Metoclopramide Tablets 10mg (Actavis UK Ltd)

Metoclopramide 10mg tablets

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

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



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



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

Index

• 1 What Metoclopramide tablets are and what they are used for



• 2 Before you take



• 3 How to take



• 4 Possible side effects



• 5 How to store



• 6 Further information

What Metoclopramide tablets are and what they are used for

Metoclopramide tablets belong to a group of medicines which speed up stomach emptying and also prevent vomiting (being sick) and may be used to:

• relieve symptoms of digestive disorders including heartburn, feeling or being sick caused by indigestion
  with wind, stomach upset, acid reflux in the gullet, hiatus hernia (causing heartburn which may be worse when bending, lying flat or after food), gallstones, stomach ulcers or after stomach operations



• treat nausea and vomiting caused by certain drugs (such as digoxin, antibiotics, rifabutin, rifampicin and methotrexate), heart failure, following operations or radiotherapy. Metoclopramide tablets may also be used to treat regular episodes of vomiting



• relieve nausea and vomiting associated with migraine



• help restore normal gut movements after operations



• help during diagnostic procedures. Metoclopramide tablets increase the passage of a barium meal in radiology treatment and makes it easier for the introduction of a tube into the stomach and intestine.

If you are under 20 years of age Metoclopramide tablets will only be used:

• for severe unmanageable vomiting of a known cause



• for sickness caused by radiotherapy or chemotherapy



• to help in passing a tube into the stomach and intestine



• before operations.

Before you take

Do not take Metoclopramide tablets and tell your doctor if you:

• are allergic (hypersensitive) to Metoclopramide tablets, procaine, procainamide or any of the other ingredients (see section 6)



• have a history of muscle disorders when using drugs with a similar action to Metoclopramide tablets



• have or have had bleeding, perforation or blockage of the stomach or intestines



• have high blood pressure due to a tumour near the kidney (phaeochromocytoma)



• have had an operation on your stomach or intestines within the last 3-4 days.

Check with your doctor or pharmacist before taking Metoclopramide tablets if you:

• have epilepsy (Metoclopramide tablets may increase the risk of having a seizure)



• have liver impairment or severe kidney disease



• suffer with allergies or asthma



• have Parkinson’s disease (Metoclopramide tablets may make your symptoms worse)



• suffer from the metabolic condition porphyria.

Taking other medicines

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

• painkillers such as aspirin or paracetamol



• ciclosporin (to prevent transplant rejection)



• medicines used to treat Parkinson’s disease such as levodopa or pergolide



• anticholinergics (eg atropine sulphate)



• lithium (to treat depression)



• medicines which can cause liver damage



• mexiletine (for irregular heart beats)



• atovaquone (to treat pneumonia)



• digoxin (to treat heart condition)



• bromocriptine (for infertility or to stop breast milk production)



• cimetidine (to treat ulcers)



• medicines that act on the brain (CNS depressants, antiepileptics, apomorphine, antipsychotics, medicines containing opioids, tetrabenazine)



• medicines to treat depression (Monoamine Oxidase Inhibitors [MAOI]) and furazolidine and procarbazine.

Pregnancy and breast-feeding

If you are pregnant especially in the first 3 months, planning to become pregnant or are breast-feeding ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

Metoclopramide tablets may cause dizziness and confusion or movement disorders. Make sure you are not affected before you drive or operate machinery.

Sugar intolerance

If you have been told you have an intolerance to some sugars, contact your doctor before taking this medicine, as it contains a type of sugar called lactose.

Surgery and tests

If you need to have an operation including having your teeth removed or blood and urine tests, tell your doctor or dentist you are taking this medicine.

How to take

Always take Metoclopramide tablets exactly as your doctor has told you. If you are not sure, check with your doctor or
pharmacist.

Avoid alcohol whilst taking this medicine.

Swallow the tablets with water.

Doses:

• Adults over 20 years (including elderly):
  10mg three times a day.

• Young adults 15-19 years:
  60kg of body weight and over: 10mg three times a day.
  30-59kg of body weight: 5mg three times a day.

• Children under 15 years:
  not recommended.

• Diagnostic procedures:
  a single dose of metoclopramide should be given 5-10 minutes before the examination.
  Adults over 20 years: 10-20mg.
  Young adults 15-19 years: 10mg.

If you have kidney or liver disease, you may be given a smaller dose.

If you take more than you should

If you (or someone else) swallow a lot of tablets at the same time, or you think a child may have swallowed any, contact your nearest hospital casualty department or tell your doctor immediately.

If you forget to take the tablets

Do not take a double dose to make up for a forgotten dose. If you forget to take a dose take it as soon as you remember it and then take the next dose at the right time.

If you stop taking the tablets

Talk to your doctor before you stop taking the tablets and follow their advice.

Possible side effects

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

Stop taking Metoclopramide tablets and contact your doctor at once if the following effects occur:

• Neuroleptic Malignant Syndrome: excessive temperature, drowsiness, rigid muscles, rapid breathing, restlessness and uncontrolled movements. This is more likely to occur if you are taking ‘neuroleptic’ medicines such as chlorpromazine or haloperidol.



• Blood: your medicine may alter the numbers and types of your blood cells, you may notice increased bruising, nosebleeds, sore throats or infections. Your doctor may want to give you a blood test.

Tell your doctor if you notice any of the following side effects or notice any other effects not listed:

• Severe allergic reactions such as swelling of the face, lips, throat or tongue, difficulty breathing, very fast heart beat or even loss of consciousness



• Central Nervous System (CNS):
  
  
  • extrapyramidal or Parkinsonian effects (difficulty in speaking or swallowing, loss of balance control, mask-like face, shuffling walk, stiffness of arms or legs, trembling and shaking of hands and fingers)
  
  
  
  • tardive dyskinesia (lip smacking or puckering; puffing of cheeks, rapid or worm-like movements of tongue, uncontrolled chewing movements, uncontrolled movements of arms and legs)
  
  
  
  • dystonic effects (spasms of facial muscles and jaw muscles which prevent the jaw from opening, rhythmic protrusion of the tongue, difficulty speaking, spasm of muscles around the eyes causing rolling movements of the eyes, unnatural positioning of the head and neck, involuntary arching of the head, neck and back)
  
  
  
  • others: dizziness, weakness, trouble in sleeping, headache, firm muscles, drowsiness, confusion, restlessness, depression. The following are more common at high doses: agitation, panic or panic-like sensation, sensation of crawling in legs (restless leg syndrome)
  
  



• Heart: low or high blood pressure, racing heart beat



• Stomach and gut: diarrhoea (with high doses), constipation, feeling sick, unusual dryness of mouth



• Genital and urine system: raised blood levels of the hormone prolactin which can cause breast milk production, breast tenderness and swelling or changes in periods



• Skin: skin rashes, which may be itchy or water retention.

If you notice any side effects, they get worse, or if you notice any not listed, please tell your doctor or pharmacist.

How to store

Keep out of the reach and sight of children.

Store below 25ºC in a dry place and protected from light.

Do not use Metoclopramide tablets after the expiry date stated on the label/carton/bottle. The expiry date refers to the last day of that month.

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

Further information

What Metoclopramide tablets contain

• The active substance (the ingredient that makes the tablet work) is 10.54mg of metoclopramide hydrochloride.



• The other ingredients colloidal silica, lactose, magnesium stearate, maize starch, microcrystalline cellulose (E460).

What Metoclopramide tablets look like and contents of the pack

Metoclopramide tablets are white uncoated tablets.

Pack sizes are 28 tablets.

