Itraconazole 100mg Capsules (Sandoz Limited)

1. Name Of The Medicinal Product

Itraconazole 100mg Capsules

2. Qualitative And Quantitative Composition

Itraconazole 100 mg.

For excipients, see 6.1

3. Pharmaceutical Form

Capsule, hard

(Size 0), opaque green, containing coated beads.

4. Clinical Particulars

4.1 Therapeutic Indications

Indications

Itraconazole is indicated for the treatment of the following fungal infections:

	• Vulvovaginal candidiasis.
	• Pityriasis versicolor.
	• Dermatophytoses caused by organisms susceptible to itraconazole (Trichophyton spp. Microsporum spp. Epidermophyton floccosum) e.g. tinea pedis, tinea cruris, tinea corporis, tinea manuum.
	• Oropharyngeal candidiasis.
	• Onychomycosis caused by dermatophytes and/or yeasts.
	• Histoplasmosis. • Maintenance therapy in AIDS patients to prevent relapse of underlying fungal infection.

Itraconazole is indicated for the treatment of the following systemic fungal conditions when first-line systemic anti-fungal therapy is inappropriate or has proved ineffective (eg. because of underlying pathology, insensitivity of the pathogen or drug toxicity):

• Aspergillosis, • candidiasis • cyptococcosis (including cryptococcal meningitis); Itraconazole may be used for the prevention of fungal infection during prolonged neutropenia when standard therapy is considered inappropriate.

4.2 Posology And Method Of Administration

Itraconazole Capsules is for oral administration and must be taken immediately after a meal for maximal absorption. Treatment schedules in adults for each indication are as follows:

Indication	Dose
Vulvovaginal candidiasis	200mg twice daily for 1 day
Pityriasis versicolor	200mg once daily for 7 days
Tinea corporis, tinea cruris	100mg once daily for 15 days
Tinea pedis, tinea manuum	100mg once daily for 30 days
Oropharyngeal candidiasis	100mg once daily for 15 days
Onychomycosis	200mg once daily for 3 months

For skin infections, optimal clinical and mycological effects are reached at 1 - 4 weeks after cessation of treatment and for nail infections at 6 - 9 months after the cessation of treatment. This is because elimination of itraconazole from skin and nails is slower than from plasma.

In Acquired Immune Deficiency Syndrome and neutropenic patients: for the treatment of oral candidiasis 200 mg once daily for 15 days is recommended due to the impaired absorption of itraconazole in these patient groups.

The length of treatment for systemic fungal infections should be dictated by the mycological and clinical response to therapy:

Indication	Dose	Remarks
Aspergillosis	200mg once daily	Increase dose to 200mg twice daily in case of invasive or disseminated disease
Candidiasis	100-200mg once daily	Increase dose to 200mg twice daily in case of invasive or disseminated disease
Non-meningeal cryptococcosis	200mg once daily
Cryptococcal meningitis	200mg twice daily
Histoplasmosis	200mg once daily - 200mg twice daily
Maintenance in AIDS	200mg once daily	See note on impaired absorption below
Prophylaxis in neutropenia	200mg once daily	See note on impaired absorption below

Impaired absorption in AIDS and neutropenic patients may lead to low itraconazole blood levels and lack of efficacy. In such cases blood level monitoring and if necessary an increase in itraconazole dose to 200mg twice daily is indicated.

In Children (below 12 years): There are inadequate data on Itraconazole in children for its use to be recommended, unless the potential benefits outweigh the risks.

In Elderly: As for use in children

4.3 Contraindications

Itraconazole is contraindicated in:

• Hypersensitivity to itraconazole or to any of the capsule excipients.

• Pregnancy. However, itraconazole may be given if the fungal infection is life-threatening and the potential benefit is considered to outweigh the potential risk to the foetus. Adequate contraceptive precautions should be taken by women of childbearing potential using Itraconazole until the next menstrual period following the end of therapy.

• Patients taking terfenadine, astemizole, mizolastine, cisapride, dofetilide, quinidine, pimozide, CYP3A4 metabolised HMG-CoA reductase inhibitors such as simvastatin and lovastatin, triazolam and oral midazolam Capsules (see also 4.5 Interactions with Other Medicaments and Other Forms of Interactions).

4.4 Special Warnings And Precautions For Use

• There is no information regarding cross hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used in prescribing Itraconazole to patients with hypersensitivity to other azoles.

• In a healthy volunteer study with intravenous Itraconazole, a transient asymptomatic decrease of the left ventricular ejection fraction was observed.

• Itraconazole has been shown to have a negative inotropic effect and has been associated with reports of congestive heart failure. Itraconazole should not be used in patients with congestive heart failure or with a history of congestive heart failure unless the benefit clearly outweighs the risk. This individual benefit/risk assessment should take into consideration factors such as the severity of the indication, the dose and duration of treatment, and individual risk factors for congestive heart failure. Such patients should be informed of the signs and symptoms of congestive heart failure, should be treated with caution, and should be monitored for signs and symptoms of congestive heart failure during treatment; if such signs or symptoms do occur during treatment, Itraconazole should be discontinued.

• Caution should be exercised when co-administering itraconazole and calcium channel blockers (see section 4.5, Interactions with other medicinal products).

• Itraconazole has a potential for clinically important drug interactions. (See 4.5: Interaction with other medicaments and other forms of interaction).

•Decreased gastric acidity:

Absorption of itraconazole is impaired when gastric acidity is decreased. In patients also receiving acid neutralising medicines (e.g. aluminium hydroxide) these should be administered at least 2 hours after the intake of Itraconazole Capsules. In patients with achlorhydria such as certain AIDS patients and patients on acid secretion suppressors (e.g. H₂-antagonists. proton-pump inhibitors) it is advisable to administer Itraconazole Capsules with a cola beverage.

• Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of itraconazole. Some of these cases involved patients with no pre-existing liver disease. Some of these cases have been observed within the first month of treatment, including some within the first week. Liver function monitoring should be considered in patients receiving Itraconazole treatment. Patients should be instructed to promptly report to their physician signs and symptoms suggestive of hepatitis such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine. In these patients treatment should be stopped immediately and liver function testing should be conducted. Most cases of serious hepatotoxicity involved patients who had pre-existing liver disease, were treated for systemic indications, had significant other medical conditions and/or were taking other hepatotoxic drugs. In patients with raised liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment should not be started unless the expected benefit exceeds the risk of hepatic injury. In such cases liver enzyme monitoring is necessary.

•Hepatic impairment:

•Itraconazole is predominantly metabolised in the liver. A slight decrease in oral bioavailability in cirrhotic patients has been observed, although this was not of statistical significance. The terminal half-life was however significantly increased. The dose should be adapted if necessary.

