PepcidTwo

1. Name Of The Medicinal Product

Pepcidtwo chewable tablet

2. Qualitative And Quantitative Composition

Famotidine 10 mg

Magnesium hydroxide 165 mg

Calcium carbonate 800 mg

For excipients, see 6.1.

3. Pharmaceutical Form

Chewable tablet

Rose coloured, round, flat, chewable tablet embossed 'P'.

4. Clinical Particulars

4.1 Therapeutic Indications

The short-term symptomatic relief of heartburn, indigestion, acid indigestion, and hyperacidity.

4.2 Posology And Method Of Administration

Adults and children 16 years of age or older:

One tablet to be chewed for the relief of symptoms. No more than two tablets to be taken in 24 hours.

Patients must seek medical advice if symptoms fail to respond, or if symptoms recur following self treatment with Pepcidtwo.

The maximum continuous treatment period is 6 days. The patient should not purchase a second pack of tablets without the advice of a pharmacist or doctor.

Elderly

No dosage adjustment is necessary.

Children less than 16 years of age

Not recommended.

4.3 Contraindications

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

These tablets are not indicated in the following patient groups unless advised by their physician:

• Patients with moderate or severe renal failure (serum calcium should be monitored in such cases)

• Patients with severe hepatic impairment

• Patients suffering from any other illness or taking any medications either physician-prescribed or self-prescribed

• Patients who are middle aged or older with new or recently changed dyspeptic symptoms

• Patients with unintended weight loss in association with dyspeptic symptoms

4.4 Special Warnings And Precautions For Use

If patients have difficulty swallowing, or abdominal discomfort persists they should seek medical advice.

Gastric cancer and simple indigestion can have some symptoms in common. Therefore it is important that patients with symptoms such as weight loss, dysphagia, or anaemia, in addition to indigestion, should seek medical advice before starting any treatment, to avoid delay in investigation and diagnosis.

Patients who are taking non-steroidal anti-inflammatory drugs, especially the elderly, should consult their doctor before taking these tablets

As Pepcidtwo contains sucrose and lactose, it should not be taken by patients with fructose intolerance, glucose-galactose malabsorption syndrome, sucrase-isomaltase deficiency, lactase insufficiency or galactosaemia.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Famotidine

No drug interactions of clinical importance have been identified. Famotidine does not interact with the cytochrome P450-linked drug metabolising enzyme system. Famotidine does not affect blood alcohol levels following oral ingestion of ethanol.

Antacids

Antacids can decrease the absorption of some medicines. Concomitant administration of Pepcidtwo is therefore not indicated unless advised by a physician (see 4.3).

4.6 Pregnancy And Lactation

Pepcidtwo is not recommended for use in pregnancy. Before a decision is made to use the product during pregnancy, the physician should weigh the potential benefits against the possible risks involved.

Famotidine is secreted in human milk and magnesium salts may enter breast milk and cause diarrhoea in infants; therefore breast-feeding mothers should either stop breast-feeding or not take the product.

4.7 Effects On Ability To Drive And Use Machines

In clinical trials with Pepcidtwo, there has been no observed impairment of the ability to drive or operate machinery.

4.8 Undesirable Effects

Pepcidtwo has been shown to be generally well tolerated. In clinical trials the most common effects were headaches followed by nausea and diarrhoea. Other symptoms noted included abdominal distension, abdominal pain, dizziness, dry mouth, dyspepsia, eructation, flatulence, nervousness, paraesthesia, taste perversion and thirst.

Other side effects reported for famotidine alone, often when given at higher doses than Pepcidtwo, include anaphylaxis, angioedema, anorexia, arthralgia, cholestatic jaundice, constipation, fatigue, leucopenia, liver enzyme abnormalities, pancytopenia, pruritus, rash, urticaria, vomiting, and, in isolated cases, worsening of existing hepatic disease. Gynaecomastia has been reported rarely. In most cases that were followed up, it was reversible on discontinuing treatment.

Antacids containing calcium and magnesium salts can cause bloating, changes in stool frequency and consistency, and fullness.

4.9 Overdose

There is no experience to date with overdosage. The usual measures to remove unabsorbed material from the gastro-intestinal tract, clinical monitoring and supportive therapy should be employed.

Patients with Zollinger-Ellison syndrome have tolerated doses up to 800 mg/day of famotidine for more than a year without development of significant adverse effects.

5. Pharmacological Properties

H₂ ANTAGONIST/ANTACID.

(A02BA53: famotidine, combinations)

5.1 Pharmacodynamic Properties

Famotidine reduces the acid and pepsin production, as well as the volume of basal, nocturnal and stimulated gastric secretion. Magnesium hydroxide and calcium carbonate are antacids and neutralise intraluminal acid on contact. Pepcidtwo combines the prolonged duration of effect of famotidine with the rapid onset of action of antacids and has an acid neutralisation capacity of 21 mEq per tablet.

A study measuring gastric and oesophageal pH conducted on 23 patients demonstrated that the administration of Pepcidtwo with 60ml of water one hour after a high-fat evening meal produced an increase of oesophageal pH within 2 minutes. The increase of the gastric pH, above the increase observed with placebo and antacid alone, remained for 12 hours.

5.2 Pharmacokinetic Properties

The pharmacokinetic properties of famotidine are not significantly modified when administered with magnesium hydroxide and calcium carbonate as Pepcidtwo.