Marketing Authorisation Holder and manufacturer

Actavis

Barnstaple

EX32 8NS

UK

Date of last revision:

November 2007

Actavis

Barnstaple

EX32 8NS

UK

50136070

Methadose 20mg / 1ml Oral Concentrate

1. Name Of The Medicinal Product

Methadose 20mg/1ml Oral Concentrate

2. Qualitative And Quantitative Composition

Active Ingredient	Per 5ml
Methadone Hydrochloride BP	100mg

3. Pharmaceutical Form

Pale brown solution for oral administration.

4. Clinical Particulars

4.1 Therapeutic Indications

For use in the treatment of opioid drug addiction (as a narcotic abstinence syndrome suppressant)

4.2 Posology And Method Of Administration

For oral administration only. This product may be used with a diluent.

Dosage Recommendations:

Adults: Initially 10-20mg per day, increasing by 10-20mg per day until there are no signs of withdrawal or intoxication. The usual dose is 40-60mg per day. The dose is adjusted according to the degree of dependence with the aim of gradual reduction.

Elderly: In the case of elderly or ill patients repeated doses should only be given with extreme caution.

Children: Not recommended for children.

This product is intended to be used with a diluent.

4.3 Contraindications

Respiratory depression, obstructive airway disease, concurrent administration with MAO inhibitors or within two weeks of discontinuation of treatment with them.

Patients dependent on non opioid drugs.

Use during an acute asthma attack is not recommended.

Known hypersensitivity to hydroxybenzoates or methadone.

Use during labour is not recommended, the prolonged duration of action increases the risk of neonatal depression.

Methadone is not suitable for children.

4.4 Special Warnings And Precautions For Use

Caution should be exercised in patients with hepatic dysfunction or renal dysfunction.

In the case of elderly or ill patients, repeated doses should only be given with extreme caution.

Addiction/tolerance/dependence

Methadone is a drug of addiction and is controlled under the Misuse of Drugs Act 1971 (Schedule 2). It has a long half-life and can therefore accumulate. A single dose which will relieve symptoms may, if repeated on a daily basis, lead to accumulation and possible death.

Tolerance and dependence may occur as with morphine.

Methadone can produce drowsiness and reduce consciousness although tolerance to these effects can occur after repeated use.

Withdrawal

Abrupt cessation of treatment can lead to withdrawal symptoms which, although similar to those with morphine, are less intense but more prolonged. Withdrawal of treatment should therefore be gradual.

Respiratory depression

Due to the slow accumulation of methadone in the tissues, respiratory depression may not be fully apparent for a week or two and may exacerbate asthma due to histamine release.

Hepatic disorders

Caution as methadone may precipitate porto-systemic encephalopathy in patients with severe liver damage.

As with other opioids, methadone may cause troublesome constipation, which is particularly dangerous in patients with severe hepatic impairment, and measures to avoid constipation should be initiated early.

Neonates/children

As there is a risk of greater respiratory depression in neonates and because there are currently insufficient published data on the use in children, methadone is not recommended in those under 16 (See sections 4.2, 5.2).

Further warnings

Babies born to mothers receiving methadone may suffer withdrawal symptoms.

Methadone should be used with great caution in patients with acute alcoholism, convulsive disorders and head injuries.

Methadone, as with other opiates, has the potential to increase intracranial pressure especially where it is already raised.

Methadone should be used with caution in patients with hypothyroidism, adrenocortical insufficiency, prostatic hyperplasia, hypotension, shock, inflammatory or obstructive bowel disorders or myasthenia gravis.

Cases of QT interval prolongation and torsades de pointes have been reported during treatment with methadone, particularly at high doses (>100 mg/d). Methadone should be administered with caution to patients at risk for development of prolonged QT interval, e.g. in case of:

- history of cardiac conduction abnormalities,

- advanced heart disease or ischaemic heart disease,

- Liver disease,

- family history of sudden death,

- Electrolyte abnormalities, i.e. hypokalaemia, hypomagnesaemia

- concomitant treatment with drugs that have a potential for QT-prolongation,

- concomitant treatment with drugs which may cause electrolyte abnormalities,

- concomitant treatment with cytochrome P450 CYP3A4 inhibitors (see section 4.5).

In patients with recognised risk factors for QT-prolongation, or in case of concomitant treatment with drugs that have a potential for QT-prolongation, ECG monitoring is recommended prior to methadone treatment, with a further ECG test at dose stabilisation.

ECG monitoring is recommended, in patients without recognised risk factors for QT-prolongation, before dose titration above 100mg/d and at seven days after titration.

Caution should be exercised in patients who are concurrently taking CNS depressants.

This product contains parahydroxybenzoates. These may cause allergic reactions (possibly delayed).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

MAOI's:

The concurrent use of MAOI's is contraindicated (see 4.3 Contraindications) as they may prolong and enhance the respiratory depressant effects of methadone.

CNS depressants:

Alcohol, anaesthetics, hypnotics and sedatives, barbiturates, phenothiazines, some other major tranquillizers and tricyclic antidepressants may increase the general depressant effects of methadone when used concomitantly. (See 4.4 Special warnings and precautions for use)

There are reports that antidepressant drugs (e.g. fluvoxamine and fluoxetine) may increase serum levels of methadone.

Histamine H₂ Antagonists:

Histamine H₂ antagonists such as cimetidine, can reduce the protein binding of methadone resulting in increased opiate action.

Rifampicin:

Reduced plasma levels and increased urinary excretion of methadone can occur with concurrent administration of rifampicin. Adjustment of the dose of methadone may be necessary.

Anticonvulsants (Phenytoin, Phenobarbital, Carbamazepine and Primidone):

Induces methadone metabolism with the risk of precipitating withdrawal syndrome. Adjustment of the dose of methadone should be considered.

pH of urine:

Drugs that acidify or alkalinise the urine may have an effect on clearance of methadone as it is increased at acidic pH and decreased at alkaline pH.

Opioid agonist analgesics:

Additive CNS depression, respiratory depression and hypotension.

Opioid antagonists:

Naloxone and naltrexone antagonises the analgesic, CNS and respiratory depressant effects of methadone and can rapidly precipitate withdrawal symptoms (See Section 4.9 Overdose). Similarly buprenorphine and pentazocine may precipitate withdrawal symptoms.

Antiretroviral Agents such as Nevirapine, Efavirenz, Nelfinavir, Ritonavir:

Based on the known metabolism of methadone, these agents may decrease plasma concentrations of methadone by increasing its hepatic metabolism. Methadone may increase the plasma concentration of zidovudine. Narcotic withdrawal syndrome has been reported in patients treated with some retroviral agents and methadone concomitantly. Methadone maintained patients beginning antiretroviral therapy should be monitored for evidence of withdrawal and the methadone dose should be adjusted accordingly.

Ciprofloxacin:

Concomitant use may lead to sedation, confusion and respiratory depression.

Other Drugs:

Methadone may have an effect on other drugs as a consequence of reduced gastro-intestinal motility.

Pregnancy Tests:

Methadone may interfere with the urine testing for pregnancy.

Cytochrome P450 3A4 inhibitors:

Methadone clearance is decreased when co-administered with drugs which inhibit CYP3A4 activity, such as some anti-HIV agents, macrolide antibiotics, cimetidine and azole antifungal agents (since the metabolism of methadone is mediated by the CYP3A4 isoenzyme).

St. John's Wort:

May lower plasma concentrations of methadone.

In patients taking drugs affecting cardiac conduction, or drugs which may affect electrolyte balance there is a risk of cardiac events when methadone is taken concurrently.

4.6 Pregnancy And Lactation

There is no evidence of safety in human pregnancy. A careful risk/benefit assessment should be made before administration to pregnant women because of possible adverse effects on the foetus and neonate including respiratory depression, low birth weight, neonatal withdrawal syndrome and increased rate of stillbirths. However, methadone has not been associated with congenital malformations.

It may be necessary to increase the dose of methadone if withdrawal symptoms develop. Increased clearance and reduced plasma levels have been reported during pregnancy.