•Renal Impairment:

The oral bioavailability of itraconazole may be lower in patients with renal insufficiency. Dose adaptation may be considered.

• If neuropathy occurs which may be attributable to Itraconazole, treatment should be discontinued.

• Fluconazole-resistant strains of Candida species cannot be assumed to be susceptible to itraconazole. Ideally, susceptibility testing should be performed before the start of Itraconazole therapy.

• This product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

(1) Drugs affecting the metabolism of itraconazole:

Interaction studies have been performed with rifampicin, rifabutin and phenytoin. Since the bioavailability of itraconazole and hydroxyitraconazole was decreased in these studies to such an extent that efficacy may be considerably reduced, the combination of itraconazole with these potent enzyme inducers is not recommended. No formal study data are available for other enzyme inducers, such as carbamazepine, phenobarbital and isoniazid, but similar effects should be anticipated.

As itraconazole is mainly metabolised through CYP3A4, potent inhibitors of this enzyme may increase the bioavailability of itraconazole. Examples are: ritonavir, indinavir and clarithromycin and erythromycin.

(2) Effects of itraconazole on the metabolism of other drugs:

Itraconazole can inhibit the metabolism of drugs that are substrates for cytochrome 3A isoenzymes. This can result in an increase and/or a prolongation of their effects, including side effects. After stopping treatment, itraconazole plasma levels decline gradually, depending on the dose and duration of treatment (see Section 5.2 Pharmacokinetic Properties). This should be taken into account when the inhibitory effect of itraconazole on co-administered drugs is considered.

Examples are:

• Drugs which must not be used during treatment with itraconazole:

Terfenadine, astemizole, mizolastine, cisapride, triazolam, oral midazolam, dofetilide, quinidine, pimozide, CYP3A4 metabolised HMG-CoA reductase inhibitors such as simvastatin and lovastatin (see section 4.3).

• Caution should be exercised when co-administering itraconazole with calcium channel blockers. In addition to possible pharmacokinetic interactions involving the drug metabolising enzyme CYP3A4, calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole.

If the following are co-administered with itraconazole, their plasma levels, clinical effects and possible side effects should be monitored. The dose of these drugs may need to be reduced during co-administration with itraconazole:

• Oral anticoagulants

• HIV protease inhibitors such as ritonavir, indinavir, saquinavir

• Certain antineoplastic agents such as vinca alkaloids, busulphan, docetaxel and trimetrexate

• CYP3A4 metabolised calcium channel blockers such as dihydropyridines and verapamil

• Certain immunosuppressive agents: cyclosporin, tacrolimus, sirolimus

• Others: digoxin, carbamazepine, buspirone, alfentanil, alprazolam, brotizolam, midazolam IV, rifabutin, methylprednisolone, ebastine, reboxetine. The importance of the concentration increase and the clinical relevance of these changes during co-administration with itraconazole remain to be established.

4.6 Pregnancy And Lactation

Pregnancy: When administered at high doses to pregnant rats (40mg/kg/day or higher) and mice (80mg/kg/day or higher), itraconazole was shown to increase the incidence of foetal abnormalities and produced adverse effects on the embryo.

Studies of the use of itraconazole in pregnant women are not available. Therefore Itraconazole should only be given in life-threatening cases of systemic mycosis and when the potential benefit outweighs the potential risk to the foetus.

Lactation: A very small amount of itraconazole is excreted in human milk. The expected benefits of Itraconazole therapy should be weighed against the risks of breast-feeding. In case of doubt, the patient should not breast-feed.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Approximately 9% of patients can be expected to experience adverse reactions while taking itraconazole. In patients receiving prolonged (approximately 1 month) continuous treatment especially, the incidence of adverse events was higher (about 15%). The most frequently reported adverse experiences were of gastrointestinal, hepatic and dermatological origin.

Based upon the post-marketing experience, the following adverse reactions have been reported very rarely (<1/10,000):

•Metabolism and Nutrition Disorders

hypokalaemia

•Nervous System Disorders

peripheral neuropathy, headache, and dizziness

•Cardiac Disorders

congestive heart failure

•Respiratory, Thoracic and Mediastinal Disorders

pulmonary oedema

•Gastrointestinal Disorders

abdominal pain, vomiting, dyspepsia, nausea, diarrhoea and constipation

•Hepato-Biliary Disorders

fatal acute liver failure, serious hepatotoxicity, hepatitis, reversible increases in hepatic enzymes

•Skin and Subcutaneous Tissue Disorders

Stevens-Johnson syndrome, angio-oedema, urticaria, alopecia and rash, and pruritus

•Reproductive System and Breast Disorders

menstrual disorder

•General Disorders and Administrative Site Conditions

allergic reaction, and oedema

4.9 Overdose

In the event of an accidental overdose, patients should be treated symptomatically with supportive measures. Within the first hour after ingestion gastric lavage may be performed. Activated charcoal may be given if appropriate. No specific antidote is available. Itraconazole cannot be removed by haemodialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Itraconazole is a substituted triazole antimycotic agent with a broad spectrum of activity that includes Candida spp and other yeasts, dermatophytes and some other pathogenic fungi. It acts by impairing the synthesis of ergosterol in fungal cell membranes.

5.2 Pharmacokinetic Properties

Peak plasma concentrations of itraconazole in the region of 1 mcg equiv/ml are reached 1.5-3 hrs after administration. In man the elimination half life is about 20 hrs. Oral intake immediately after a meal doubled the peak level 3-4 hrs after intake.

Peak concentrations of itraconazole in keratinous tissues, especially skin, are up to 3 times higher than in plasma. Therapeutic levels in the skin persist for up to 2-4 weeks after stopping treatment as elimination is related to epidermal regeneration, rather than redistribution into the systemic circulation.

Itraconazole is extensively metabolised by the liver to a large number of metabolites, which constitute 40% of the excreted dose. Faecal excretion of parent drug varies from 3-18% of the dose, and urinary excretion of unchanged drug is less than 0.03%.

5.3 Preclinical Safety Data

There is no other relevant information in addition to that provided in previous sections.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sugar spheres

Poloxamer 188

Hypromellose

 

Capsule shell.

Titanium dioxide (E171)

Indigo carmine (E132)

Gelatin

Quinoline yellow (E104)

6.2 Incompatibilities

None known.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Do not store above 25°C.

Store in the original package.

6.5 Nature And Contents Of Container

Aluminium-Aluminium blister

Pack sizes: 4, 6, 14, 15, 18, 28, 60, 84, 100 capsules.