Famotidine:

Famotidine obeys linear kinetics. Famotidine is rapidly absorbed with dose-related peak plasma concentration occurring at 1-3 hours after administration. The mean bioavailability of an oral dose is 40-45 %. It is not modified when taken during meals. First-pass metabolism is minimal. Repeated doses do not lead to accumulation of the drug. Protein binding in the plasma is relatively low (15-20 %). The plasma half-life after a single oral dose or multiple repeated doses (for 5 days) is approximately 3 hours. Metabolism occurs in the liver, with formation of an inactive metabolite, the sulfoxide. Following oral administration, the mean urinary excretion of famotidine is 65-70 % of the absorbed dose, 25 to 30 % as unchanged compound. Renal clearance is 250 to 450ml/min, indicating some tubular excretion. A small amount may be excreted as the sulfoxide. The half-life is prolonged in patients with renal impairment.

Antacids

Calcium carbonate and magnesium hydroxide are converted to soluble chloride salts by gastric acid. Approximately 10% of the calcium and 15-20% of the magnesium are absorbed, and the remaining soluble chlorides are reconverted to insoluble salts, and are eliminated in the faeces. In individuals with normal kidney function the small amounts of calcium and magnesium that are absorbed are rapidly excreted by the kidneys.

5.3 Preclinical Safety Data

Extensive preclinical safety studies have been performed with famotidine in dogs, rats, mice and rabbits using oral and intravenous routes of administration. Minimal toxicological effects (after acute, subacute or chronic administration) have been observed, even at extremely high dosage levels and for extended periods of administration. No evidence of teratogenic, mutagenic or carcinogenic effects or alteration of reproductive function has been seen.

Only limited toxicology data are available for magnesium hydroxide and calcium carbonate. These data indicate no special hazard for humans under normal conditions of use. Ossification abnormalities have been described in animals treated with calcium carbonate at high doses or long periods.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Dextrates

Confectioner's sugar (sucrose and maize starch)

Lactose monohydrate

Peppermint flavour (peppermint oil, modified food starch, maltodextrine, citric acid (E330), sodium ascorbate (E301), water)

Cellulose acetate

Magnesium stearate

Hypromellose (E464)

Hydroxypropyl cellulose (E463)

Sodium lauryl sulphate

Pregelatinised maize starch

Cream flavour (sweet orange oils, ethanol, esters of acetic and butanoic acids, aliphatic alcohols and ketones, phenols, aliphatic and aromatic aldehydes, benzaldehyde, dextrin, maltodextrine, glucose, corn starch, calcium silicate, powdered vanilla extract, heliotropine, vanillin, silicone dioxide, water)

Red ferric oxide (E172).

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

2 years for strip packs (Paper/PE/Aluminium/EAA)

3 years for blister packs (PVC/ACLAR)

6.4 Special Precautions For Storage

No special precautions for storage

6.5 Nature And Contents Of Container

Blister packs (PVC/ACLAR) or strip packs (Paper/PE/Aluminium/EAA) containing:

2, 4, 6, 8, 10 and 12 tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

McNeil Products Limited

Foundation Park

Roxborough Way

Maidenhead

Berkshire

SL6 3UG

United Kingdom

8. Marketing Authorisation Number(S)

PL 15513/0348

9. Date Of First Authorisation/Renewal Of The Authorisation

15 December 2008

10. Date Of Revision Of The Text

01 March 2011

Prostin VR Sterile Solution

Prostin VR Sterile Solution for Injection

Alprostadil

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.



• 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.

In this leaflet:

• 1. What Prostin VR Sterile Solution is and what it is used for



• 2. Before your baby is given Prostin VR Sterile Solution



• 3. How Prostin VR Sterile Solution is given to your baby



• 4. Possible side effects



• 5. How to store Prostin VR Sterile Solution



• 6. Further information

What Prostin VR Sterile Solution is and what it is used for

Prostin VR Sterile Solution is a medicine given to new born babies through an injection into the vein or a catheter (fine tube) into an artery.

While a baby is in the womb, before it is born, it does not breathe. For this reason, in a baby’s heart there is a special, small blood vessel called the ‘ductus arteriosus’ that allows blood to pass through the heart without going through the lungs. Once the baby is born and breathing normally, this is no longer needed, and the ductus arteriosus would close off.

If the baby has certain conditions affecting the heart it may still be beneficial to keep this channel ( the ‘ductus arteriosus’) stay open until the heart condition can be corrected by surgery,. This is what Prostin VR can do ie. it relaxes the muscles in the wall of the ductus arteriosus while the baby still requires this. Once the baby has had an operation to correct the heart problem, then the ductus arteriosus will no longer be needed and can be allowed to close.

Your baby may have one of several problems in which it is necessary to keep open the ductus arteriosus until an operation can take place. Your baby’s doctor will explain which problem affects your baby.

Prostin VR Sterile Solution contains a medicine called ‘alprostadil’ which is a synthetic copy of a natural prostaglandin chemical which occurs in your body. Prostaglandins are a group of complex set of chemicals made by the body tissues; some of them can cause muscles, which occur in the walls of certain blood vessels to relax.

Before your baby is given Prostin VR Sterile Solution

All babies can have Prostin VR if they really need it. The doctor will carry out tests before deciding whether to give the medicine to your baby.

Take special care with Prostin VR:

There are some circumstances where special precautions may need to be taken. These include:

• If your baby has a tendency to bleed easily. The doctor will be cautious when using this medicine as it may prevent blood from clotting properly.



• If your baby suffers from an obstruction of the blood flow into the lungs, blood will be flowing through the ductus arteriosus from the main artery of the lungs. In this case, Prostin VR can be given through a catheter (fine tube) placed at or just above the junction between the main artery and the ductus arteriosus or can be given intravenously (by a drip into a vein).



