weight.

Sodium valproate tablets may be given twice daily. The tablets should be swallowed whole and not crushed or chewed.

Dosage Usual requirements are as follows:

Adults

Dosage should start at 600mg daily increasing by 200mg at three day intervals until control is achieved. This is generally within the dosage range 1000mg to 2000mg per day, i.e. 20-30mg/kg/day body weight. Where adequate control is not achieved within this range the dose may be further increased to 2500mg per day.

Children over 20kg

Initial dosage should be 400mg/day (irrespective of weight) with spaced increases until control is achieved; this is usually within the range 20-30mg/kg body weight per day. Where adequate control is not achieved within this range the dose may be increased to 35mg/kg body weight per day.

Children under 20kg

20mg/kg of body weight per day; in severe cases this may be increased but only in patients in whom plasma valproic acid levels can be monitored. Above 40mg/kg/day, clinical chemistry and haematological parameters should be monitored.

Use in the elderly

Although the pharmacokinetics of valproate are modified in the elderly, they have limited clinical significance and dosage should be determined by seizure control. The volume of distribution is increased in the elderly and because of decreased binding to serum albumin, the proportion of free drug is increased. This will affect the clinical interpretation of plasma valproic acid levels.

In patients with renal insufficiency

It may be necessary to decrease the dosage. Dosage should be adjusted according to clinical monitoring since monitoring of plasma concentrations may be misleading. (See 5.2, Pharmocokinetic properties.)

In patients with hepatic insufficiency

Salicylates should not be used concomitantly with valproate since they employ the same metabolic pathway (see also sections 4.4 Special Warnings and Precautions for Use and 4.8 Undesirable Effects).

Liver dysfunction, including hepatic failure resulting in fatalities, has occurred in patients whose treatment included valproic acid (see sections 4.3 Contraindications and 4.4 Special Warnings and Precautions for Use).

Salicylates should not be used in children under 16 years (see aspirin/salicylate product information on Reye's syndrome). In addition in conjunction with sodium valproate, concomitant use in children under 3 years can increase the risk of liver toxicity (see section 4.4.1 Special warnings).

Combined Therapy

When starting sodium valproate in patients already on other anticonvulsants, these should be tapered slowly; initiation of sodium valproate therapy should then be gradual, with target dose being reached after about 2 weeks. In certain cases it may be necessary to raise the dose by 5 to 10mg/kg/day when used in combination with anticonvulsants which induce liver enzyme activity, e.g. phenytoin, phenobarbital and carbamazepine. Once known enzyme inducers have been withdrawn it may be possible to maintain seizure control on a reduced dose of sodium valproate. When barbiturates are being administered concomitantly and particularly if sedation is observed (particularly in children) the dosage of barbiturate should be reduced.

NB: In children requiring doses higher than 40mg/kg/day clinical chemistry and haematological parameters should be monitored.

Optimum dosage is mainly determined by seizure control and routine measurement of plasma levels is unnecessary. However, a method for measurement of plasma levels is available and may be helpful where there is poor control or side effects are suspected see section 5.2 Pharmacokinetic properties).

4.3 Contraindications

- Active liver disease

- Personal or family history of severe hepatic dysfunction, especially drug related

- Hypersensitivity to sodium valproate

- Porphyria

4.4 Special Warnings And Precautions For Use

Although there is no specific evidence of sudden recurrence of underlying symptoms following withdrawal of valproate, discontinuation should normally only be done under the supervision of a specialist in a gradual manner. This is due to the possibility of sudden alterations in plasma concentrations giving rise to a recurrence of symptoms. NICE has advised that generic switching of valproate preparations is not normally recommended due to the clinical implications of possible variations in plasma concentrations.

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

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

4.4.1 Special warnings

Liver dysfunction:

Conditions of occurrence:

Severe liver damage, including hepatic failure sometimes resulting in fatalities, has been very rarely reported.