6.6 Special Precautions For Disposal And Other Handling

Not applicable

Administrative Data

7. Marketing Authorisation Holder

Sandoz Ltd

Woolmer Way

Bordon

Hampshire

GU35 9QE

8. Marketing Authorisation Number(S)

PL 04416/0555

9. Date Of First Authorisation/Renewal Of The Authorisation

6^th July 2004

10. Date Of Revision Of The Text

Iressa 250 mg film-coated tablets

Iressa 250 mg film-coated tablets

gefitinib

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

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


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


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


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

In this leaflet:

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


• 2. Before you take Iressa


• 3. How to take Iressa


• 4. Possible side effects


• 5. How to store Iressa


• 6. Further information

What Iressa is and what it is used for

Iressa contains the active substance gefitinib which blocks a protein called ‘epidermal growth factor receptor’ (EGFR). This protein is involved in the growth and spread of cancer cells.

Iressa is used to treat adults with non-small cell lung cancer. This cancer is a disease in which malignant (cancer) cells form in the tissues of the lung.

Before you take Iressa

Do not take Iressa

• If you are allergic (hypersensitive) to gefitinib or any of the other ingredients of Iressa (listed in section 6, ‘What Iressa contains’).


• If you are breast-feeding.

Take special care with Iressa

Check with your doctor or pharmacist before taking Iressa.

• If you have ever had any other lung problems. Some lung problems may get worse during treatment with Iressa.


• If you have ever had problems with your liver.

Using other medicines

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

In particular, tell your doctor or pharmacist if you are taking any of the following medicines:

• Phenytoin or carbamazepine (for epilepsy).


• Rifampicin (for tuberculosis).


• Itraconazole (for fungal infections).


• Barbiturates (a type of medicine used for sleeping problems).


• Herbal remedies containing St John’s wort (Hypericum perforatum, used for depression and anxiety).


• Proton-pump inhibitors, H₂-antagonists and antacids (for ulcers, indigestion, heartburn and to reduce acids in the stomach).

These medicines may affect the way Iressa works.

• Warfarin (a so-called oral anticoagulant, to prevent blood clots). If you are taking a medicine containing this
  active substance, your doctor may need to do blood tests more often.

If any of the above applies to you, or if you are not sure, check with your doctor or pharmacist before taking Iressa.

Pregnancy and breast-feeding

Talk to your doctor before taking this medicine if you are pregnant, may become pregnant or are breast-feeding.

It is recommended that you avoid becoming pregnant during treatment with Iressa because Iressa could harm your baby.

Do not take Iressa if you are breast-feeding.

Driving and using machines

Iressa has no or negligible influence on your ability to drive or use any tools or machines. However, if you feel weak whilst taking this medicine, take care driving or using tools or machines.

Important information about some of the ingredients of Iressa

This medicine contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

How to take Iressa

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

• The usual dose is one 250 mg tablet per day.


• Take the tablet at about the same time each day.


• You can take the tablet with or without food.


• Do not take antacids (to reduce the acid level of your stomach) 2 hours before or 1 hour after taking Iressa.

If you have trouble swallowing the tablet, dissolve it in half a glass of still (non-fizzy) water. Do not use any other liquids. Do not crush the tablet. Swirl the water until the tablet has dissolved. This may take up to 20 minutes. Drink the liquid straight away. To make sure that you have drunk all of the medicine, rinse the glass very well with half a glass of water and drink it.

If you take more Iressa than you should

If you have taken more tablets than you should, talk to a doctor or pharmacist straight away.

If you forget to take Iressa

What to do if you forget to take a tablet, depends on how long it is until your next dose.

• If it is 12 hours or more until your next dose: take the missed tablet as soon as you remember. Then take the next dose as usual.


• If it is less than 12 hours until your next dose: skip the missed tablet. Then take the next tablet at the usual time.

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

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

Possible side effects

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

These side effects may occur with certain frequencies, which are defined as follows:

• 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.

Tell your doctor immediately if you notice any of the following side effects - you may need urgent medical treatment:

• Allergic reaction (uncommon), particularly if symptoms include swollen face, tongue or throat, difficulty to swallow, hives and difficulties to breathe.


• Serious breathlessness, or sudden worsening breathlessness, possibly with a cough or fever. This may mean that you have an inflammation of the lungs called ‘interstitial lung disease’. This may affect about 1 in 100 patients taking Iressa and can be life-threatening.


• Severe skin reactions (rare) affecting large areas of your body. The signs may include redness, pain, ulcers, blisters, and shedding of the skin. The lips, nose, eyes and genitals may also be affected.


• Dehydration (common) caused by long term or severe diarrhoea, vomiting (being sick), nausea (feeling sick) or loss of appetite.


• Eye problems (uncommon), such as pain, redness changes in vision or ingrowing eyelashes. This may mean that you have an ulcer on the surface of the eye (cornea).

Tell your doctor if you notice any of the following side effects:

Very common side effects

• Diarrhoea.


• Vomiting.


• Nausea.


• Skin reactions such as an acne-like rash, which is sometimes itchy with dry skin.


• Loss of appetite.


• Weakness.


• Dry, red or sore mouth.


• Increase of a liver enzyme known as alanine aminotransferase in a blood test; if too high, your doctor may tell you to stop taking Iressa.

Common side effects

• Dry, red or itchy eyes.


• Red and sore eyelids.


• Nail problems.


• Hair loss.


• Fever.


• Bleeding (such as nose bleed or blood in your urine).


• Protein in your urine (shown in a urine test).


• Increase of bilirubin and the other liver enzyme known as aspartate aminotransferase in a blood test; if too high, your doctor may tell you to stop taking Iressa.


• Increase of creatinine levels in a blood test (related to kidney function).

Uncommon side effects

• Inflammation of the pancreas. The signs include very severe pain in the upper part of the stomach area and severe nausea and vomiting.

Rare side effects

• Inflammation of the liver. The signs may include a general feeling of being unwell and yellowing of the skin and eyes (jaundice).

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

How to store Iressa

Keep out of the reach and sight of children.

Do not use Iressa after the expiry date which is stated on the carton, blister and overwrap foil after EXP. The expiry date refers to the last day of that month.

Store in the original package in order to protect from moisture.

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 Iressa contains

• The active substance is gefitinib. Each tablet contains 250 mg of gefitinib.


• The other ingredients are lactose monohydrate, microcrystalline cellulose (E460), croscarmellose sodium, povidone (K29-32) (E1201), sodium laurilsulfate, magnesium stearate, hypromellose (E464), macrogol 300, titanium dioxide (E171), yellow iron oxide (E172) and red iron oxide (E172).

What Iressa looks like and contents of the pack

Iressa is a round brown tablet marked with ‘IRESSA 250’ on one side and plain on the other.

Iressa comes in blister packs of 30 tablets.