• If your baby develops interrupted breathing (apnoea) or a slow heart beat, this medicine should be stopped and appropriate medical treatment should be given. This most often occurs in babies weighing less than 2 kg at birth. It usually happens within the first hour of the medicine being given. Doctors and nurses will watch your baby carefully in case they need to ventilate him or her (give oxygen) until normal breathing starts again. This medicine will only be used where there are facilities to do this. If the baby develops a high temperature or low blood pressure, the drug should be given at a slower rate until these symptoms subside.



• If your baby suffers from feeding problems. This medicine may cause thickening of the stomach wall, such that emptying of the stomach contents may be difficult opening from the stomach. This effect has been linked with the total amount of medicine given and the length of time it is given for. If your baby is given this medicine for more than 120 hours, the doctor will watch carefully for this problem which will cause the baby to vomit after feeds.



• If this medicine is given for a very long time period as the walls of the ductus arteriosus and of the artery that connects the heart to the lungs (pulmonary artery) may weaken.

Taking other medicines:

Babies born with heart problems usually have to be given several different medicines. These medicines may be to:

• improve the pumping action of the heart. These drugs act directly on the heart muscle and belong to a group of drugs called “cardiac glycosides”; an example is digoxin;



• raise the blood pressure, e.g. dopamine or isoproterenol;



• reduce the volume of the blood and hence the workload on the heart; these drugs are called “diuretics” or water tablets; an example is frusemide;



• fight infections (antibiotics, such as penicillin or gentamicin).

Prostin VR can be given at the same time as these medicines; no interactions with these medicines have been reported.

How Prostin VR Sterile Solution is given to your baby

This medicine must only be given by a doctor in a hospital or in a place where intensive care facilities are immediately available if needed.

This medicine can be given by an intravenous drip or through an artery by way of a tube (catheter).

The small volume (1 ml) of medicine must be diluted with larger volumes of a special salt or sugar solution. The amount of solution used will depend on how the medicine is to be given.

Different babies need different amounts of Prostin VR Sterile Solution. Your doctor will give the smallest amount needed for the shortest length of time to give a good result. The doctor will have carefully worked out the risks of giving the medicine over a long period in a very ill baby, against the possible benefits that the baby will get from the treatment or the risks of reducing or stopping Prostin VR treatment early.

As soon as tests show that the baby is responding, the rate will be reduced to the lowest possible dose that will maintain the response. (If your baby has an obstruction to the flow of blood to the lungs, the doctor will be looking for an increase in the amount of oxygen in the blood; if your baby has an obstruction in the flow of blood to the rest of the body, the doctor will be looking for an increase in the blood pressure and a fall in the acidity of the blood).

As soon as the baby starts to have the medicine, the pressure of the blood in the arteries will be checked at regular intervals. As Prostin VR relaxes muscles in other blood vessels this may cause a lowering of the baby’s blood pressure. (To do this, the doctor may use the catheter through which the drug is being given, or a stethoscope or an ultrasound device). If this pressure falls significantly, the rate at which Prostin VR Sterile Solution is being given will be reduced straight away.

Your baby’s doctor or nursing staff will be able to tell you if the medicine is working properly.

Possible side effects

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

Your baby may react to the medicine in other ways. Starting with the most common and decreasing in frequency the reactions that he or she may develop are:

• a high temperature for a short time period (transient pyrexia);



• a heart beat that is slower than normal (bradycardia);



• fits (seizures);



• low blood pressure;



• a heart beat that is faster than normal (tachycardia);



• diarrhoea



• Flushing of the skin may occur. This happens more often when the medicine is given by catheter into an artery and is usually relieved by repositioning the tip of the catheter.

The following have occurred in babies given Prostin VR. It is possible that they are adverse reactions to the drug, but may not have been caused by it:

• infection;



• stopping of the heart;



• clotting and bleeding throughout the circulation (disseminated intravascular coagulation)



• low levels of potassium in the blood, which if not corrected can cause muscle weakness and an abnormal heart rhythm;



• swelling caused by too much fluid in the body.

A test has shown that Prostin VR does not cause changes in the cells of the body that can cause cancer (mutations).

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

How to store Prostin VR Sterile Solution

The medicine will be kept out of the reach and sight of children.

Do not use Prostin VR after the expiry date which is stated on the label. The expiry date refers to the last day of that month.

Your hospital pharmacist will store this medicine in a refrigerator.

Further information

What Prostin VR Sterile Solution contains

The active substance is called alprostadil. Each ampoule (small, closed glass container) contains 500 micrograms of alprostadil.

The other (inactive) ingredient is 1ml dehydrated ethanol (alcohol).

What Prostin VR Sterile Solution looks like and contents of the pack

Prostin VR is packed in packs of 5 x 1 ml ampoules.

Marketing Authorisation Holder:

Pharmacia Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

UK

Manufacturer:

Pfizer Manufacturing Belgium NV

Rijksweg 12

B-2870 Puurs

Belgium

For further information on this medicine, please contact Pfizer Medical Information on: 01304 616161.

This leaflet was last updated in July 2008.

Ref: PR 2_1

Pro-Epanutin Concentrate for Infusion / Solution for Injection (Pfizer Limited)

1. Name Of The Medicinal Product

Pro-Epanutin 75 mg/ml, Concentrate for solution for infusion/Solution for injection

(Pro-Dilantin, PROAURANTIN, Cereneu)

2. Qualitative And Quantitative Composition

One ml of Pro-Epanutin contains 75 mg of fosphenytoin sodium (equivalent to 50 mg of phenytoin sodium) and referred to as 50 mg PE (see Section 4.2).