Experience in epilepsy has indicated that patients most at risk, especially in cases of multiple anticonvulsant therapy, are infants and in particular young children under the age of 3 years and those with severe seizure disorders, organic brain disease, and (or) congenital metabolic or degenerative disease associated with mental retardation.

After the age of 3 years, the incidence of occurrence is significantly reduced and progressively decreases with age.

The concomitant use of salicylates should be avoided in children under 3 years due to the risk of liver toxicity. Additionally, salicylates should not be used in children under 16 years (see aspirin/salicylate product information on Reye's syndrome).

Monotherapy is recommended in children under the age of 3 years when prescribing sodium valproate, but the potential benefit of sodium valproate should be weighed against the risk of liver damage or pancreatitis in such patients prior to initiation of therapy.

In most cases, such liver damage occurred during the first 6 months of therapy, the period of maximum risk being 2-12 weeks.

Suggestive signs:

Clinical symptoms are essential for early diagnosis. In particular the following conditions, which may precede jaundice, should be taken into consideration, especially in patients at risk (see above: 'Conditions of occurrence'):

- non specific symptoms, usually of sudden onset, such as asthenia, malaise, anorexia, lethargy, oedema and drowsiness, which are sometimes associated with repeated vomiting and abdominal pain.

- in patients with epilepsy, recurrence of seizures.

These are an indication for immediate withdrawal of the drug.

Patients (or their family for children) should be instructed to report immediately any such signs to a physician should they occur. Investigations including clinical examination and biological assessment of liver function should be undertaken immediately.

Detection:

Liver function should be measured before therapy and then periodically monitored during the first 6 months of therapy, especially in those who seem most at risk, and those with a prior history of liver disease.

Amongst usual investigations, tests which reflect protein synthesis, particularly prothrombin rate, are most relevant.

Confirmation of an abnormally low prothrombin rate, particularly in association with other biological abnormalities (significant decrease in fibrinogen and coagulation factors; increased bilirubin level and raised transaminases) requires cessation of sodium valproate therapy.

As a matter of precaution and in case they are taken concomitantly salicylates should also be discontinued since they employ the same metabolic pathway.

As with most antiepileptic drugs, increased liver enzymes are common, particularly at the beginning of therapy; they are also transient.

More extensive biological investigations (including prothrombin rate) are recommended in these patients; a reduction in dosage may be considered when appropriate and tests should be repeated as necessary.

Pancreatitis: Pancreatitis, which may be severe and result in fatalities, has been very rarely reported. Patients experiencing nausea, vomiting or acute abdominal pain should have a prompt medical evaluation (including measurement of serum amylase).Young children are at particular risk; this risk decreases with increasing age. Severe seizures and severe neurological impairment with combination anticonvulsant therapy may be risk factors. Hepatic failure with pancreatitis increases the risk of fatal outcome. In case of pancreatitis, valproate should be discontinued.

Women of childbearing potential (see section 4.6): This medicine should not be used in women of child-bearing potential unless clearly necessary (i.e. in situations where other treatments are ineffective or not tolerated). This assessment is to be made before sodium valproate is prescribed for the first time, or when a woman of child-bearing potential treated with sodium valproate plan a pregnancy. Women of child-bearing potential must use effective contraception during treatment.

Carbapenem agents: The concomitant use of valproate and carbapenem agents is not recommended.

4.4.2 Precautions

Haematological: Blood tests (blood cell count, including platelet count, bleeding time and coagulation tests) are recommended prior to initiation of therapy or before surgery, and in case of spontaneous bruising or bleeding (see section 4.8 Undesirable Effects).

Renal insufficiency:

In patients with renal insufficiency, it may be necessary to decrease dosage. As monitoring of plasma concentrations may be misleading, dosage should be adjusted according to clinical monitoring (see sections 4.2 Posology and Method of Administration and 5.2. Pharmacokinetic Properties).