It should not be used during labour, (see 4.3 Contraindications).

Methadone is excreted in breast milk. Breast feeding is not recommended during methadone treatment.

4.7 Effects On Ability To Drive And Use Machines

This may be severely affected during and after treatment with Methadone as it may cause drowsiness and reduce alertness. The time after which such activities may be safely resumed is extremely patient dependent and must be decided by the physician.

4.8 Undesirable Effects

CNS Effects

Respiratory depression particularly with larger doses, dependence, drowsiness, confusion, nausea and vomiting particularly at the start of treatment can occur. Changes of mood, including euphoria, and hallucinations are occasionally reported. Methadone has the potential to increase intracranial pressure, particularly in circumstances where it is already raised.

Effects on the Autonomic Nervous System

Constipation, dry mouth, eyes and nose, and less commonly micturition difficulties are observed.

Cardiovascular Effects

Bradycardia, palpitation and orthostatic hypotension can occur. Cases of QT prolongation and torsades de pointes have been rarely reported.

Other Undesirable Effects

Facial flushing, vertigo, headache, hypothermia, restlessness, exacerbation of existing asthma, decreased libido, galactorrhoea, dysmenorrhoea and amenorrhoea, rashes and miosis can also occur. Long-term administration may produce excessive sweating and raised prolactin levels.

4.9 Overdose

Symptoms: Serious overdosage is characterised by respiratory depression, extreme somnolence progressing to stupor or coma, maximally constricted pupils, skeletal muscle flaccidity, cold and clammy skin and sometimes bradycardia and hypotension. In severe overdosage, apnoea, circulatory collapse, cardiac arrest and death may occur.

Treatment: A patent airway and assisted or controlled ventilation must be assured.

Narcotic antagonists may be required but it should be remembered that Methadone is a long acting depressant (36 to 48 hours) whereas antagonists act for 1 to 3 hours, so that treatment with the latter must be repeated as needed.

An antagonist should not be administered, however, in the absence of clinically significant respiratory or cardiovascular depression.

Nalorphine (0.1mg per Kg) or Levallorphan (0.02mg per Kg) should be given intravenously as soon as possible and repeated, if necessary, every 15 minutes.

Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated.

In a person physically dependent on narcotics, administration of the usual dose of narcotic antagonist will precipitate an acute withdrawal syndrome; use of the antagonist in such a person should be avoided if possible but if it must be used to treat serious respiratory depression it should be administered with great care.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Methadone is an opioid agonist with actions predominantly at the µ receptor. The analgesic activity of the racemate is almost entirely due to the l-isomer, which is at least 10 times more potent as an analgesic than the d-isomer. The d-isomer lacks significant respiratory depressant activity but does have anti-tussive effects. Methadone also has some agonist actions at the K and σ opiate receptors. These actions result in analgesia, depression of respiration, suppression of cough, nausea and vomiting (via an effect on the chemoreceptor trigger zone) and constipation. An effect on the nucleus of the automotor nerve, and perhaps on opioid receptors in the pupillary muscles causes pupillary constriction. All these effects are reversible by naloxone with a pA₂ value similar to its antagonism of Morphine. Like many basic drugs, Methadone enters mast cells and releases histamine by a non-immunological mechanism. It causes a dependence syndrome of the Morphine type.

5.2 Pharmacokinetic Properties

Methadone is one of the more lipid soluble opioids, and is well absorbed from the gastrointestinal tract, but undergoes fairly extensive first pass metabolism. It is bound to albumin and other plasma proteins and to tissue proteins (probably lipoproteins), the concentrations in lung, liver and kidneys being much higher than in the blood.

The pharmacokinetics of Methadone are unusual, in that there is extensive binding to tissue proteins and fairly slow transfer between some parts of this tissue reservoir and the plasma. With an intramuscular dose of 10mg, a peak plasma concentration of 75µg per litre is reached in one hour. With regular oral doses of 100-120mg daily, plasma concentrations rise from trough levels of approximately 500µg/L to a peak of about 900µg/L in 4 hours. Marked variations in plasma levels occur in dependent persons on a stable dose of oral Methadone, without any relation to symptoms. Methadone is secreted in sweat and found in saliva and in high concentration in gastric juice. The concentration in cord blood is about half the maternal levels.

The half life after a single oral dose is 12-18 (mean 15) hours, partly reflecting distribution into tissue stores, as well as metabolic and renal clearance. With regular doses, the tissue reservoir is already partly filled, and so the half life is extended to 13 to 47 (mean 25) hours reflecting only clearance. In the first 96 hours after administration, 15 - 60% can be recovered from the urine, and as the dose is increased so a higher proportion of unchanged Methadone is found there. Acidification of the urine can increase the renal clearance by a factor of at least three, and thus appreciably reduce the half life time of elimination.

5.3 Preclinical Safety Data

None stated

6. Pharmaceutical Particulars

6.1 List Of Excipients

Propylene Glycol

Propyl Hydroxybenzoate

Methyl Hydroxybenzoate

Caramel E150

Purified Water

6.2 Incompatibilities

None Known

6.3 Shelf Life

Shelf life - 2 years

Shelf life after first opening container - 3 months

Shelf life after dilution - 3 months

6.4 Special Precautions For Storage

Store below 25°C but not in a refrigerator.

6.5 Nature And Contents Of Container

Amber (type III) glass bottle with aluminium, EPE wadded ROPP closures or HDPE, EPE wadded, child resistant tamper evident closures or HDPE, EPE wadded, tamper evident closures to contain 100ml, 150ml, 200ml or 500ml of product.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

This product is intended for use with a diluent.

Administrative Data

7. Marketing Authorisation Holder

Rosemont Pharmaceuticals Ltd

Rosemont House

Yorkdale Industrial Park

Braithwaite Street

Leeds

LS11 9XE

8. Marketing Authorisation Number(S)

0427/0100

9. Date Of First Authorisation/Renewal Of The Authorisation

31.1.96

10. Date Of Revision Of The Text

9^th September 2008

Metalyse 10,000 units

Metalyse

10,000 units powder and solvent for solution for injection

Tenecteplase

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

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


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


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

In this leaflet:

1. What METALYSE is and what it is used for

2. Before you receive METALYSE

3. How is METALYSE administered

4. Possible side effects

5. How to store METALYSE

6. Further information

What Metalyse Is And What It Is Used For

METALYSE is a powder and solvent for solution for injection. This means that each pack contains:

• one vial of 10,000 units METALYSE powder and one pre-filled syringe containing 10 ml water for injections.

Before use, the solvent (water for injections) is added to the powder to form a solution that is given by injection.

METALYSE belongs to a group of medicines called thrombolytic agents. These medicines help to dissolve blood clots. Tenecteplase is a recombinant fibrin-specific plasminogen activator.

METALYSE is used to treat myocardial infarctions (heart attacks) within 6 hours after the onset of symptoms and helps to dissolve the blood clots that have formed in the blood vessels of the heart. This helps to prevent the damage caused by heart attacks and has been shown to save lives.

Before You Receive Metalyse

METALYSE will not be prescribed and given by your doctor

• if you have previously had a sudden life-threatening allergic reaction (severe hypersensitivity) to the active ingredient tenecteplase, to gentamicin (a trace residue from the manufacturing process) or any of the other ingredients of METALYSE. If treatment with Metalyse is nevertheless considered to be necessary, facilities for reanimation should be immediately available in case of need;


• if you have, or have recently had, an illness that increases your risk of bleeding (haemorrhage), including:
  
  
  • a bleeding disorder or tendency to bleed (haemorrhage)
  • stroke (cerebrovascular event)
  • very high, uncontrolled blood pressure
  • a head injury
  • severe liver disease
  • a stomach ulcer (peptic ulcer)
  • varicose veins in the gullet (oesophageal varices)
  • abnormality of the blood vessels (e.g. an aneurysm)
  • certain tumours
  • inflammation of the lining around the heart (pericarditis); inflammation or infection of the heart valves (endocarditis);


• if you are taking tablets/capsules used to “thin” the blood, such as warfarin or coumarin (anti-coagulants);


• if you have an inflamed pancreas (pancreatitis);


• if you have recently had major surgery including surgery to your brain or spine;


• if you have been given cardiopulmonary resuscitation (chest compressions) for more than 2 minutes duration, in the last two weeks.