Each 10 ml vial contains 750 mg of fosphenytoin sodium (equivalent to 500 mg of phenytoin sodium) and referred to as 500 mg PE.

Each 2 ml vial contains 150 mg of fosphenytoin sodium (equivalent to 100 mg of phenytoin sodium) and referred to as 100 mg PE.

For a full list of excipients, see Section 6.1

3. Pharmaceutical Form

Concentrate for solution for infusion/Solution for injection.

Pro-Epanutin is a clear, colourless to pale yellow, sterile solution buffered with trometamol adjusted to pH 8.6 to 9.0 with hydrochloric acid.

4. Clinical Particulars

4.1 Therapeutic Indications

Pro-Epanutin is indicated:

• for the control of status epilepticus of the tonic-clonic (grand mal) type (see Section 4.2).

• for prevention and treatment of seizures occurring in connection with neurosurgery and/or head trauma.

• as substitute for oral phenytoin if oral administration is not possible and/or contra-indicated.

4.2 Posology And Method Of Administration

IMPORTANT NOTE: Throughout all Pro-Epanutin product labelling, the amount and concentration of fosphenytoin is always expressed in terms of phenytoin sodium equivalents (PE) to avoid the need to perform molecular weight-based adjustments when converting between fosphenytoin and phenytoin sodium doses. Pro-Epanutin should always be prescribed and dispensed in phenytoin sodium equivalent units (PE). Note, however, that fosphenytoin has important differences in administration from parenteral phenytoin sodium (see Section 4.4 Special Warnings and Precautions for Use).

Phenytoin sodium equivalents (PE):

1.5 mg of fosphenytoin is equivalent to 1 mg PE (phenytoin sodium equivalent)

Administration:

Pro-Epanutin may be administered by IV infusion or by IM injection. The intramuscular route should be considered when there is not an urgent need to control seizures. Pro-Epanutin should not be administered by IM route in emergency situations such as status epilepticus.

Products with particulate matter or discoloration should not be used.

Intravenous infusion:

For IV infusion, Pro-Epanutin should be diluted in 5% glucose or 0.9% sodium chloride solution. The concentration should range from 1.5 to 25 mg PE/mL.

Because of the risk of hypotension, the recommended rate of administration by IV infusion in routine clinical settings is 50-100 mg PE/minute. Even in an emergency, it should not exceed 150 mg PE/minute. The use of a device controlling the rate of infusion is recommended.

Please refer to tables 1 to 10 for examples of dosing, dilution and infusion time calculations.

Continuous monitoring of electrocardiogram, blood pressure and respiratory function for the duration of the infusion is essential. The patient should also be observed throughout the period where maximal plasma phenytoin concentrations occur. This is approximately 30 minutes after the end of the Pro-Epanutin infusions.

Cardiac resuscitative equipment should be available (see Section 4.4 Special Warnings and Precautions for Use).

Please refer to Tables 1-10 for examples of dosing, dilution, and infusion time calculations
Population	Indication	Dosing Table
Adults	Status epilepticus	Loading dose	Table 1
Status epilepticus	Maintenance dose	Table 2
Seizure treatment or prophylaxis	Loading dose	Table 3
Seizure treatment or prophylaxis	Maintenance dose	Table 4
Temporary substitution for oral phenytoin	Table 5
Children	Status epilepticus	Loading dose	Table 6
Status epilepticus	Maintenance dose	Table 7
Seizure treatment or prophylaxis	Loading dose	Table 8
Seizure treatment or prophylaxis	Maintenance dose	Table 9
Temporary substitution for oral phenytoin	Table 10

DOSAGE IN ADULTS

(For Dose reduction in the Elderly please see guidance towards the end of this section.)

Status Epilepticus

Intramuscular administration of Pro-Epanutin is contra-indicated in the treatment of status epilepticus.

Loading dose:

In order to obtain rapid seizure control in patients with continuous seizure activity, IV diazepam or lorazepam should be administered prior to administration of Pro-Epanutin.

The loading dose of Pro-Epanutin is 15 mg PE/kg administered as a single dose by IV infusion.

Recommended IV infusion rate for loading dose: 100 to 150mg PE/min (should not exceed 150 mg PE/minute even for emergency use). See Table 1 for infusion times.

If administration of Pro-Epanutin does not terminate seizures, the use of alternative anticonvulsants should be considered.

Table 1: displays dosing information for status epilepticus loading dose in adults.

TABLE 1 STATUS EPILEPTICUS LOADING DOSE (ADULTS)
Examples of IV loading doses of 15mg PE/kg, and recommendations for dilution (to 25mg PE/ml) and IV infusion times (at maximum rate of 150 mg PE/min) by body weight
Weight (Kg)	Dose (mg PE)	Volume of Pro-Epanutin (50mg PE/ml)	Volume (ml) of diluent (5% glucose or 0.9% sodium chloride) for final concentration of 25 mg PE/ml	Minimum Infusion Time (mins) to achieve the maximum recommended infusion rate of 150mg PE / minute
No. of 10 ml vials to open	Volume (ml) to draw up
100	1500	3	30	30	10
95	1425	3	28.5	28.5	9.5
90	1350	3	27	27	9
85	1275	3	25.5	25.5	8.5
80	1200	3	24	24	8
75	1125	3	22.5	22.5	7.5
70	1050	3	21	21	7
65	975	2	19.5	19.5	6.5
60	900	2	18	18	6
55	825	2	16.5	16.5	5.5
50	750	2	15	15	5
45	675	2	13.5	13.5	4 .5

Maintenance dose:

The recommended maintenance dose of Pro-Epanutin of 4 to 5 mg PE/kg/day may be given by IV infusion or by IM injection. The total daily dose may be given in one or two divided doses.