Systemic lupus erythematosus: Although immune disorders have only rarely been noted during the use of sodium valproate, the potential benefit of sodium valproate should be weighed against its potential risk in patients with systemic lupus erythematosus (see also section 4.8 Undesirable Effects).

Hyperammonaemia: When a urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment because of the risk of hyperammonaemia with valproate.

Weight gain: Sodium valproate very commonly causes weight gain, which may be marked and progressive. Patients should be warned of the risk of weight gain at the initiation of therapy and appropriate strategies should be adopted to minimise it (see section 4.8 Undesirable Effects).

Pregnancy: Women of childbearing potential should not be started on sodium valproate without specialist neurological advice.

Adequate counselling should be made available to all pregnant women with epilepsy of childbearing potential regarding the risks associated with pregnancy because of the potential teratogenic risk to the foetus (see also section 4.6 Pregnancy and Lactation).

Diabetic patients: Valproate is eliminated mainly through the kidneys, partly in the form of ketone bodies; this may give false positives in the urine testing of possible diabetics.

Alcohol: Alcohol intake is not recommended during treatment with valproate.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

4.5.1 Effects of Valproate on other drugs

- Antipsychotics, MAO inhibitors, antidepressants and benzodiazepines

Valproate may potentiate the effect of other psychotropics such as antipsychotics, MAO inhibitors, antidepressants and benzodiazepines; therefore, clinical monitoring is advised and the dosage of other psychotropics should be adjusted when appropriate.

In particular, a clinical study has suggested that adding olanzapine to valproate or lithium therapy may significantly increase the risk of certain adverse events associated with olanzapine e.g. neutropenia, tremor, dry mouth, increased appetite and weight gain, speech disorder and somnolence.

- Lithium

Sodium valproate has no effect on serum lithium levels

- Phenobarbital

Valproate increases phenobarbital plasma concentrations (due to inhibition of hepatic catabolism) and sedation may occur, particularly in children. Therefore, clinical monitoring is recommended throughout the first 15 days of combined treatment with immediate reduction of phenobarbital doses if sedation occurs and determination of phenobarbital plasma levels when appropriate.

- Primidone

Valproate increases primidone plasma levels with exacerbation of its adverse effects (such as sedation); these signs cease with long term treatment. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.

- Phenytoin

Valproate decreases phenytoin total plasma concentration. Moreover valproate increases phenytoin free form with possible overdosage symptoms (valproic acid displaces phenytoin from its plasma protein binding sites and reduces its hepatic catabolism). Therefore clinical monitoring is recommended; when phenytoin plasma levels are determined, the free form should be evaluated.

- Carbamazepine

Clinical toxicity has been reported when valproate was administered with carbamazepine as valproate may potentiate toxic effects of carbamazepine. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.

- Lamotrigine

Sodium valproate reduces the metabolism of lamotrigine and increases the lamotrigine mean half life by nearly two fold. This interaction may lead to increased lamotrigine toxicity, in particular serious skin rashes.

Therefore, clinical monitoring is recommended and dosages should be adjusted (lamotrigine dosage decreased) when appropriate.

- Felbamate

-Valproic acid may decrease the felbamate mean clearance by up to 16%.

- Zidovudine

Valproate may raise zidovudine plasma concentration leading to increased zidovudine toxicity.

- Vitamin K-dependent anticoagulants

The anticoagulant effect of warfarin and other coumarin anticoagulants may be increased following displacement from plasma protein binding sites by valproic acid. The prothrombin time should be closely monitored.

- Temozolomide

Co-administration of temozolomide and valproate may cause a small decrease in the clearance of temozolomide that is not thought to be clinically relevant.

4.5.2 Effects of other drugs on Valproate

Antiepileptics with enzyme inducing effect (including phenytoin, phenobarbital, carbamazepine) decrease valproic acid plasma concentrations. Dosages should be adjusted according to clinical response and blood levels in case of combined therapy.