Your doctor will take special care with METALYSE

• if you have had any allergic reaction other than a sudden life-threatening allergic reaction (severe hypersensitive) to the active substance tenecteplase, to gentamicin (a trace residue from the manufacturing process), or to any of the other ingredients of Metalyse (see section 6: “Further information”);


• if you have high blood pressure;


• if you have problems with circulation of blood in the brain (cerebrovascular disease);


• if you have had gastrointestinal (gut) or genitourinary bleeding within the last ten days (this may cause blood in stools or urine);


• if you have a heart valve abnormality (e.g. mitral stenosis) with an abnormal heart rhythm (e.g. atrial fibrillation);


• if you have had an intramuscular injection in the last two days;


• if you are aged over 75 years;


• if you weigh less than 60 kg.

Taking other medicines

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

Pregnancy and breast-feeding

Ask your doctor for advice before you are given METALYSE.

How Is Metalyse Administered

The doctor calculates your dose of METALYSE according to your bodyweight, based on the following scheme:

Bodyweight less than 60kg 6,000 units

Bodyweight 60 to 70kg 7,000 units

Bodyweight 70 to 80kg 8,000 units

Bodyweight 80 to 90kg 9,000 units

Bodyweight above 90kg 10,000 units

Your doctor will give you medication to prevent blood clotting in addition to METALYSE, as soon as possible after your chest pain starts.

METALYSE is given by a single injection into a vein by a doctor who is experienced in the use of this type of drug.

Your doctor will give METALYSE as soon as possible after your chest pain starts as a single dose.

Repetition is not recommended.

Possible Side Effects

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

Evaluation of side effects is based on the following frequencies:

very common: affects more than 1 user in 10

common: affects 1 to 10 users in 100

uncommon: affects 1 to 10 users in 1,000

rare: affects 1 to 10 users in 10,000

very rare: affects less than 1 user in 10,000

not known: frequency cannot be estimated from the available data

The side effects described below have been experienced by people given METALYSE:

Very Common:

• bleeding

Common:

• bleeding at the injection or puncture site


• nosebleeds


• genitourinary bleeding (you may notice blood in your urine)


• bruising


• gastro-intestinal bleeding (e.g. bleeding from the stomach or bowel)

Uncommon:

• irregular heart beat (reperfusion arrhythmias), sometimes leading to cardiac arrest


• internal bleeding in the abdomen (retroperitoneal bleeding)


• bleeding in the brain (cerebral haemorrhage). Death or permanent disability may occur following bleeding in the brain or other serious bleeding events


• bleeding in the eyes (eye haemorrhage)

Rare:

• low blood pressure (hypotension)


• bleeding in the lungs (pulmonary haemorrhage)


• hypersensitivity (anaphylactoid reactions) e.g. rash, hives (urticaria), swelling of the throat


• bleeding into the area surrounding the heart (haemopericardium)


• blood clot in the lung (pulmonary embolism) and in the vessels of other organ systems (thrombotic embolisation)

Not known:

• fat embolism (clots consisting of fat)


• nausea


• vomiting


• body temperature increased (fever)


• blood transfusions as consequence of bleedings

As with other thrombolytic agents, the following events have been reported as sequelae of myocardial infarction and/or thrombolytic administration:

Very common:

• Low blood pressure (hypotension)


• Irregular heart beat


• Chest pain (angina pectoris)

Common:

• Further heart attack (recurrent ischaemia)


• Heart failure


• Shock due to heart failure


• Inflammation of the lining around the heart


• Fluid in the lungs (pulmonary oedema)

Uncommon:

• Heart arrest


• Problem with the heart valve or heart lining (mitral valve incompetence, pericardial effusion)


• Blood clot in the veins (venous thrombosis)


• Fluid between the heart lining and the heart (cardiac tamponade)


• Rupture of the heart muscle (myocardial rupture)

Rare:

• Blood clot in the lung (pulmonary embolism)

These cardiovascular events can be life-threatening and may lead to death.

In case of bleeding in the brain events related to the nervous system have been reported e.g. drowsiness (somnolence), speech disorders, palsy of parts of the body (hemiparesis) and fits (convulsions).

Tell your doctor immediately if you think you are experiencing any of these side effects.

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

How To Store Metalyse

Keep out of the reach and sight of children.

Do not store above 30°C.

Keep the container in the outer carton in order to protect from light.

Once METALYSE has been reconstituted it may be stored for 24 hours at 2-8°C and 8 hours at 30°C. However, for microbiological reasons your doctor will normally use the reconstituted solution for injection immediately.

Do not use METALYSE after the expiry date which is stated on the label/ carton.

Further Information

What METALYSE contains

• The active substance is tenecteplase. One vial contains 10,000 units of tenecteplase. One pre-filled syringe contains 10 ml of water for injections.


• The other ingredients are L-arginine, phosphoric acid and polysorbate 20.


• The METALYSE solvent is water for injections.


• Gentamicin is contained as trace residue from the manufacturing process

What METALYSE looks like and contents of the pack

The folding box contains one vial with a lyophilised powder, one ready for use syringe with a solvent, one vial adapter and one needle.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH

Binger Strasse 173

D-55216 Ingelheim am Rhein

Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG

Birkendorfer Strasse 65

D-88397 Biberach/Riss

Germany

For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

United Kingdom

Boehringer Ingelheim Ltd.

Tel:+44 1344 424 600

This leaflet was last approved in 06/2010

Detailed information on this medicine is available on the European Medicines Agency (EMA) web site: http://www.ema.europa.eu

74367-01

Methadone Hydrochloride DTF 1mg / 1ml Oral Solution (Plastic Packs)

Methadone Hydrochloride DTF 1mg/1ml Oral Solution

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

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


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


• This medicine has been prescribed only 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 or pharmacist.

In this leaflet

• 1. What Methadone Hydrochloride DTF 1mg/1ml Oral Solution is and what it is used for


• 2. Before you take Methadone Hydrochloride DTF 1mg/1ml Oral Solution


• 3. How to take Methadone Hydrochloride DTF 1mg/1ml Oral Solution


• 4. Possible side effects


• 5. How to store Methadone Hydrochloride DTF 1mg/1ml Oral Solution


• 6. Further information

What Methadone Hydrochloride DTF 1mg/1ml Oral Solution is and what it is used for

The name of your medicine is Methadone Hydrochloride DTF 1mg/1ml Oral Solution (referred to as Methadone Solution in this leaflet). It contains methadone hydrochloride. This belongs to a group of medicines called Narcotic Analgesics.

Methadone is used:

• to treat opioid drug addiction


• to treat moderate to severe pain

Before you take Methadone Hydrochloride DTF 1mg/1ml Oral Solution

Do not take Methadone Solution and tell your doctor if:

• you are allergic (hypersensitive) to methadone or any other ingredients in this liquid (see section 6 below). An allergic reaction can include a rash, itching or shortness of breath


• you have severe breathing problems or a history of asthma. You must not use this medicine during an asthma attack. If you give this medicine to yourself (self-administration), wait until the asthma attack has passed and you are fully recovered


• you are taking Monoamine Oxidase Inhibitors (MAOIs) used to treat depression or if you have taken a MAOI medicine in the past two weeks (see ‘Taking other medicines’)


• you are dependent on any other drugs


• you are in labour


• children must not be given this medicine.