Marketing Authorisation Holder

AstraZeneca AB

S-151 85 Södertälje

Sweden

Manufacturer

AstraZeneca UK Limited

Macclesfield

Cheshire

SK10 2NA

United Kingdom

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

United Kingdom

AstraZeneca UK Ltd

Tel:+ 44 1582 836 836

This leaflet was last approved in

June 2009

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

Leaflet prepared: June 2009

© AstraZeneca 2009

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

ONC 09 0012

Ipecacuanha and Morphine Mixture BP 1980

1. Name Of The Medicinal Product

Ipecacuanha and Morphine Mixture BP 1980

2. Qualitative And Quantitative Composition

Morphine Hydrochloride BP	0.458mg per 5ml.
Ipecacuanha Tincture BP 1999	0.1ml per 5ml.
Liquorice Liquid Extract BP	0.525ml per 5ml.

3. Pharmaceutical Form

Mixture

4. Clinical Particulars

4.1 Therapeutic Indications

For the symptomatic relief of coughs.

4.2 Posology And Method Of Administration

Oral.

Recommended doses and dosage schedule

Adults, the elderly and children over 12 years: 10ml.

This dose can he repeated up to 4 times in any 24 hours.

Children under 12 years: Not recommended.

4.3 Contraindications

Due to the presence of morphine this product is contraindicated in respiratory depression. It should not be given during an attack of bronchial asthma or in heart failure secondary to chronic lung disease.

4.4 Special Warnings And Precautions For Use

Caution is advised in patients with asthma, hepatic and renal disease, and a history of drug abuse.

Labels state:

Do not exceed the stated dose. If symptoms persist consult your doctor. Keep all medicines away from children. Shake the bottle.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant administration of other central nervous system depressants eg. alcohol, hypnotics, sedatives, may result in an enhancement of effects.

It may antagonise the effect of metoclopramide.

4.6 Pregnancy And Lactation

As with all medicines use should be avoided during pregnancy, especially in the first trimester, and in lactation unless recommended by a doctor.

4.7 Effects On Ability To Drive And Use Machines

Although morphine may cause drowsiness, it is not expected that the quantities present in this product will have an effect on the ability to drive etc.

4.8 Undesirable Effects

Adverse effects would not be expected to occur when this preparation is taken at the recommended dose. However, a number of effects are known to arise from administration of morphine, the commonest of these being nausea, vomiting, constipation, drowsiness and confusion.

4.9 Overdose

Overdose with this preparation is unlikely to occur due to the low concentrations of the active ingredients present.

Large doses of ipecacuanha irritate the gastro-intestinal tract and may give rise to bloody vomiting and diarrhoea. Absorption of emetine may have adverse effects on the heart, such as conduction abnormalities or myocardial infarction.

Respiratory depression, nausea and vomiting may occur due to the morphine.

After acute overdosage of ipecacuanha, activated charcoal should be given to delay absorption, followed by gastric lavage if necessary. Excessive vomiting should be controlled by administration of an ant-emetic, and fluid and electrolyte imbalance corrected if necessary.

In acute opiold poisoning the stomach should be emptied by aspiration and lavage, intensive supportive therapy may be required to correct respiratory failure and shock.

Severe respiratory depression and coma produced by excessive doses of opioids can be counteracted by the administration of naloxone given intravenously at a dose of 0.4 to 2mg, repeated at 2-3 minute intervals if necessary, up to 10mg.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Ipecacuanha is an expectorant, and in larger doses an emetic.

Morphine is an opioid analgesic acting mainly on the central nervous system and smooth muscle. It is used for relief of moderate to severe pain and is also effective as a cough suppressant.

5.2 Pharmacokinetic Properties

Emetine one of the major alkaloids of ipecacuanha is excreted or metabolised slowly, it has been detected in urine 40-60 days after discontinuation of treatment.

Morphine salts are absorbed from the gastro-intestinal tract. Morphine is distributed throughout the body. It crosses the placenta and traces have been found in milk and sweat.

Conjugation to morphine 3- and 6- glucuronides occurs in the liver. About 10% of a dose is excreted through the bile into the faeces, the remainder being excreted in the urine in the form of conjugates. About 90% of total morphine is excreted in 24 hours with traces up to 48 hours.

5.3 Preclinical Safety Data

None.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Treacle Black Commercial, Peppermint Oil BP, Ethanol (96%) BP, Diethyl Ether (Peroxide Free), Chloroform BP, Syrup BP and Purified Water BP.

6.2 Incompatibilities

None known.

6.3 Shelf Life

18 months unopened, 8 weeks after first opening.

6.4 Special Precautions For Storage

Store below 25°C.

6.5 Nature And Contents Of Container

200ml: Amber glass bottle with plastic screw cap and liner or white 28mm Child-resistant cap with Tamper Evident band and EPE/Saranex Liner.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Thornton & Ross Limited

Linthwaith Laboratories

Huddersfield

HD7 5QH

8. Marketing Authorisation Number(S)

PL 00240/6491R

9. Date Of First Authorisation/Renewal Of The Authorisation

05/03/2009

10. Date Of Revision Of The Text

30/10/2009

Irinotecan 20 mg / ml concentrate for solution for infusion

Irinotecan 20 mg/ml concentrate for solution for infusion

Irinotecan hydrochloride trihydrate

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

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


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


• 
  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 Irinotecan is and what it is used for


• 2. Before you use Irinotecan


• 3. How to use Irinotecan


• 4. Possible side effects


• 5. How to store Irinotecan


• 6. Further information

What Irinotecan is and what it is used for

Irinotecan belongs to a group of medicines called cytostatics (anti-cancer medicines).

Irinotecan is used for the treatment of advanced cancer of the colon and rectum in adults, either in a combination with other medicines or alone.

Before you use Irinotecan

Do not use Irinotecan if you

• are allergic (hypersensitive) to irinotecan hydrochloride trihydrate or any of the other ingredients of Irinotecan


• have any other bowel disease or a history of bowel obstruction


• are pregnant or breast feeding


• have increased levels of bilirubin in the blood (more than 3 times the upper limit of normal)


• have severe bone marrow failure


• are in a poor general health (evaluated by an international standard)


• are using the natural remedy St Johns’ Wort (Hypericum perforatum)

Take special care with Irinotecan

This medicine is intended for adults only. Check with your doctor if this medicine has been prescribed for use in a child.

Special care is also needed in elderly patients.

As Irinotecan is an anti-cancer medicine it will be administered to you in a special unit and under the supervision of a doctor qualified in the use of anti-cancer medicines. The unit’s personnel will explain to you what you need to take special care of during and after the treatment. This leaflet may help you to remember that.