On the other hand, combination of felbamate and valproate decreases valproic acid clearance by 22% to 50% and consequently increase the valproic acid plasma concentrations. Valproate dosage should be monitored.

Mefloquine and chloroquine increase valproic acid metabolism and may lower the seizure threshold; therefore epileptic seizures may occur in cases of combined therapy. Accordingly, the dosage of sodium valproate may need adjustment.

In case of concomitant use of valproate and highly protein bound agents (e.g. aspirin), free valproic acid plasma levels may be increased.

Valproic acid plasma levels may be increased (as a result of reduced hepatic metabolism) in case of concomitant use with cimetidine or erythromycin.

Carbapenem antibiotics such as imipenem, panipenem and meropenem: Decreases in blood levels of valproic acid have been reported when it is co-administered with carbapenem agents resulting in a 60%-100% decrease in valproic acid levels within two dayssometimes associated with convulsions. Due to the rapid onset and the extent of the decrease, co-administration of carbapenem agents in patients stabilised on valproic acid should be avoided (section 4.4). If treatment with these antibiotics cannot be avoided, close monitoring of valproic acid blood levels should be performed.

Colestyramine may decrease the absorption of valproate.

Rifampicin may decrease the valproic acid blood levels resulting in a lack of therapeutic effect. Therefore, valproate dosage adjustment may be necessary when it is co-administered with rifampicin.

4.5.3 Other Interactions

Caution is advised when using sodium valproate in combination with newer anti-epileptics whose pharmacodynamics may not be well established.

Valproate usually has no enzyme-inducing effect; as a consequence, valproate does not reduce efficacy of oestroprogestative agents in women receiving hormonal contraception, including the oral contraceptive pill.

Concomitant administration of valproate and topiramate has been associated with encephalopathy and/or hyperammonaemia. In patients taking these two drugs, careful monitoring for signs and symptoms is advised in particularly at-risk patients such as those with pre-existing encephalopathy.

4.6 Pregnancy And Lactation

Women of childbearing potential should not be started on sodium valproate without specialist neurological advice.

Adequate counselling should be made available to all women with epilepsy of childbearing potential regarding the risks associated with pregnancy because of the potential teratogenic risk to the foetus (See also section 4.6.1). Women who are taking sodium valproate and who may become pregnant should receive specialist neurological advice and the benefits of its use should be weighed against the risks.

Sodium valproate is the antiepileptic of choice in patients with certain types of epilepsy such as generalised epilepsy ± myoclonus/photosensitivity. For partial epilepsy, sodium valproate should be used only in patients resistant to other treatment. If pregnancy is planned, consideration should be given to cessation of sodium valproate treatment, if appropriate.

When sodium valproate treatment is deemed necessary, precautions to minimize the potential teratogenic risk should be followed. (See also section 4.6.1 paragraph entitled “In view of the above”)

4.6.1 Pregnancy

- Risk associated with epilepsy and antiepileptics

In offspring born to mothers with epilepsy receiving any anti-epileptic treatment, the overall rate of malformations has been demonstrated to be higher than the rate (approximately 3 %) reported in the general population. An increased number of children with malformations have been reported in cases of multiple drug therapy. Malformations most frequently encountered are cleft lip and cardio-vascular malformations.

No sudden discontinuation in the anti-epileptic therapy should be undertaken as this may lead to breakthrough seizures which could have serious consequences for both the mother and the foetus.

Antiepileptic drugs should be withdrawn under specialist supervision.

- Risk associated with seizures

During pregnancy, maternal tonic clonic seizures and status epilepticus with hypoxia carry a particular risk of death for mother and the unborn child.

- Risk associated with valproate

In animals: teratogenic effects have been demonstrated in the mouse, rat and rabbit.

There is animal experimental evidence that high plasma peak levels and the size of an individual dose are associated with neural tube defects.