Do not take this medicine if any of the above apply to you. If you are not sure, talk to your doctor before taking methadone.

Take special care with Methadone Solution

Before you take this medicine, tell your doctor if:

• you have liver or kidney problems


• you have epilepsy


• you are addicted to alcohol


• you have or have recently had a head injury


• you have low thyroid function (hypothyroid)


• you have problems with your adrenal glands. These are linked to your kidneys


• you have an enlarged prostate gland


• you have low blood pressure


• you are in shock


• you have a muscle weakness disease called myasthenia gravis


• you have bowel problems


• you have a history of irregular heart beat


• you have a history of heart disease


• you have a family history of people dying suddenly without cause


• you have low potassium, sodium or magnesium levels


• you are pregnant or breast-feeding


• you are extremely ill or an older person. You may be more sensitive to the medicine.

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

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This includes medicines bought without a prescription, including herbal medicines. This is because methadone can affect the way some other medicines work. Also some medicines can affect the way methadone works.

You must not take Methadone Solution:

• at the same time or within 2 weeks of taking Monoamine Oxidase Inhibitors (MAOIs).

Some medicines can increase the risk of heart problems when used with methadone. Talk to your doctor before taking methadone if you are taking:

• medicines for heart problems such as verapamil and enalapril


• medicines which affect electrolyte balance such as diuretics (water tablets) or lithium.

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

• medicines that dull your senses such as medicines for depression (for example, fluvoxamine, fluoxetine), medicines to help you sleep (including anaesthetics) and medicines to calm you down called tranquillisers


• cimetidine, used to treat stomach ulcers


• rifampicin, used to treat tuberculosis (TB)


• medicines used to treat epilepsy such as phenytoin, carbamazepine, phenobarbital and primidone


• medicines that make your urine acidic such as ascorbic acid (vitamin C)


• narcotic painkillers such as codeine and pentazocine


• naloxone used to reverse the effects of opioid drugs


• medicines used to stop opioid drugs working such as naltrexone and buprenorphine


• medicines used to treat HIV such as nevirapine, efavirenz and nelfinavir. The doctor may have to change the amount of methadone you take whilst on these medicines


• antibiotics such as ciprofloxacin or macrolide antibiotics for example erythromycin


• medicines used to treat fungal infections such as ketoconazole or fluconazole


• St. John’s Wort - a herbal preparation for depression.

If any of the above apply to you, talk to your doctor before taking Methadone Solution.

Taking Methadone Solution with food and drink

Do not drink alcohol whilst taking Methadone Solution. This is because Methadone Solution can make you feel sleepy and drinking alcohol will make you even more sleepy.

Pregnancy and Breast-feeding

• talk to your doctor before taking Methadone Solution if you are pregnant or likely to become pregnant


• take care if you are taking a pregnancy test as the methadone may interfere with the results


• you should not take this medicine whilst you are in labour


• do not breast-feed if you are taking Methadone Solution.

Driving and using machines

Methadone Solution will severely affect your ability to drive or use machines, whilst taking it and afterwards.

You should only start doing these activities again with the permission of your doctor.

Important information about what is in Methadone Solution:

This medicine contains:

• methyl and propyl parahydroxybenzoates. These may cause an allergic reaction. This allergy may happen some time after starting the medicine


• sucrose (0.9g per 5ml) and liquid maltitol. If your doctor has told you that you cannot tolerate some sugars, see your doctor before taking this medicine. The amount of sucrose should be taken into account if you have diabetes. Sucrose may be harmful to your teeth


• colours - tartrazine (E102) and sunset yellow (E110). These may cause allergic reactions.

How to take Methadone Hydrochloride DTF 1mg/1ml Oral Solution

Take this medicine as your doctor or pharmacist has told you. Look on the label and ask your doctor or pharmacist if you are not sure.

Taking this medicine

• this medicine contains 1mg of methadone in each 1ml


• take this medicine by mouth.

Adults

For addiction

• the starting dose is 10mg to 20mg (10ml to 20ml) each day


• the doctor can increase this to 40mg to 60mg (40ml to 60ml) each day.

For pain

• the usual dose is 5mg to 10mg (5ml to 10ml) every 6 to 8 hours


• the dose may be changed by your doctor.

Older people and very ill people

• if you have to have repeated doses of this medicine, the doctor may want to monitor you more closely.

Children

Children must not take this medicine.

If you take more Methadone Solution than you should

• if you take more of this medicine than you should, talk to a doctor or go to your nearest hospital straight away. Take the medicine pack with you


• the signs you may notice are difficulty in breathing; feeling very drowsy which may lead to a stupor or coma; very small pupils; cold and clammy skin; a very slow pulse rate and muscle weakness. In extreme cases, you may stop breathing, your blood flow may stop, you may have a heart attack which could lead to death.

If you forget to take Methadone Solution

• if you forget a dose do not take it. Wait until the next dose is due and take only that amount


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

If you stop taking Methadone Solution

• do not stop taking this medicine unless your doctor tells you to as you may suffer withdrawal effects


• your doctor will tell you how to lower the dose gradually.

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

Possible side effects

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

Stop taking this medicine and see a doctor straight away if you have an allergic reaction to Methadone Solution.

An allergic reaction may include:

• swelling of your face, lips, tongue or throat or difficulty breathing or swallowing


• severe itching of your skin with raised lumps.

Stop taking this medicine and see a doctor straight away if you have any of the following:

• heart problems. The signs of this may include changes in the way your heart beats, such as it beating faster or missed heart beats, breathing difficulties and dizziness


• if your breathing becomes slow and shallow.

Keep taking the medicine but tell your doctor straight away if you get any of the following side effects:

• if you have asthma and it gets worse


• worsening of the pressure inside your head if you already have this condition following an injury to your brain or brain disease.

Tell your doctor if you get any of these side effects:

• feeling sick (nausea) or being sick (vomiting)


• constipation


• sweating a lot more than usual


• feeling dizzy, particularly when standing up. This may be a sign that you have low blood pressure


• small pupils


• breast growth and production of breast milk


• difficulty in passing water (urine), pain in the lower back and abdomen caused by muscle spasms


• dry mouth, eyes or nose, facial flushing


• feeling drowsy, confused or restless


• changes in your mood, feeling "high" or over excited


• seeing or hearing things that are not there (hallucinations)


• headache, rashes


• low body heat (hypothermia)


• lower sexual urge or desire


• painful periods or lack of periods.

You may notice that some of the side effects become less severe with time as you get used to the methadone.

When taken for a long period of time, it is possible that you may become dependent on methadone solution.

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

How to store Methadone Hydrochloride DTF 1mg/1ml Oral Solution

• Keep out of the reach and sight of children


• Store below 25°C but not in a refrigerator. Protect from light


• Do not use after the expiry date (month, year) stated on the label and carton


• Use within 1 month of opening


• If it is out of date or you no longer want it, take it back to the pharmacy


• Do not use Methadone Solution if you notice anything wrong with the medicine. Talk to your pharmacist


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

Further information

What Methadone Solution contains

• The active ingredient is methadone hydrochloride


• The other ingredients are methyl hydroxybenzoate (E218), propyl hydroxybenzoate (E216), propylene glycol (E1520), liquid maltitol (E965), sucrose, tartrazine (E102), sunset yellow (E110), green s (E142), poloxamer 188, simethicone emulsion 30% and purified water.

What Methadone Solution looks like and contents of the pack

• A green solution.

It is available in plastic bottles of 2500ml and 5000ml. Other pack sizes are available.

Marketing Authorisation Holder and Manufacturer

Rosemont Pharmaceuticals Ltd.

Yorkdale Industrial Park

Braithwaite Street

Leeds

LS11 9XE

UK

This leaflet was last approved in December 2009

P0494

Metvix 160 mg / g cream

1. Name Of The Medicinal Product

Metvix 160 mg/g cream.