1) The first 24 hours after administration of Irinotecan

During administration of Irinotecan (30-90 min.) and shortly after administration you may experience some of the following symptoms:

• diarrhoea


• sweating


• abdominal pain


• watering eyes


• visual disturbance


• excessive mouth watering

The medical term for these symptoms is acute cholinergic syndrome which can be treated (with atropine). If you have any of these symptoms immediately tell your doctor who will give you any treatment necessary.

2) From the day after treatment with Irinotecan until next treatment

During this period you may experience various symptoms, which may be serious and require immediate treatment and close supervision.

Diarrhoea

If your diarrhoea starts more than 24 hours after administration of Irinotecan (“delayed diarrhoea”) it may be serious. It is often seen about 5 days after administration. The diarrhoea should be treated immediately and kept under close supervision. Immediately after the first liquid stools do the following:

• 1. Take any anti-diarrhoeal treatment that the doctor has given you, exactly as he/she has told you. The treatment may not be changed without consulting the doctor. Recommended anti-diarrhoeal treatment is loperamide (4 mg for the first intake and then 2 mg every 2 hours, also during the night). This should be continued for at least 12 hours after the last liquid stools. The recommended dosage of loperamide may not be taken for more than 48 hours.


• 2. Drink large amounts of water and rehydration fluids, immediately (i.e. water, soda water, fizzy drinks, soup or oral rehydration therapy)


• 3. Immediately inform your doctor who is supervising the treatment, and tell him/her about the diarrhoea. If you are not able to reach the doctor, contact the unit at the hospital supervising the Irinotecan treatment. It is very important that they are aware of the diarrhoea.

You must immediately tell the doctor, or the unit supervising the treatment, if

• 
  you have nausea, vomiting or any fever as well as diarrhoea
  


• 
  you still have diarrhoea 48 hours after starting the diarrhoea treatment
  

Note! Do not take any treatment for diarrhoea other than that given to you by your doctor and the fluids described above. Follow the doctor’s instructions. The anti-diarrhoeal treatment should not be used to prevent a further episode of diarrhoea, even though you have experienced delayed diarrhoea at previous cycles.

Fever

If the body temperature increases over 38°C it may be a sign of infection, especially if you also have diarrhoea. If you have any fever (over 38°C) contact your doctor or the unit immediately so that they can give you any treatment necessary.

Nausea and vomiting

If you have nausea and/or vomiting contact your doctor or the unit immediately

Neutropenia

Irinotecan may cause a decrease in the number of some of your white blood cells, which play an important role in fighting infections. This is called neutropenia. Neutropenia is often seen during treatment with Irinotecan and is reversible. Your doctor should arrange for you to have regular blood tests to monitor these white blood cells. Neutropenia is serious and should be treated immediately and carefully monitored.

Breathing difficulties

If you have any breathing difficulties contact your doctor immediately.

Impaired liver function

Before treatment with Irinotecan is started and before every following treatment cycle the liver function should be monitored (by blood tests).

If you have one or more of the symptoms mentioned, after you have returned home from the hospital, you should immediately contact the doctor or the unit supervising the Irinotecan treatment.

Impaired kidney function

As this medicine has not been tested in patients with kidney problems, please check with your doctor if you have any kidney problems.

Using other medicines

Please tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. This is also valid for herbal medicines, strong vitamins and minerals.

Some medicines may alter the effects of Irinotecan e.g. ketoconazole (for the treatment of fungal infections), rifampicin (for the treatment of tuberculosis) and some medicines for the treatment of epilepsy (carbamazepine, phenobarbital and phenytoin).

The herbal medicine St John’s Wort (Hypericum perforatum) may not be used concurrent with Irinotecan and not between treatments, as it may decrease the effect of irinotecan.

If you require an operation, please tell your doctor or anaesthetist that you are using this medicine, as it may alter the affect of some medicines used during surgery.

Pregnancy and breast-feeding

Irinotecan must not be used during pregnancy.

Women of child-bearing age should avoid becoming pregnant.

Contraceptive measures must be taken by both male and female patients during and for at least three months after cessation of therapy. Still, if you become pregnant during this period you must immediately inform your doctor.

Breast-feeding must be discontinued for the duration of irinotecan therapy.

Driving and using machines

In some cases Irinotecan may cause side effects which affect the ability to drive and use tools and machines. Contact your doctor or pharmacist if you are unsure.

During the first 24 hours after administration of Irinotecan you may feel dizzy or have visual disturbances. If this happens to you do not drive or use any tools or machines.

Important information about some of the ingredients of Irinotecan

Irinotecan contains sorbitol. If you suffer from an intolerance to some sugars, tell your doctor before you are given this medicinal product.

How to use Irinotecan

Irinotecan will be given as an infusion into your veins over a period of 30•90 minutes. The amount of infusion you are given will depend on your age, size and general medical condition. It will also depend on any other treatment you may have received for your cancer. Your doctor will calculate your body surface area in square meters (m2).

• If you have previously been treated with 5-fluorouracil you will normally be treated with Irinotecan alone starting with a dose of 350 mg/m2 every 3 weeks.


• If you have not had previous chemotherapy you will normally receive 180 mg/m2 Irinotecan every two weeks. This will be followed by folinic acid and 5-fluorouracil.

These dosages may be adjusted by your doctor depending on your condition and any side-effects you may have.

Possible side effects

Like all medicines, Irinotecan can cause side effects, although not everybody gets them. Your doctor will discuss these side effects with you and explain the risks and benefits of your treatment. Some of these side effects must be treated immediately, see also information in section “Take special care with Irinotecan ”.

Very common side effects (more than 1 in 10 patients):

• Blood disorders: Neutropenia (decreased number of some white blood cells), thrombocytopenia (decreased number of blood platelets), anaemia.


• Delayed diarrhoea.


• Nausea, vomiting.


• Hair loss (the hair grows again after end of treatment).


• In combination therapy transient serum levels of some enzymes (ALT, AST, alkaline phosphatase) or bilirubin

Common side effects (less than 1 in 10 patients):

• Acute cholinergic syndrome: the main symptoms are defined as early diarrhoea and various other symptoms such as abdominal pain; red, sore, itching or weeping eyes (conjunctivitis); running nose (rhinitis); low blood pressure; widening of the blood vessels; sweating, chills; a feeling of general discomfort and illness; dizziness; visual disturbances, pupil contraction; watering eyes and increased salivation, occurring during or within the first 24 hours after the infusion of Irinotecan .


• Fever, infections.


• Fever associated with a severe decrease in the number of some white blood cells


• Dehydration, commonly associated with diarrhoea and /or vomiting.


• Constipation.


• Fatigue.


• Increased levels of liver enzymes and creatinine in the blood

Uncommon side effects (Less than 1 in 100 patients):

• Allergic reactions.


• Mild skin reactions; mild reactions at the infusion site.


• Early effects such as breathing difficulties.


• Lung disease (interstitial pulmonary disease).