In humans: Available data suggest an increased incidence of minor or major malformations including neural tube defect, cranio-facial defects, malformations of the limbs, cardiovascular malformations, hypospadias and multiple anomalies involving various body systems in offspring born to mothers with epilepsy treated with valproate. The data suggest that the use of valproate is associated with a greater risk of certain types of these malformations (in particular neural tube defects) than some other anti-epileptic drugs.

Data have suggested an association between in-utero exposure to valproate and the risk of developmental delay (frequently associated with dysmorphic features), particularly of verbal IQ. However, the interpretation of the observed findings in offspring born to mothers with epilepsy treated with sodium valproate remains uncertain, in the view of possible confounding factors such as low maternal IQ, genetic, social, environmental factors and poor maternal seizure control during pregnancy.

Both valproate monotherapy and valproate as part of polytherapy are associated with abnormal pregnancy outcome. Available data suggest that antiepileptic polytherapy including sodium valproate is associated with a higher risk of abnormal pregnancy outcome than sodium valproate monotherapy.

Autism spectrum disorders have also been reported in children exposed to valproate in utero.

- In view of the above data

The following recommendations should be taken into consideration: This medicine should not be used during pregnancy and in women of child-bearing potential unless clearly necessary (i.e. in situations where other treatments are ineffective or not tolerated. This assessment is to be made before sodium valproate is prescribed for the first time, or when a woman of child-bearing potential, treated with sodium valproate plans a pregnancy. Women of child-bearing potential must use effective contraception during treatment. Women of child-bearing potential should be informed of the risks and benefits of the use of sodium valproate during pregnancy.

If a woman plans a pregnancy or becomes pregnant, sodium valproate therapy should be reassessed whatever the indication:

• In epilepsy, valproate therapy should not be discontinued without reassessment of the benefit risk. If further to a careful evaluation of the risks and benefits, sodium valproate treatment is to be continued during pregnancy it is recommended to use sodium valproate in divided doses over the day at the lowest effective dose. The use of a prolonged release formulation may be preferable to any other treatment form.

• In addition, if appropriate, folate supplementation should be started before pregnancy at a relevant dosage (5mg daily) as it may minimise the risk of neural tube defects.

• Specialised prenatal monitoring should be instituted in order to detect the possible occurrence of neural tube defects or other malformations.

The available evidence suggests that anticonvulsant monotherapy is preferred. Dosage should be reviewed before conception and the lowest effective dose used, in divided doses, as abnormal pregnancy outcome tends to be associated with higher total daily dosage and with the size of an individual dose. The incidence of neural tube defects rises with increasing dosage, particularly above 1000mg daily. The administration in several divided doses over the day and the use of a prolonged release formulation is preferable in order to avoid high peak plasma levels.

Pregnancies should be carefully screened by ultrasound, and other techniques if appropriate (see Section 4.4 Special Warnings and Special Precautions for use).

- Risk in the neonate

Very rare cases of haemorrhagic syndrome have been reported in neonates whose mothers have taken valproate during pregnancy. This haemorrhagic syndrome is related to hypofibrinogenemia; afibrinogenemia has also been reported and may be fatal. These are possibly associated with a decrease of coagulation factors. However, this syndrome has to be distinguished from the decrease of the vitamin-K factors induced by phenobarbital and other anti-epileptic enzyme inducing drugs.

Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates.

Cases of hypoglycaemia have been reported in neonates, whose mothers have taken valproate during the third trimester of the pregnancy.

4.6.2 Lactation

Excretion of valproate in breast milk is low, with a concentration between 1 % to 10 % of total maternal serum levels. Although there appears to be no contra-indication to breastfeeding, physicians are advised that in any individual case, consideration should be given to the safety profile of sodium valproate, specifically haematological disorders (see section 4.8 Undesirable Effects).

4.7 Effects On Ability To Drive And Use Machines

Use of sodium valproate may provide seizure control such that the patient may be eligible to hold a driving licence.