Recommended IV infusion rate for maintenance dose: 50 to 100 mg PE/minute. See Table 2 for infusion times.

Maintenance doses should be adjusted according to patient response and trough plasma phenytoin concentrations (see Therapeutic Drug Monitoring).

Transfer to maintenance therapy with oral phenytoin should be made when appropriate.

Table 2: displays dosing information for status epilepticus maintenance dose in adults.

TABLE 2 STATUS EPILEPTICUS MAINTENANCE DOSE (ADULTS)
Examples for maximum IV maintenance doses of 5mg PE/kg, recommendations for dilution* (to 25mg PE/ml or to 1.5mg PE/ml), and IV infusion times (at maximum rate of 100mg PE/minute) by body weight
Weight (Kg)	Dose (mg PE)	Volume of Pro-Epanutin (50mg PE/ml)	Volume (ml) of diluent* ( 5% glucose or 0.9% sodium chloride)	Minimum Infusion Time (mins) to achieve the maximum recommended infusion rate of 100mg PE / minute
No. of 10ml vials to open	Volume (ml) to draw up	for final concentration of 25 mg PE/ml	for final concentration of 1.5 mg PE/ml
100	500	1	10	10	323	5
90	450	1	9	9	291	4.5
80	400	1	8	8	259	4
70	350	1	7	7	226	3.5
60	300	1	6	6	194	3
50	250	1	5	5	162	2.5
*For IV infusion the final concentration should range between 1.5 and 25 mg PE/ml

Treatment or Prophylaxis of Seizures

Loading dose:

The loading dose of Pro-Epanutin is 10 to 15 mg PE/kg given as a single dose by IV infusion or by IM injection.

Recommended IV infusion rate for treatment or prophylaxis of seizures loading dose: 50 to 100 mg PE/minute (should not exceed 150 mg PE/minute). See Table 3 for infusion times.

Table 3 displays dosing information for seizure treatment or prophylaxis loading dose in adults

TABLE 3 TREATMENT OR PROPHYLAXIS OF SEIZURES LOADING DOSE (ADULTS)
Examples for IV loading doses of 10mg PE/kga, and recommendations for dilution* (to 25mg PE/ml or to 1.5mg PE/ml) and IV infusion times (at maximum rate of 100mg PE/minute) by body weight
Weight (Kg)	Dose (mg PE)	Volume of Pro-Epanutin (50mg PE/ml)	Volume (ml) of diluent* ( 5% glucose or 0.9% sodium chloride)	Minimum Infusion Time (mins) to achieve the maximum recommended infusion rate of 100mg PE / minute
No. of 10ml vials to open	Volume (ml) to draw up	for final concentration of 25 mg PE/ml	For final concentration of 1.5mg PE/ml
100	1000	2	20	20	647	10
90	900	2	18	18	582	9
80	800	2	16	16	517	8
70	700	2	14	14	453	7
60	600	2	12	12	388	6
50	500	1	10	10	323	5
*For IV infusion the final concentration should range between 1.5 and 25 mg PE/ml a Please refer to Table 1 for examples of calculations for loading doses of 15mg PE/kg

Maintenance dose:

The recommended maintenance dose of Pro-Epanutin of 4 to 5 mg PE/kg/day may be given by IV infusion or by IM injection. The total daily dose may be given in one or two divided doses.

Recommended IV infusion rate for maintenance dose: 50 to 100 mg PE/minute. See Table 4 for infusion times.

Maintenance doses should be adjusted according to patient response and trough plasma phenytoin concentrations (see Therapeutic Drug Monitoring).

Transfer to maintenance therapy with oral phenytoin should be made when appropriate.

Table 4 displays dosing information for seizure treatment or prophylaxis maintenance dose in adults.

TABLE 4 TREATMENT OR PROPHYLAXIS OF SEIZURES MAINTENANCE DOSE (ADULTS)
Examples for maximum IV maintenance doses of 5mg PE/kg, recommendations for dilution* (to 25mg PE/ml or to 1.5mg PE/ml), and IV infusion times (at maximum infusion rate of 100mg PE/minute) by body weight
Weight (Kg)	Dose (mg PE)	Volume of Pro-Epanutin (50mg PE/ml)	Volume (ml) of diluent* ( 5% glucose or 0.9% sodium chloride)	Minimum Infusion Time (mins) to achieve the maximum recommended infusion rate of 100mg PE / minute
No. of 10ml vials to open	Volume (ml) to draw up	for final concentration of 25 mg PE/ml	for final concentration of 1.5mg PE/ml
100	500	1	10	10	323	5
90	450	1	9	9	291	4.5
80	400	1	8	8	259	4
70	350	1	7	7	226	3.5
60	300	1	6	6	194	3
50	250	1	5	5	162	2.5
*For IV infusion the final concentration should range between 1.5 to 25 mg PE/ml

Temporary substitution of oral phenytoin therapy with Pro-Epanutin.

The same dose and dosing frequency as for oral phenytoin therapy should be used and can be administered by IV infusion or by IM injection.

Recommended IV infusion rate for temporary substitution dosing: 50 to 100 mg PE/minute. See Table 5 for infusion times.

Therapeutic drug monitoring may be useful whenever switching between products and/or routes of administration. Doses should be adjusted according to patient response and trough plasma phenytoin concentrations (see Therapeutic Drug Monitoring).