• Intestinal blockage.


• Abdominal pain and inflammation, causing diarrhoea (a condition known as pseudomembraneous colitis)


• Infrequent cases of renal insufficiency, low blood pressure or cardio-circulatory failure have been observed in patients who experienced episodes of dehydration associated with diarrhoea and/or vomiting or sepsis.

Rare side effects (Less than 1 in 1000 patients):

• Severe allergic reactions (anaphylactic/anaphylactoid reactions). If this happens you should tell your doctor immediately


• Early effects such as muscular contraction or cramps and numbness (paraesthesia).


• Gastrointestinal bleeding and inflammation of the colon including the appendix.


• Intestinal perforation; Anorexia; abdominal pain; inflammation of the mucous membranes.


• Inflammation of the pancreas.


• Increased blood pressure during and following administration.


• Decreased levels of potassium and sodium in the blood, mostly related to diarrhoea and vomiting.

Very rare side effects (Less than 1 in 10,000 patients)

• Transient speech disorders.


• Increase in levels of some digestive enzymes which break down sugars and fats

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 Irinotecan

Keep out of the reach and sight of children.

Do not freeze.

For single use only.

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

Do not use this medicinal product after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of that month.

The product should be diluted and used immediately after opening.

If prepared aseptically, the diluted solution can be stored for 24 hours at temperatures up to 30°C and for 48 hours at 2-8°C (e.g. in a fridge).

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

Further information

What Irinotecan contains

• The active substance is irinotecan hydrochloride trihydrate


• 1 ml of concentrate contains 20 mg irinotecan hydrochloride trihydrate equivalent to 17.33 mg of irinotecan.


• One 2ml vial contains 40 mg irinotecan hydrochloride trihydrate.


• One 5ml vial contains 100 mg irinotecan hydrochloride trihydrate.


• One 25ml vial contains 500 mg irinotecan hydrochloride trihydrate.


• The other ingredients are sorbitol E420, lactic acid, sodium hydroxide, hydrochloric acid and water for injections

What Irinotecan looks like and contents of the pack

Irinotecan 20 mg/ml concentrate for solution for infusion is a clear, colourless to slightly yellow solution.

Pack size:

1 x 2 ml vial

1 x 5 ml vial

1 x 25 ml vial

Marketing Authorisation Holder

Actavis Group hf.

Reykjavíkurvegi 76-78

IS-220 Hafnarfjörður

Iceland

Manufacturer

Actavis Nordic A/S

Ørnegårdsvej 16

DK-2820 Gentofte

Denmark

Or

S.C. SINDAN• PHARMA S.R.L.

11 Ion Mihalache Blvd

011171 Bucharest

Romania

This medicinal product is authorised in the Member States of the EEA under the following names:

Austria: Irinotecan Actavis 20mg/ml, Konzentrat zur Herstellung einer Infusionslösung

Belgium: IRINOTECAN ACTAVIS GROUP 20mg/ml, solution à diluer pour perfusion

Germany: Irinotecan-Actavis 20 mg/ml Konzentrat zur Herstellung einer Infusionslösung

France: IRINOTECAN ACTAVIS 20mg/ml, solution à diluer pour perfusion

Ireland: Irinotecan hydrochloride 20mg/ml Concentrate for solution for infusion;

Malta: Irinotecan Actavis 20mg/ml Concentrate for solution for infusion

Portugal: Irinotecano Actavis

Spain: Irinotecan Actavis 20mg/ml concentrado para solución para perfusión

Czech, Slovakia: Irinotecan HCL Actavis 20 mg/ml

Denmark, Estonia, Finland, Iceland, Italy, Lithuania, Latvia, Netherlands, Norway, Sweden: Irinotecan Actavis

Hungary, Poland, Slovenia: Irinotesin

This leaflet was last approved in March 2010.

Actavis

Barnstaple

EX32 8NS

UK

SINPL025

Imigran 10mg and 20mg Nasal Spray

1. Name Of The Medicinal Product

Imigran 10 mg Nasal Spray.

Imigran 20 mg Nasal Spray.

2. Qualitative And Quantitative Composition

Imigran 10 mg Nasal Spray: Unit dose spray device for intranasal administration. The device delivers 10 mg of sumatriptan in 0.1 mL of an aqueous buffered solution.

Imigran 20 mg Nasal Spray: Unit dose spray device for intranasal administration. The device delivers 20 mg of sumatriptan in 0.1 mL of an aqueous buffered solution.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Nasal Spray, solution.

Clear pale yellow to dark yellow liquid, in glass vials in a single dose nasal spray device.

4. Clinical Particulars

4.1 Therapeutic Indications

Imigran Nasal Spray is indicated for the acute treatment of migraine attacks with or without aura.

4.2 Posology And Method Of Administration

Imigran Nasal Spray should not be used prophylactically.

Imigran is recommended as monotherapy for the acute treatment of a migraine attack and should not be given concomitantly with ergotamine or derivatives of ergotamine (including methysergide) (see section 4.3).

It is advisable that Imigran be given as early as possible after the onset of a migraine headache. It is equally effective at whatever stage of the attack it is administered.

Adults (18 years of age and over)

The optimal dose of Imigran Nasal Spray is 20 mg for administration into one nostril. However, due to inter/intra patient variability of both the migraine attacks and the absorption of sumatriptan, 10 mg may be effective in some patients.

If a patient does not respond to the first dose of Imigran, a second dose should not be taken for the same attack. In these cases the attack can be treated with paracetamol, aspirin or non-steroidal anti-inflammatory drugs. Imigran may be taken for subsequent attacks.

If the patient has responded to the first dose but the symptoms recur, a second dose may be given in the following 24 hours, provided that there is a minimum interval of 2 hours between the two doses.

No more than two doses of Imigran 20 mg Nasal Spray should be taken in any 24-hour period.

Adolescents (12–17 years of age)

Use of sumatriptan in adolescents should be on the recommendation of a specialist or physician who has significant experience in treating migraine, taking into account local guidance.

The recommended dose of Imigran Nasal Spray is 10 mg for administration into one nostril.

If a patient does not respond to the first dose of Imigran, a second dose should not be taken for the same attack. In these cases the attack can be treated with paracetamol, aspirin or non-steroidal anti-inflammatory drugs.

Imigran may be taken for subsequent attacks.

If the patient has responded to the first dose but the symptoms recur, a second dose may be given in the following 24 hours, provided that there is a minimum interval of 2 hours between the two doses.

No more than two doses of Imigran 10 mg Nasal Spray should be taken in any 24-hour period.

Children (under 12 years of age)

Imigran Nasal Spray is not recommended for use in children under 12 years of age due to insufficient data on safety and efficacy.