Patients should be warned of the risk of transient drowsiness, especially in cases of anticonvulsant polytherapy or association with benzodiazepines (see section 4.5 Interactions with Other Medicaments and Other Forms of Interaction).

4.8 Undesirable Effects

Congenital and familial/genetic disorders: (see section 4.6 Pregnancy and Lactation)

Hepato-biliary disorders: rare cases of liver injury (see section 4.4.1 Warnings) Severe liver damage, including hepatic failure sometimes resulting in death, has been reported (see also sections 4.2, 4.3 and 4.4.1). Increased liver enzymes are common, particularly early in treatment, and may be transient (see section 4.4.1).

Gastrointestinal disorders (nausea, gastralgia, diarrhoea) frequently occur at the start of treatment, but they usually disappear after a few days without discontinuing treatment. These problems can usually be overcome by taking sodium valproate with or after food or by using Gastro-resistant Sodium Valproate.

Very rare cases of pancreatitis, sometimes lethal, have been reported (see section 4.4 Special Warnings and Special Precautions for Use).

Nervous system disorders:

Sedation has been reported occasionally, usually when in combination with other anticonvulsants. In monotherapy it occurred early in treatment on rare occasions and is usually transient. Rare cases of lethargy occasionally progressing to stupor, sometimes with associated hallucinations or convulsions have been reported. Encephalopathy and coma have very rarely been observed. These cases have often been associated with too high a starting dose or too rapid a dose escalation or concomitant use of other anticonvulsants, notably phenobarbital or topiramate. They have usually been reversible on withdrawal of treatment or reduction of dosage.

Very rare cases of extrapyramidal symptoms which may not be reversible including reversible parkinsonism, or reversible dementia associated with reversible cerebral atrophy have been reported. Dose-related ataxia and fine postural tremor have occasionally been reported.

An increase in alertness may occur; this is generally beneficial but occasionally aggression, hyperactivity and behavioural deterioration have been reported.

Psychiatric disorder: Confusion has been reported

Metabolic disorders:

Cases of isolated and moderate hyperammonaemia without change in liver function tests may occur frequently, are usually transient and should not cause treatment discontinuation. However, they may present clinically as vomiting, ataxia, and increasing clouding of consciousness. Should these symptoms occur sodium valproate should be discontinued. Very rare cases of hyponatraemia have been reported.

Hyperammonaemia associated with neurological symptoms has also been reported (see section 4.4.2 Precautions). In such cases further investigations should be considered.

Syndrome of inappropriate secretion of ADH (SIADH).

Blood and lymphatic system disorders:

Frequent occurrence of thrombocytopenia, rare cases of anaemia, leucopenia or pancytopenia. The blood picture returned to normal when the drug was discontinued.

Bone marrow failure, including red cell aplasia.

Agranulocytosis.

Isolated findings of a reduction in blood fibrinogen and/or an increase in prothrombin time have been reported, usually without associated clinical signs and particularly with high doses (sodium valproate has an inhibitory effect on the second phase of platelet aggregation). Spontaneous bruising or bleeding is an indication for withdrawal of medication pending investigations (see also section 4.6 Pregnancy and Lactation).

Skin and subcutaneous tissue disorders:

Rash rarely occurs with valproate. In very rare cases toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme have been reported.

Transient hair loss, which may sometimes be dose-related, has often been reported. Regrowth normally begins within six months, although the hair may become more curly than previously. Hirsutism and acne have been very rarely reported.

Reproductive system and breast disorders:

Amenorrhoea and dysmenorrhoea have been reported. Very rarely gynaecomastia has occurred. Male infertility.

Vascular disorders:

The occurrence of vasculitis has occasionally been reported.

Ear disorders:

Hearing loss, either reversible or irreversible has been reported rarely; however a cause and effect relationship has not been established.