Fosphenytoin has not been evaluated systemically for more than 5 days.

Table 5 displays dosing information for the temporary substitution of oral phenytoin in adults.

TABLE 5 TEMPORARY SUBSTITUTION OF ORAL PHENYTOIN THERAPY (ADULTS)
Examples of equivalent doses and recommendations for dilution* (to 25mg PE/ml or to 1.5mg PE/ml), and IV infusion times (at maximum rate of 100mg PE/minute)
Dose (mg phenytoin sodium)	Dose (mg PE)	Volume of Pro-Epanutin (50mg PE/ml)	Volume (ml) of diluent* ( 5% glucose or 0.9% sodium chloride)	Minimum Infusion Time (mins) to achieve the maximum recommended infusion rate of 100mg PE / minute
No. of 10 ml vials to open	Volume (ml) to draw up	for final concentration of 25 mg PE/ml	for final concentration of 1.5mg PE/ml
500	500	1	10	10	323	5
450	450	1	9	9	291	4.5
400	400	1	8	8	259	4
350	350	1	7	7	226	3.5
300	300	1	6	6	194	3
250	250	1	5	5	162	2.5
*For IV infusion the final concentration should range between 1.5 to 25 mg PE/ml

DOSAGE IN CHILDREN

Pro-Epanutin may be administered to children (ages 5 and above) by IV infusion only, at the same mg PE/kg dose used for adults. The doses of Pro-Epanutin for children have been predicted from the known pharmacokinetics of Pro-Epanutin in adults and children aged 5 to 10 years and of parenteral phenytoin in adults and children.

Intramuscular administration in children is not recommended.

Status Epilepticus

Loading dose

In order to obtain rapid seizure control in patients with continuous seizure activity IV diazepam or lorazepam should be administered prior to administration of Pro-Epanutin.

The loading dose of Pro-Epanutin is 15 mg PE/kg administered as a single dose by IV infusion.

Recommended IV infusion rate loading dose: 2 to 3 mg PE/kg/min (should not exceed 3mg PE/kg/minute or 150mg PE/minute). See Table 6 for infusion times.

If administration of Pro-Epanutin does not terminate seizures, the use of alternative anticonvulsants should be considered.

Table 6 displays dosing information for status epilepticus loading dose in children.

TABLE 6 STATUS EPILEPTICUS LOADING DOSE (CHILDREN)

Pericyazine 10mg Tablets

1. Name Of The Medicinal Product

Pericyazine 10mg Tablets

2. Qualitative And Quantitative Composition

Pericyazine 10mg

3. Pharmaceutical Form

Pericyazine 10mg Tablets: Circular, very pale lime-yellow tablet, with one face impressed 'S172' and a break-line on reverse.

4. Clinical Particulars

4.1 Therapeutic Indications

a) In adults with schizophrenia or other psychoses, for the treatment of symptoms or prevention of relapse.

b) In anxiety, psychomotor agitation, violent or dangerously impulsive behaviour. Pericyazine is used as an adjunct to the short-term management of these conditions.

4.2 Posology And Method Of Administration

Route of administration: oral .

Dosage requirement varies with the individual and the severity of the condition being treated. Initial dosage should be low with progressive increases until the desired response is obtained, after which dosage should be adjusted to maintain control of the symptoms.

Severe conditions

Indication (a)

Adults: Initially 75 mg per day in divided doses. Dosage should be increased by 25 mg per day at weekly intervals until the optimum effect is achieved. Maintenance therapy would not normally be expected to exceed 300 mg per day.

Elderly: Initially 15-30 mg per day in divided doses. If this is well tolerated the dosage may be increased if necessary for optimum control of behaviour.

Mild or moderate conditions

Indication (b)

Adults: Initially 15-30 mg daily, divided into two portions with a larger dose being given in the evening.

Elderly: 5-10 mg per day is suggested as a starting dose. It may be divided so that a larger portion is given in the evening. Half or quarter the normal adult dose may be sufficient for maintenance therapy.

Pericyazine tablets are not recommended for children.

4.3 Contraindications

See use in pregnancy below. Known hypersensitivity to pericyazine or to any of the other ingredients.

4.4 Special Warnings And Precautions For Use

Neuroleptics should be avoided in patients with liver or renal dysfunction, Parkinson's disease, hypothyroidism, cardiac failure, phaeochromocytoma, myasthenia gravis, prostrate hypertrophy. It should be avoided in patients known to be hypersensitive to phenothiazines or with a history of narrow angle glaucoma or agranulocytosis. It should be used with caution in the elderly, particularly during very hot or very cold weather (risk of hyper-hypothermia).

Close monitoring is required in patients with epilepsy or a history of seizures, as phenothiazines may lower the seizure threshold.

As agranulocytosis may occur rarely, regular monitoring of the complete blood count is recommended.

It is imperative that treatment be discontinued in the event of unexplained fever, as this may be a sign of neuroleptic malignant syndrome (pallor, hyperthermia, autonomic dysfunction, altered consciousness, muscle rigidity). Signs of autonomic dysfunction, such as sweating and arterial instability, may precede the onset of hyperthermia and serve as early warning signs. Although neuroleptic malignant syndrome may be idiosyncratic in origin, dehydration and organic brain disease are predisposing factors.

The occurrence of unexplained infections or fever may be evidence of blood dyscrasia (see section 4.8 below), and requires immediate haematological investigation.

Acute withdrawal symptoms, including nausea, vomiting and insomnia, have very rarely been reported following the abrupt cessation of high doses of neuroleptics. Relapse may also occur, and the emergence of extrapyramidal reactions has been reported. Therefore, gradual withdrawal is advisable.