Elderly (over 65)

There is no experience of the use of Imigran Nasal Spray in patients over 65. The pharmacokinetics in elderly patients have not been sufficiently studied. Therefore the use of sumatriptan is not recommended until further data are available.

4.3 Contraindications

Hypersensitivity to sumatriptan or to any of the excipients.

Sumatriptan should not be given to patients who have had myocardial infarction or have ischaemic heart disease, coronary vasospasm (Prinzmetal's angina), peripheral vascular disease or symptoms or signs consistent with ischaemic heart disease.

Sumatriptan should not be administered to patients with a history of cerebrovascular accident (CVA) or transient ischaemic attack (TIA).

Sumatriptan should not be administered to patients with severe hepatic impairment.

The use of sumatriptan in patients with moderate and severe hypertension and mild uncontrolled hypertension is contraindicated.

The concomitant administration of ergotamine, or derivatives of ergotamine (including methysergide) or any triptan/5-hydroxytryptamine₁ (5-HT₁) receptor agonist is contraindicated (see Section 4.5).

Concurrent administration of monoamine oxidase inhibitors (MAOIs) and sumatriptan is contraindicated.

Imigran must not be used within 2 weeks of discontinuation of therapy with monoamine oxidase inhibitors.

4.4 Special Warnings And Precautions For Use

Imigran Nasal Spray should only be used where there is a clear diagnosis of migraine.

Sumatriptan is not indicated for use in the management of hemiplegic, basilar or ophthalmoplegic migraine.

As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions.

It should be noted that migraineurs may be at increased risk of certain cerebrovascular events (e.g. CVA, TIA).

Following administration, sumatriptan can be associated with transient symptoms including chest pain and tightness, which may be intense and involve the throat (see Section 4.8). Where such symptoms are thought to indicate ischaemic heart disease, no further doses of sumatriptan should be given and an appropriate evaluation should be carried out.

Sumatriptan should not be given to patients with risk factors for ischaemic heart disease, including those patients who are heavy smokers or users of nicotine substitution therapies, without prior cardiovascular evaluation (see Section 4.3.).Special consideration should be give to postmenopausal women and males over 40 with these risk factors. These evaluations however, may not identify every patient who has cardiac disease and, in very rare cases, serious cardiac events have occurred in patients without underlying cardiovascular disease and in adolescents (see section 4.8).

There have been rare post-marketing reports describing patients with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following the use of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan. Serotonin syndrome has been reported following concomitant treatment with triptans and serotonin noradrenaline reuptake inhibitors (SNRIs).

If concomitant treatment with sumatriptan and an SSRI/SNRI is clinically warranted, appropriate observation of the patient is advised (see Section 4.5)

Sumatriptan should be administered with caution to patients with conditions that may affect significantly the absorption, metabolism, or excretion of the drug, e.g. impaired hepatic or renal function.

Sumatriptan should be used with caution in patients with a history of seizures or other risk factors which lower the seizure threshold, as seizures have been reported in association with sumatriptan (see Section 4.8).

Patients with known hypersensitivity to sulphonamides may exhibit an allergic reaction following administration of sumatriptan. Reactions may range from cutaneous hypersensitivity to anaphylaxis. Evidence of cross sensitivity is limited however, caution should be exercised before using sumatriptan in these patients.

Undesirable effects may be more common during concomitant use of triptans and herbal preparations containing St John's Wort (Hypericum perforatum).

Prolonged use of any type of painkiller for headaches can make them worse. If this situation is experienced or suspected, medical advice should be obtained and treatment should be discontinued. The diagnosis of medication overuse headache (MOH) should be suspected in patients who have frequent or daily headaches despite (or because of) the regular use of headache medications.

The recommended dose of Imigran should not be exceeded

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

There is no evidence of interactions with propranolol, flunarizine, pizotifen or alcohol.

There are limited data on an interaction with preparations containing ergotamine or another triptan/5-HT receptor agonist. The increased risk of coronary vasospasm is a theoretical possibility and concomitant administration is contraindicated (see section 4.3).

The period of time that should elapse between the use of sumatriptan and ergotamine-containing preparations or another triptan/5-HT₁ receptor agonist is not known. This will also depend on the doses and types of products used. The effects may be additive. It is advised to wait at least 24 hours following the use of ergotamine-containing preparations or another triptan/5-HT₁ receptor agonist before administering sumatriptan. Conversely, it is advised to wait at least 6 hours following use of sumatriptan before administering an ergotamine-containing product and at least 24 hours before administering another triptan/5-HT₁ receptor agonist.

An interaction may occur between sumatriptan and MAOIs and concomitant administration is contraindicated (see Section 4.3).

There have been rare post-marketing reports describing patients with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following the use of SSRIs and sumatriptan. Serotonin syndrome has also been reported following concomitant treatment with triptans and SNRIs (see section 4.4).

4.6 Pregnancy And Lactation

Post-marketing data on the use of sumatriptan during the first trimester of pregnancy in over 1,000 women are available. Although these data contain insufficient information to draw definitive conclusions, they do not point to an increased risk of congenital defects. Experience with the use of sumatriptan in the second and third trimester is limited.

Evaluation of experimental animal studies does not indicate direct teratogenic effects or harmful effects on peri- and postnatal development. However, embryo-foetal viability might be affected in the rabbit (see Section 5.3 Preclinical Safety Data). Administration of sumatriptan should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.

It has been demonstrated that following subcutaneous administration sumatriptan is secreted into breast milk. Infant exposure can be minimised by avoiding breast-feeding for 12 hours after treatment, during which time any breast milk expressed should be discarded.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Drowsiness may occur as a result of migraine or its treatment with sumatriptan. This may influence the ability to drive and to operate machinery.

4.8 Undesirable Effects

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000) and very rare (<1/10,000), i not known (cannot be estimated from the available data). Some of the symptoms reported as undesirable effects may be associated symptoms of migraine. Adverse events reported in adults have also been observed in adolescents. These include very rare reports of coronary artery vasospasm and myocardial infarction (See section 4.4).