Renal and urinary disorders:

There have been isolated reports of a reversible Fanconi's syndrome (a defect in proximal renal tubular function giving rise to glycosuria, amino aciduria, phosphaturia, and uricosuria), but the mode of action is as yet unclear.

Very rare cases of enuresis have been reported.

Immune system disorders:

Angioedema, Drug Rash with Eosinophilia, Systemic Symptoms (DRESS) syndrome, and allergic reactions (ranging from rash to hypersensitivity reactions) have been reported.

General disorders:

Very rare cases of non-severe peripheral oedema have been reported.

Increase in weight may also occur. Weight gain being a risk factor for polycystic ovary syndrome, it should be carefully monitored (see section 4.4 Special Warnings and Special Precautions for Use).

4.9 Overdose

Cases of accidental and deliberate valproate overdosage have been reported. At plasma concentrations of up to 5 to 6 times the maximum therapeutic levels, there are unlikely to be any symptoms other than nausea, vomiting and dizziness.

Signs of massive overdose, i.e. plasma concentration 10 to 20 times maximum therapeutic levels, usually include CNS depression or coma with muscular hypotonia, hyporeflexia, miosis, impaired respiratory function, metabolic acidosis. A favourable outcome is usual, however some deaths have occurred following massive overdose.

Symptoms may however be variable and seizures have been reported in the presence of very high plasma levels (see also section 5.2 Pharmacokinetic Properties).

Cases of intracranial hypertension related to cerebral oedema have been reported.

Hospital management of overdose should be symptomatic:, including cardio-respiratory monitoring. Gastric lavage may be useful up to 10 to 12 hours following ingestion.

Haemodialysis and haemoperfusion have been used successfully.

Naloxone has been successfully used in a few isolated cases, sometimes in association with activated charcoal given orally. In case of massive overdose, haemodialysis and haemoperfusion have been used successfully.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Sodium valproate and valproic acid are anticonvulsants.

In certain in-vitro studies it was reported that sodium valproate could stimulate HIV replication but studies on peripheral blood mononuclear cells from HIV-infected subjects show that sodium valproate does not have a mitogen-like effect on inducing HIV replication. Indeed the effect of sodium valproate on HIV replication ex-vivo is highly variable, modest in quantity, appears to be unrelated to the dose and has not been documented in man.

5.2 Pharmacokinetic Properties

The half life of sodium valproate is usually reported to be within the range 8-20 hours. It is usually shorter in children.

In patients with severe renal insufficiency it may be necessary to alter dosage in accordance with free serum valproic acid levels.

The reported effective therapeutic range for plasma valproic acid levels is 40-100mg/litre (278-694 micromol/litre). This reported range may depend on time of sampling and presence of co-medication. The percentage of free (unbound) drug is usually between 6% and 15% of the total plasma levels. An increased incidence of adverse effects may occur with plasma levels above the effective therapeutic range.

The pharmacological (or therapeutic) effects of sodium valproate may not be clearly correlated with the total or free (unbound) plasma valproic acid levels.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Povidone, talc, calcium silicate, magnesium stearate, hypromellose 6, citric acid anhydrous, macrogel 6000, polyvinyl acetate phthalate, diethyl phthalate, stearic acid, violet lake solids (containing titanium dioxide, amaranth lake, indigo carmine lake and hydroxypropyl cellulose).

6.2 Incompatibilities

There are no major incompatibilities.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Sodium valproate is hygroscopic. The tablets should not be removed from their foil until immediately before they are taken. Where possible, blister strips should not be cut. Store in a dry place below 30°C.

6.5 Nature And Contents Of Container

Sodium Valproate 500 Gastro-resistant Tablets are supplied in blister packs further packed into a cardboard carton. Pack sizes 100 and 112 tablets.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS, UK

8. Marketing Authorisation Number(S)

PL 17780/0454

9. Date Of First Authorisation/Renewal Of The Authorisation

18 June 2009

10. Date Of Revision Of The Text

14 July 2011