In schizophrenia, the response to neuroleptic treatment may be delayed. If treatment is withdrawn, the recurrence of symptoms may not become apparent for some time.

Neuroleptic phenothiazines may potentiate QT interval prolongation which increases the risk of onset of serious ventricular arrhythmias of the torsade de pointes type, which is potentially fatal (sudden death). QT prolongation is exacerbated, in particular, in the presence of bradycardia, hypokalaemia, and congenital or acquired (i.e. drug induced) QT prolongation. The risk-benefit should be fully assessed before pericyazine treatment is commenced. If the clinical situation permits, medical and laboratory evaluations (e.g. biochemical status and ECG) should be performed to rule out possible risk factors (e.g. cardiac disease; family history of QT prolongation; metabolic abnormalities such as hypokalaemia, hypocalcaemia or hypomagnesaemia; starvation; alcohol abuse; concomitant therapy with other drugs known to prolong the QT interval) before initiating treatment withpericyazine and during the initial phase of treatment, or as deemed necessary during the treatment (see also sections 4.5 & 4.8).

Avoid concomitant treatment with other neuroleptics (see section 4.5).

Stroke: In randomised clinical trials versus placebo performed in a population of elderly patients with dementia and treated with certain atypical antipsychotic drugs, a 3-fold increase of the risk of cerebrovascular events has been observed. The mechanism of such risk increase is not known. An increase in the risk with other antipsychotic drugs or other populations of patients cannot be excluded. Pericyazine should be used with caution in patients with stroke risk factors.

As with all antipsychotic drugs, Pericyazine should not be used alone where depression is predominant. However, it may be combined with antidepressant therapy to treat those conditions in which depression and psychosis coexist.

Because of the risk of photosensitisation, patients should be advised to avoid exposure to direct sunlight.

In those frequently handling preparations of phenothiazines, the greatest care must be taken to avoid contact of the drug with the skin, since contact skin sensitisation occurs rarely.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with pericyazine and preventive measures undertaken.

Hyperglycaemia or intolerance to glucose has been reported in patients with pericyazine.

Patients with an established diagnosis of diabetes mellitus or with risk factors for the development of diabetes who are started on pericyazine, should get appropriate glycaemic monitoring during treatment (see section 4.8).

Increased Mortality in Elderly people with Dementia

Data from two large observational studies showed that elderly people with dementia who are treated with conventional (Typical) antipyschotics are at a small increased risk of death compared with those who are not treated. There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of the increased risk is not known.

Pericyazine is not licensed for the treatment of dementia-related behavioural disturbances.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interactions of phenothiazine neuroleptics:

The CNS depressant actions of neuroleptic agents may be intensified (additively) by alcohol, barbiturates and other sedatives. Respiratory depression may occur.

The hypotensive effect of most antihypertensive drugs, especially alpha adrenoceptor blocking agents may be exaggerated by neuroleptics.

There is an increased risk of arrhythmias when neuroleptics are used with concomitant QT prolonging drugs (including certain antiarrhythmics, antidepressants, and other antipsychotics) and drugs causing electrolyte imbalance (see sections 4.4 and 4.8).

The mild anticholinergic effect of neuroleptics may be enhanced by other anticholinergic drugs, possibly leading to constipation, heat stroke, etc.

The action of some drugs may be opposed by neuroleptics; these include amfetamine, levodopa, clonidine, guanethidine, adrenaline.

Where treatment for neuroleptic-induced extrapyramidal symptoms is required, anticholinergic antiparkinsonian agents should be used in preference to levodopa, since neuroleptics antagonise the antiparkinsonian action of dopaminergics.

Anticholinergic agents may reduce the antipsychotic effect of neuroleptics.

Some drugs interfere with absorption of neuroleptic agents: antacids, anti-Parkinson drugs, lithium. Increases or decreases in the plasma concentrations of a number of drugs, e.g: propranolol, phenobarbital have been observed but were not of clinical significance. High doses of neuroleptics may reduce the response to hypoglycaemic agents the dosage of which might have to be raised.

In patients treated concurrently with neuroleptics and lithium, there have been rare reports of neurotoxicity.

Adrenaline must not be used in patients overdosed with neuroleptics.

Simultaneous administration of desferrioxamine and prochlorperazine has been observed to induce a transient metabolic encephalopathy characterised by loss of consciousness for 48-72 hours. It is possible this may occur with Pericyazine since it shares many of the pharmacological properties of prochlorperazine.

There is an increased risk of agranulocytosis when neuroleptics are used concurrently with drugs with myelosuppressive potential, such as carbamazepine or certain antibiotics and cytotoxics.

4.6 Pregnancy And Lactation

There is inadequate evidence of the safety of pericyazine in human. There is evidence with some neuroleptics of harmful effects in animals. Like other drugs pericyazine should be avoided in pregnancy unless the physician considers it essential. It may occasionally prolong labour and at such a time should be withheld until the cervix is dilated 3-4 cm. Possible adverse effects on the foetus include lethargy or paradoxical hyperexcitability, tremor and low Apgar score.

Phenothiazines may be excreted in milk, therefore breastfeeding should be suspended during treatment.

4.7 Effects On Ability To Drive And Use Machines

Patients should be warned about drowsiness during early days of treatment, and advised not to drive or operate machinery. The elderly are particularly susceptible to postural hypotension.