2. Qualitative And Quantitative Composition

Metvix cream contains 160 mg/g of methyl aminolevulinate (as hydrochloride) equivalent to 16.0% of methyl aminolevulinate (as hydrochloride).

The excipients include cetostearyl alcohol (40 mg/g), methyl parahydroxybenzoate (E 218; 2 mg/g), propyl parahydroxybenzoate (E 216; 1 mg/g) and arachis oil (30 mg/g).

For excipients, see 6.1.

3. Pharmaceutical Form

Cream.

The colour is cream to pale yellow.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of thin or non-hyperkeratotic and non-pigmented actinic keratoses on the face and scalp when other therapies are considered less appropriate.

Only for treatment of superficial and/or nodular basal cell carcinoma unsuitable for other available therapies due to possible treatment related morbidity and poor cosmetic outcome; such as lesions on the mid-face or ears, lesions on severely sun damaged skin, large lesions, or recurrent lesions.

Treatment of squamous cell carcinoma in situ (Bowen´s disease) when surgical excision is considered less appropriate.

4.2 Posology And Method Of Administration

Adults (including the elderly)

For treatment of actinic keratoses (AK) one session of photodynamic therapy should be administered. Treated lesions should be evaluated after three months and if needed, treatment should be repeated with a second therapy session. For treatment of basal cell carcinoma (BCC) and Bowen's disease two sessions should be administered with an interval of one week between sessions. Before applying Metvix cream, the lesion surface should be prepared to remove scales and crusts and roughen the surface of the lesions. Nodular BCC lesions are often covered by an intact epidermal keratin layer which should be removed. Exposed tumour material should be removed gently without any attempt to excise beyond the tumour margins.

Apply a layer of Metvix cream (about 1 mm thick) by using a spatula to the lesion and the surrounding 5-10 mm of normal skin. Cover the treated area with an occlusive dressing for 3 hours.

Remove the dressing, and clean the area with saline and immediately expose the lesion to red light with a continuous spectrum of 570-670 nm and a total light dose of 75 J/cm² at the lesion surface. Red light with a narrower spectrum giving the same activation of accumulated porphyrins may be used. The light intensity at the lesion surface should not exceed 200 mW/cm².

Only CE marked lamps should be used, equipped with necessary filters and/or reflecting mirrors to minimize exposure to heat, blue light and UV radiation. It is important to ensure that the correct light dose is administered. The light dose is determined by factors such as the size of the light field, the distance between lamp and skin surface and illumination time. These factors vary with lamp type, and the lamp should be used according to the user manual. The light dose delivered should be monitored if a suitable detector is available.

Patient and operator should adhere to safety instructions provided with the light source. During illumination patient and operator should wear protective goggles which correspond to the lamp light spectrum.

Healthy untreated skin surrounding the lesion does not need to be protected during illumination.

Multiple lesions may be treated during the same treatment session.

Lesion responses should be assessed after three months, and at this response evaluation, lesion sites showing non-complete response may be retreated if desired. It is recommended that the response of BCC and Bowen's disease lesions be confirmed by histological examination of biopsy material. Subsequently, close long term clinical monitoring of BCC and Bowen´s disease is recommended, with histology if necessary.

Children and adolescents:

There is no experience of treating patients below the age of 18 years.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients which includes arachis oil.

Morpheaform basal cell carcinoma.

Porphyria.

4.4 Special Warnings And Precautions For Use

Metvix should only be administered in the presence of a physician, a nurse or other health care professionals trained in the use of photodynamic therapy with Metvix.

Metvix is not recommended during pregnancy (see 4.6).

Thick (hyperkeratotic) actinic keratoses should not be treated with Metvix. There is no experience of treating lesions which are pigmented, highly infiltrating or located on the genitalia with Metvix cream. There is no experience of treating Bowen´s disease lesions larger than 40 mm. As with cryotherapy and 5-FU therapy of Bowen´s disease, response rates of large lesions (>20 mm in diameter) are lower than those of small lesions. There is no experience of treating Bowen´s disease in transplant patients on immunosuppressive therapy or in patients with a history of arsenic exposure.

Methyl aminolevulinate may cause sensitization by skin contact resulting in application site eczema or allergic contact dermatitis. The excipient cetostearyl alcohol may cause local skin reactions (e.g. contact dermatitis), methyl- and propyl parahydroxybenzoate (E218, E216) may cause allergic reactions (possibly delayed).

Any UV-therapy should be discontinued before treatment. As a general precaution, sun exposure of the treated lesion sites and surrounding skin should be avoided for about 2 days following treatment.

Direct eye contact with Metvix cream should be avoided.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No specific interaction studies have been performed with methyl aminolevulinate.

4.6 Pregnancy And Lactation

Pregnancy

For methyl aminolevulinate, no clinical data on exposed pregnancies are available. Reproductive toxicity studies in animals have not been performed. Metvix is not recommended during pregnancy (see 4.4).

Lactation

The amount of methyl aminolevulinate excreted into human breast milk following topical administration of Metvix cream is not known. In the absence of clinical experience, breast-feeding should be discontinued for 48 hours after application of Metvix cream.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

a) Approximately 60 % of patients experience reactions localised to the treatment site that are attributable to toxic effects of the photodynamic therapy (phototoxicity) or to preparation of the lesion.

The most frequent symptoms are painful and burning skin sensation typically beginning during illumination or soon after and lasting for a few hours with resolving on the day of treatment. The symptoms are usually of mild or moderate severity and rarely require early termination of illumination. The most frequent signs of phototoxicity are erythema and scab. The majority are of mild or moderate severity and persist for 1 to 2 weeks or occasionally longer.

Repeated treatment with Metvix is associated reduced frequency and severity of local phototoxic reactions.

b) The incidence of adverse reactions in a clinical trial population of 932 patients receiving the standard treatment regimen, is shown in the table below.

Body system (MedDRA)	Frequency*	Adverse reaction
Nervous system disorders	Common	Paraesthesia, headache
Eye disorders	Uncommon	Eye swelling, eye pain
Vascular disorders	Uncommon	Wound haemorrhage
Gastrointestinal disorders	Uncommon	Nausea
Skin and subcutaneous tissue disorders	Very common	Pain of skin, skin burning sensation, scab, erythema
Common	Skin infection, skin ulcer, skin oedema, skin swelling, blister, skin hemorrhage, pruritus, skin exfoliation, skin warm
Uncommon	Urticaria, rash, skin irritation, photosensitivity reaction, skin hypopigmentation, skin hyperpigmentation, heat rash, skin discomfort
General disorders and administration site conditions	Common	Application site discharge, feeling hot
Uncommon	Fatigue
* Very common adverse reactions: Adverse reactions occurring in Common adverse reactions: Adverse reactions occurring in Uncommon adverse reactions: Adverse reactions occurring in Adverse reactions reported by more than two patients in the clinical studies are included.

Application site eczema and allergic contact dermatitis have been described in post-marketing reports. Most cases were localised to the treatment area and were not severe; rarely erythema and swelling have been more extensive.

A study conducted in immunocompromised organ transplant recipients did not identify any safety concern in this population, adverse events being similar to those reported in trials in immunocompetent patients.

4.9 Overdose

The severity of local phototoxic reactions such as erythema, pain and burning sensation may increase in case of prolonged application time or very high light intensity.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group:

Antineoplastic agent, ATC Code: L01X D03

Mechanism of Action:

After topical application of methyl aminolevulinate, porphyrins accumulate intracellularly in the treated skin lesions. The intracellular porphyrins (including PpIX) are photoactive, fluorescing compounds and, upon light activation in the presence of oxygen, singlet oxygen is formed which causes damage to cellular compartments, in particular the mitochondria. Light activation of accumulated porphyrins leads to a photochemical reaction and thereby phototoxicity to the light-exposed target cells.