Immune system disorders
Not known:	Hypersensitivity reactions ranging from cutaneous hypersensitivity (such as urticaria) to anaphylaxis.
Nervous system disorders
Very common:	Dysgeusia/unpleasant taste.
Common:	Dizziness, drowsiness, sensory disturbance including paraesthesia andhypoaesthesia.
Not known:	Seizures, although some have occurred in patients with either a history of seizures or concurrent conditions predisposing to seizures. There are also reports in patients where no such predisposing factors are apparent; Tremor, dystonia, nystagmus, scotoma.
Eye disorders
Not known:	Flickering, diplopia, reduced vision. Loss of vision including reports of permanent defects. However, visual disorders may also occur during a migraine attack itself.
Cardiac disorders
Not known:	Bradycardia, tachycardia, palpitations, cardiac arrhythmias, transient ischaemic ECG changes, coronary artery vasospasm, angina, myocardial infarction (see Contraindications, Special Warnings and Precautions for Use).
Vascular disorders
Common:	Transient increases in blood pressure arising soon after treatment. Flushing.
Not known:	Hypotension, Raynaud's phenomenon.
Respiratory, thoracic and mediastinal disorders
Common:	Following administration of sumatriptan nasal spray mild, transient irritation or burning sensation in the nose or throat or epistaxis have been reported. Dyspnoea.
Gastrointestinal disorders
Common:	Nausea and vomiting occurred in some patients but it is unclear if this is related to sumatriptan or the underlying condition.
Not known:	Ischaemic colitis
	Diarrhoea.
Musculoskeletal and connective tissue disorders
Common:	Sensations of heaviness (usually transient and may be intense and can affect any part of the body including the chest and throat). Myalgia.
Not known:	Neck stiffness.
	Arthralgia
General disorders and administration site conditions
Common:	Pain, sensations of heat, pressure or tightness (these events are usually transient and may be intense and can affect any part of the body including the chest and throat);feelings of weakness, fatigue (both events are mostly mild to moderate in intensity and transient).
Investigations
Very rare:	Minor disturbances in liver function tests have occasionally been observed.
Psychiatric disorders
Not known:	Anxiety.
Skin and subcutaneous tissue disorders
Not known:	Hyperhidrosis.

4.9 Overdose

Single doses of sumatriptan up to 40 mg intranasally, in excess of 16 mg subcutaneously and 400 mg orally have not been associated with side effects other than those mentioned.

In clinical studies volunteers have received 20 mg of sumatriptan by the intranasal route three times a day for a period of 4 days without significant adverse effects.

If overdosage occurs, the patient should be monitored for at least 10 hours and standard supportive treatment applied as required. It is unknown what effect haemodialysis or peritoneal dialysis has on the plasma concentrations of sumatriptan.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Selective 5-HT1 receptor agonists.

ATC code: N02CC01.

Sumatriptan is a selective vascular 5-hydroxytryptamine-1-(5-HT1d) receptor agonist with no effect on other 5-HT receptor (5-HT2–5-HT7) subtypes. The vascular 5-HT1d receptor is found predominantly in cranial blood vessels and mediates vasoconstriction. In animals, sumatriptan selectively constricts the carotid arterial circulation, which supplies blood to the extracranial and intracranial tissues such as the meninges. Dilatation and/or oedema in these vessels is thought to be the underlying mechanism of migraine in man. In addition, evidence from animal studies suggests that sumatriptan inhibits trigeminal nerve activity. Both cranial vasoconstriction and inhibition of trigeminal nerve activity may contribute to the anti-migraine action of sumatriptan in humans.

Clinical response begins 15 minutes following a 20 mg dose given by intranasal administration.

Because of its route of administration, Imigran Nasal Spray may be particularly suitable for patients who suffer nausea and vomiting during a migraine attack.

The magnitude of treatment effect is smaller in adolescents compared with adults.

5.2 Pharmacokinetic Properties

After intranasal administration, sumatriptan is rapidly absorbed, median times to maximum plasma concentrations being 1.5 (range: 0.25-3) hours in adults and 2 (range: 0.5-3) hours in adolescents. After a 20 mg dose, the mean maximum concentration is 13ng/mL. Mean intranasal bioavailability, relative to subcutaneous administration is about 16%, partly due to pre-systemic metabolism.

Following oral administration, presystemic clearance is reduced in patients with hepatic impairment resulting in increased plasma levels of sumatriptan. A similar increase is expected following intranasal administration.

Plasma protein binding is low (14–21%) and the mean volume of distribution is 170L. The elimination half-life is approximately 2 hours. The mean total plasma clearance is approximately 1160mL/min and the mean renal plasma clearance is approximately 260mL/min.

A pharmacokinetic study in adolescent subjects (12–17 years) indicated that the mean maximum plasma concentration was 13.9ng/mL and mean elimination half-life was approximately 2 hours following a 20 mg intranasal dose. Population pharmacokinetic modelling indicated that clearance and volume of distribution both increase with body size in the adolescent population resulting in higher exposure in lower bodyweight adolescents.

Non-renal clearance accounts for about 80% of the total clearance. Sumatriptan is eliminated primarily by oxidative metabolism mediated by monoamine oxidase A. The major metabolite, the indole acetic acid analogue of sumatriptan, is mainly excreted in urine, where it is present as a free acid and the glucuronide conjugate. It has no known 5-HT1 or 5-HT2 activity. Minor metabolites have not been identified. The pharmacokinetic profile of intranasal sumatriptan does not appear to be significantly affected by migraine attacks.

The kinetics in the elderly have been insufficiently studied to justify a statement on possible differences in kinetics between elderly and young volunteers.

5.3 Preclinical Safety Data

In non-clinical studies carried out to test for local and ocular irritancy, following administration of sumatriptan nasal spray, there was no nasal irritancy seen in laboratory animals and no ocular irritancy observed when the spray was applied directly to the eyes of rabbits.

Experimental studies of acute and chronic toxicity showed no evidence of toxic effects within the human therapeutic dose range. In a rat fertility study a reduction in success of insemination was seen at exposures sufficiently in excess of the maximum human exposure. In rabbits, embryo-lethality without marked teratogenic defects was seen.

Sumatriptan was devoid of genotoxic and carcinogenic activity in in-vitro systems and animal studies.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Potassium Dihydrogen Phosphate

Dibasic Sodium Phosphate anhydrous

Sulphuric Acid

Sodium Hydroxide

Purified Water.

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 30°C. Do not freeze.

Imigran Nasal Spray should be kept in the sealed blister, preferably in the box, to protect from light.

6.5 Nature And Contents Of Container

The container consists of a type I Ph.Eur. glass vial with rubber stopper and applicator.

Imigran 10 mg Nasal Spray: unit dose spray device containing 0.1mL solution.

Pack contains 1, 2, 4, 6, 12, or 18 sprays.

Imigran 20 mg Nasal Spray: unit dose spray device containing 0.1mL solution.

Pack contains 1, 2, 4, 6, 12, or 18 sprays.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Glaxo Wellcome UK Ltd

Trading as

GlaxoSmithKline UK

Stockley Park West

Uxbridge

Middlesex

UB11 1BT.

8. Marketing Authorisation Number(S)

Imigran 10mg Nasal Spray:	PL 10949/0260
Imigran 20mg Nasal Spray:	PL 10949/0261

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 29/05/1996

Date of last renewal: 29/03/2006

10. Date Of Revision Of The Text

23^rd Dec 2009