4.8 Undesirable Effects

Liver function: jaundice, occurs in a very small percentage of patients taking neuroleptics. A premonitory sign may be a sudden onset of fever after one to three weeks of treatment followed by the development of jaundice. Neuroleptic jaundice has the biochemical and other characteristics of obstructive (cholestatic) jaundice and is associated with obstruction of the canaliculi by bile thrombi; the frequent presence of an accompanying eosinophilia indicates the allergic nature of this phenomenon. Liver injury has been reported very rarely in patients treated with pericyazine. Treatment should be withheld on the development of jaundice.

Cardiorespiratory: hypotension, usually postural, commonly occurs. Elderly or volume depleted subjects are particularly susceptible.

ECG changes, include QT prolongation (as with other neuroleptics), ST depression, U-Wave and T-Wave changes. Cardiac arrhythmias, including ventricular arrhythmias and atrial arrhythmias, a-v block, ventricular tachycardia, which may result in ventricular fibrillation or cardiac arrest have been reported during neuroleptic phenothiazine therapy, possibly related to dosage. Pre-existing cardiac disease, old age, hypokalaemia and concurrent tricyclic antidepressants may predispose.

There have been isolated reports of sudden death, with possible cases of cardiac origin (see section 4.4, above), as well as cases of unexplained sudden death, in patients receiving neuroleptic phenothiazines.

Respiratory depression is possible in susceptible patients.

Blood picture: a mild leukopenia occurs in up to 30% of patients on prolonged high dosage of neuroleptics; agranulocytosis may occur rarely; it is not dose-related.

Extrapyramidal: acute dystonias or dyskinesias, usually transitory are commoner in children and young adults, and usually occur within the first four days of treatment or after dosage increases.

	• Akathisia characteristically occurs after large initial doses.
	• Parkinsonism is commoner in adults and the elderly. It usually develops after weeks or months of treatment. One or more of the following may be seen: tremor, rigidity, akinesia, or other features of Parkinsonism. Commonly just tremor.
	• Tardive dyskinesia: if this occurs it is usually, but not necessarily after prolonged or high dosage. It can even occur after treatment has been stopped. Dosage should therefore be kept low whenever possible.

Skin and eyes: contact skin sensitisation may occur rarely in those frequently handling preparations of phenothiazines (see section 4.4, above. Skin rashes of various kinds may also be seen in patients treated with the drug. Patients on high dosage should be warned that they may develop photosensitivity in sunny weather and should avoid exposure to direct sunlight.

Endocrine: hyperprolactinaemia which may result in galactorrhoea, gynaecomastia, amenorrhoea; impotence.

Priapism has very rarely been reported in patients treated with pericyazine.

Neuroleptic malignant syndrome (hyperthermia, rigidity autonomic dysfunction and altered consciousness) may occur with any neuroleptic.

Minor side effects are nasal stuffiness, dry mouth, insomnia, agitation

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs (see also section 4.4).

Intolerance to glucose, hyperglycaemia (see section 4.4).

4.9 Overdose

Toxicity and treatment of overdosage:

Symptoms of neuroleptic overdosage include drowsiness or loss of consciousness, hypotension, tachycardia, ECG changes, ventricular arrhythmias and hypothermia. Severe extrapyramidal dyskinesias may occur.

If the patient is seen sufficiently soon (up to 6 hours) after ingestion of a toxic dose, gastric lavage may be attempted. Pharmacological induction of emesis is unlikely to be of any use. Activated charcoal should be given. There is no specific antidote. Treatment is supportive.

Generalised vasodilatation may result in circulatory collapse; raising the patient's legs may suffice; in severe cases, volume expansion by intravenous fluids may be needed; infusion fluids should be warmed before administration in order not to aggravate hypothermia.

Positive inotropic agents such as dopamine may be tried if fluid replacement is insufficient to correct the circulatory collapse. Peripheral vasoconstrictor agents are not generally recommended; avoid the use of adrenaline.

Ventricular or supraventricular tachy-arrhythmias usually respond to restoration of normal body temperature and correction of circulatory or metabolic disturbances. If persistent or life threatening, appropriate anti-arrhythmic therapy may be considered. Avoid lidocaine, and as far as possible long acting, anti-arrhythmic drugs.

Pronounced central nervous system depression requires airway maintenance or, in extreme circumstances, assisted respiration. Severe dystonic reactions usually respond to procyclidine (5-10 mg) or orphenedrine (20-40 mg) administered intramuscularly or intravenously. Convulsions should be treated with intravenous diazepam.

Neuroleptic malignant syndrome should be treated with cooling. Dantrolene sodium may be tried.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pericyazine is a neuroleptic with cardiovascular and antihistamine effects similar to those of chlorpromazine, but it has a stronger antiserotonin effect and a powerful central sedative effect.

5.2 Pharmacokinetic Properties

Kinetics: there is little information about plasma concentrations, distribution and excretion in humans. The rate of metabolism and excretion of phenothiazines decreases in old age.

5.3 Preclinical Safety Data

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

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose anhydrous USP, Microcrystalline cellulose (E460), Sodium starch glycollate, Magnesium stearate BP, Colloidal silicon dioxide (E551), Methyl hydroxybenzoate BP (E218).

6.2 Incompatibilities

None known.

6.3 Shelf Life

60 months.

6.4 Special Precautions For Storage

Protect from light.

6.5 Nature And Contents Of Container

Securitainer or HDPE bottle containing 500 tablets.

PVDC coated UPVC aluminium foil blister containing 84 tablets.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS, UK

8. Marketing Authorisation Number(S)

PL 17780/0459

9. Date Of First Authorisation/Renewal Of The Authorisation

17 July 2009

10. Date Of Revision Of The Text

6 April 2010

Legal status

POM