5.2 Pharmacokinetic Properties

In vitro dermal absorption of radiolabelled methyl aminolevulinate applied to human skin has been studied. After 24 hours the mean cumulative absorption through human skin was 0.26 % of the administered dose. A skin depot containing 4.9 % of the dose was formed. No corresponding studies in human skin with damage similar to actinic keratosis lesions and additionally roughened surface or without stratum corneum were performed.

In humans, a higher degree of accumulation of porphyrins in lesions compared to normal skin has been demonstrated with Metvix cream. After application of the cream for 3 hours and subsequent illumination with non-coherent light of 570-670 nm wavelength and a total light dose of 75 J/cm², complete photobleaching occurs with levels of porphyrins returning to pre-treatment values.

5.3 Preclinical Safety Data

Preclinical studies on general toxicity and genotoxicity studies in the presence or absence of photoactivation, do not indicate potential risks for man. Carcinogenicity studies or studies on the reproductive function have not been performed with methyl aminolevulinate.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Self-emulsifying glyceryl monostearate

cetostearyl alcohol

poloxyl 40 stearate

methyl parahydroxybenzoate (E 218)

propyl parahydroxybenzoate (E 216)

disodium edetate

glycerol

white soft paraffin

cholesterol

isopropyl myristate

arachis oil

refined almond oil

oleyl alcohol

purified water.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

Unopened: 15 months.

1 week after first opening of the container.

6.4 Special Precautions For Storage

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

6.5 Nature And Contents Of Container

Aluminium tube with internal protective lacquer and a latex seal. Screw cap of HDPE.

Metvix cream is supplied in a tube containing 2 g cream.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Galderma (UK) Ltd

Meridien House

69-71 Clarendon Road

Watford

Herts

WD17 1DS

UK

8. Marketing Authorisation Number(S)

PL 10590/0048

9. Date Of First Authorisation/Renewal Of The Authorisation

20/07/2006

10. Date Of Revision Of The Text

July 2010

Methadone 1mg / ml Oral Solution BP - Sugar Free

1. Name Of The Medicinal Product

Methadone 1mg/ml Oral Solution BP - Sugar Free.

2. Qualitative And Quantitative Composition

Methadone Hydrochloride 1mg/ml.

For excipients, see 6.1

3. Pharmaceutical Form

An oral solution, which is a green coloured free flowing mobile liquid.

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment of dependence on opioid drugs.

4.2 Posology And Method Of Administration

Adults

10 – 20mg (10 – 20ml) should be taken as an initial daily dose by oral administration. The dose should be increased cautiously by 10 – 20mg daily until no signs of withdrawal or intoxication occur. The usual dose for maintenance is 40 – 60mg daily. The dose can then be gradually decreased, when appropriate, until total withdrawal is achieved.

Elderly

Methadone 1mg/ml Oral Solution B.P. - Sugar Free, should be used cautiously in elderly patients.

Children

Not recommended for use in children.

4.3 Contraindications

• Hypersensitivity to methadone or to any of the excipients.

• Respiratory depression, obstructive airways disease and during an acute asthma attack,

• Patients dependent on non-opioid drugs,

• Concurrent administration with monoamine oxidase inhibitors (including moclobemide) or within 2 weeks of discontinuation of them.

• Head injury and raised intracranial pressure (further rise in intracranial pressure – papillary response affected; see section 4.8).

• Where there is a risk of paralytic ileus.

• Acute alcoholism (see section 4.5).

• Use during labour (prolonged duration of action increases the risk of neonatal depression).

• Children (serious risk of toxicity).

4.4 Special Warnings And Precautions For Use

In the case of elderly or ill patients, repeated doses should only be given with extreme caution. Methadone is a drug of addiction and is controlled under the Misuse of Drugs Act 1971 (Schedule 2).

Tolerance and dependence of the morphine type may occur. Methadone should be given with caution to patients with a history of asthma (see section 4.3), convulsive disorders, depressed respiratory reserve, hypotension, shock, prostatic hyperplasia, adrenocortical insufficiency, inflammatory or obstructive bowel disorders, myasthenia gravis or hypothyroidism. In cases of hepatic or renal impairment the use of methadone should be avoided or given in reduced doses.

Methadone 1mg/ml Oral Solution B.P. - Sugar Free, contains benzoic acid and dyes. Benzoic acid is a mild irritant to the skin, eyes and mucous membrane. It may increase the risk of jaundice in newborn babies.

E110 can cause allergic-type reactions including asthma. Allergy is more common in those people who are allergic to aspirin.

When taken according to the dosage recommendations each 5ml dose supplies up to 1.4g of sorbitol. Unsuitable in hereditary fructose intolerance. Can cause stomach upset and diarrhoea.

This product contains 0.19% v/v of ethanol. Harmful for those suffering from liver disease, alcoholism, epilepsy, brain injury or disease as well as for pregnant women and children. May modify the effect of other medicines.

Cases of QT interval prolongation and torsade de pointes have been reported during treatment with methadone, particularly at high doses (>100mg/d). Methadone should be administered with caution to patients at risk of development of prolonged QT interval, e.g. in case of:

- history of cardiac conduction abnormalities,

- advanced heart disease or ischaemic heart disease,

- Liver disease,

- family history of sudden death,

- Electrolyte abnormalities, i.e. hypokalaemia, hypomagnesaemia

- concomitant treatments with drugs that have a potential for QT-prolongation,

- concomitant treatment with drugs which may cause electrolyte abnormalities,

- concominant treatment with cytochrome P450 CYP 3A4 inhibitors (see section 4.5).

In patients with recognised risk factors of QT prolongation, or in case of concomitant treatment with drugs that have a potential for QT prolongation, ECG monitoring is recommended prior to methadone treatment, with a further ECG test at dose stabilisation. ECG monitoring is recommended in patients without recognised risk factors for QT prolongation, before dose titration above 100mg/d, and at seven days after titration.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interactions potentiating the effects of methadone;

Cytochrome P450 3A4 inhibitors: methadone clearance is decreased when co-administered with drugs which inhibit CYP3A4 activity, such as some anti-HIV agents, macrolide antibiotics, cimetidine, ciprofloxacin and azole antifungal agents (since the metabolism of methadone is mediated by the CYP3A4 isoenzyme).

Cimetidine and phenytoin – may lead to potentiation of opioid activity due to displacement of methadone from protein binding sites. However, as phenytoin is also a hepatic enzyme inducer, it may lower plasma methadone levels (see below).

Fluvoxamine may increase plasma concentrations of methadone.

The depressant effects of methadone are likely to be enhanced by depressants of the CNS, such as other opioid analgesics, alcohol (see section 4.3), anaesthetics, antipsychotics, anxiolytics, hypnotics and sedatives, major and minor tranquilisers and phenothiazines. As well as CNS depression, there may be respiratory depression and/or hypotension. Tricyclic antidepressants may exert a similar effect.

Interactions reducing the effects of methadone;

The opioid antagonists, naloxone and naltrexone, will precipitate an acute withdrawal syndrome in methadone-dependent individuals. Naloxone will also antagonise the analgesic, CNS and respiratory depressant effects of methadone.

Buprenorphine and pentazocine may also rapidly precipitate withdrawal symptoms in patients addicted to methadone.

The hepatic enzyme-inducing drugs, nevirapine, rifampicin (and other rifamycins), phenytoin, phenobarbital and carbamazepine may lower plasma methadone levels and produce symptoms of withdrawal in methadone dependent patients. Similar effects have been reported with efavirenz nelfinavir, ritonavir and possibly abacavir.

Urinary acidifiers: Acidification of the urine will increase the rate of elimination of methadone by the kidney thereby reducing plasma concentrations.

Effects of methadone on other drugs;

Methadone may increase plasma desipramine levels and increase desipramine side-effects when given concurrently.

Zidovudine – methadone may increase the plasma concentrations of zidovudine.

Mexiletine – methadone may delay mexiletine absorption.

Metoclopramide and domperidone – the gastrointestinal effects may be antagonised by methadone.

Methadone treatment has been found to decrease the rate of absorption and decrease the bioavailability of the nucleoside reverse transcriptase inhibitors didanosine and to a lesser extent stavudine.

Other important interactions;

In patients taking drugs affecting cardiac conduction or drugs which may affect electrolyte balance, there is a risk of cardiac events when methadone is taken concurrently.

As serious and sometimes fatal reactions have occurred following administration of pethidine to patients receiving MAOIs, other drugs related to pethidine are contraindicated in patients taking MAOI's (including moclobemide) or within 14 days of stopping such treatment, (see section 4.3) as there is a risk of CNS excitation or depression.

Cross tolerance and cross dependence can be expected between other opioids acting at the same receptors.

4.6 Pregnancy And Lactation

Pregnancy:

There is no or inadequate evidence of safety in human pregnancy, but the drug has been widely used for many years without apparent ill consequence and animal studies have not shown any hazard.

Methadone should only be used in pregnancy if the physician considers that the potential benefits outweigh the risks. It should be used cautiously under the close supervision of a physician if the physician considers it essential to continue or initiate (in the case of an i.v. opioid user) methadone maintenance. It may be necessary to increase the dose of methadone if withdrawal symptoms develop as increased clearance and reduced plasma levels have been reported during pregnancy.

Infants of methadone-maintained mothers may experience symptoms of withdrawal in utero and following birth.

Methadone should not be used during labour as the prolonged duration of action increases the risk of neonatal depression.

Lactation:

Methadone is excreted in breast milk. A decision must be made whether to discontinue breastfeeding or discontinue the methadone therapy.

4.7 Effects On Ability To Drive And Use Machines

Methadone may produce drowsiness and patients should be advised not to drive or operate machinery if affected. Once affected, the time after which such activities may be resumed is extremely variable between patients and should be decided by the physician.

4.8 Undesirable Effects

Blood and lymphatic system disorders

Lymphocytosis

Endocrine disorders

Adrenal insufficiency, increased prolactin concentrations, decreased testosterone concentrations

Psychiatric disorders

Dependence, hallucinations, confusion, mood changes including dysphoria, decreased libido

Nervous system disorders

Methadone may increase intra-cranial pressure, particularly when it is already raised. Dizziness, headache, drowsiness

Eye disorders

Miosis

Ear and labyrinth disorders

Vertigo

Cardiac disorders

Cases of QT prolongation and torsade de pointes have been rarely reported. Bradycardia, palpitations, tachycardia

Vascular disorders

Hypotension, facial flushing

Respiratory, thoracic and mediastinal disorders

Respiratory depression, Exacerbation of existing asthma

Gastrointestinal disorders

Nausea, vomiting, constipation, dry mouth

Hepatobiliary disorders

Biliary spasm

Skin and subcutaneous tissue disorders

Rashes, pruritus, urticaria, excessive sweating

Renal and urinary disorders

Difficulty in micturation, ureteric spasm, antidiuretic effect

Reproductive system and breast disorders

Erectile dysfunction, reductions in the ejaculate volume and seminal vesicular and prostatic secretions

General disorders and administration site conditions

Abrupt cessation or reduction of the dose of methadone will result in symptoms of withdrawal. In prolonged use it should not be administered more than twice daily to avoid the risk of accumulation and overdosage.

Hypothermia.

Investigations

Globulins increased, blood albumin increased

4.9 Overdose

Symptoms: Overdose of methadone is characterised by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), pulmonary oedema, extreme somnolence, progressing to stupor or coma, maximally constricted pupils, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. The presence and signs of drug abuse supports the diagnosis.

In children, methadone overdose produces drowsiness, floppiness, constricted pupils and apnoea.

In severe overdosage, particularly by the intravenous route, apnoea, circulatory collapse, cardiac arrest and death may occur.

Emergency procedures: If ingestion is recent, gastric aspiration and lavage can be employed after acute poisoning.

Primary attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Narcotic antagonists can be used to counteract the potentially lethal respiratory depression in a non-tolerant individual, especially a child. Methadone is, however, a long-acting depressant (36-48 hours) whereas the antagonists act for much shorter periods (1-3 hours). The patient must, therefore, be monitored continuously for recurrence of respiratory depression and treated repeatedly with the narcotic antagonist as needed. If the respiratory depression is only due to overdosage with methadone, the use of other respiratory stimulants is not indicated.

An antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression. Intravenously administered narcotic antagonists (naloxone, nalorphine or levallorphan) can be used to reverse signs of intoxication and should be given repeatedly until the patient's status remains satisfactory.

Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated.

In an individual physically dependent on narcotics, the administration of the usual dose of a narcotic antagonist will precipitate an acute withdrawal syndrome. The severity of this syndrome will depend on the degree of physical dependence and the dose of the antagonist administered. The use of a narcotic antagonist in such a person should be avoided if possible. If it must be used to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care and by titration with smaller than usual doses of the antagonist.

Patients should be monitored for signs of relapse for at least 48 hours.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Methadone is a µ agonist with pharmacological properties similar to morphine.

Its long duration of action enables it to be used daily on a supervised basis in opioid dependent individuals.

5.2 Pharmacokinetic Properties

Methadone is well absorbed from the gastrointestinal tract with peak plasma levels occurring 1-5 hours after a single dose. Wide variations in plasma levels occur during maintenance therapy. Plasma levels may decrease on long term maintenance suggesting tolerance to develop possibly as a result of auto-induction of hepatic microsomal enzymes.

Methadone is widely distributed in the tissues. It diffuses across the placenta and is excreted in breast milk. Plasma protein binding is 60-90%. After repeated administration, there is a gradual accumulation in the tissues and on discontinuation low concentrations in the plasma are maintained by slow release from extravascular binding sites accounting for the relatively mild but protracted withdrawal syndrome.

N-demethylation to the inactive major metabolite 2-ethylidine-1, 5-dimethyl-3, 3-diphenylpyrrolidine and other pyrrolidines and pyrroline occurs in the liver. These metabolites are excreted in the faeces and urine together with unchanged methadone. Urinary excretion is increased with an acidic urine. The elimination half-life is long and varies considerably with a range of 15-60 hours having been reported. Decreased excretion of methadone and its metabolites occur in liver dysfunction and urinary elimination is reduced in renal failure.

In methadone-maintained pregnant women, trough plasma levels have been found to be significantly lower and total or unbound methadone clearance greater during pregnancy than after delivery.

5.3 Preclinical Safety Data

No data of relevance, which is additional to that already, included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Benzoic Acid Solution (contains propylene glycol)

Green S Dye (E142)

Sorbitol Solution (70% non-crystallising)

Saccharin Sodium

Quinoline Yellow Solution Compound (containing Chloroform, Ethanol, Glycerol, Quinoline Yellow (E104), Yellow Dye Sunset (E110))

Purified Water

6.2 Incompatibilities

None reported.

6.3 Shelf Life

3 years unopened.

Use within 56 days of first opening

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

500ml: Round high density polythene bottle with 28mm tamper evident cap with polyethylene laminate wad.

1Lt, 2Lt and 5Lt HDPE bottle with 38mm polypropylene, tamper evident cap with polyethylene laminate wad.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Thornton & Ross Ltd

Linthwaite

Huddersfield, HD7 5QH

8. Marketing Authorisation Number(S)

PL 00240/0044

9. Date Of First Authorisation/Renewal Of The Authorisation

21.11.02

10. Date Of Revision Of The Text

08/11/2011