Virgan Eye Gel

1. Name Of The Medicinal Product

VIRGAN eye gel.

2. Qualitative And Quantitative Composition

Active Ingredient.

Ganciclovir 0.15%

3. Pharmaceutical Form

Eye gel.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of acute herpetic keratitis (dendritic and geographic ulcers).

4.2 Posology And Method Of Administration

Instil one drop of gel in the inferior conjunctival sac of the eye to be treated, 5 times a day until complete corneal re-epithelialisation. Then 3 instillations a day for 7 days after healing. The treatment does not usually exceed 21 days.

Use in the elderly:

The dosage in the elderly is the same as in adults (see above). There is no need to adjust the dosage in the elderly as in clinical trials patients up to the age of 85 years have been treated and no specific health concerns were observed.

Use in children:

VIRGAN eye gel is not recommended for use in children.

Only limited clinical trial data are available. (7 children, range 2-14 years).

4.3 Contraindications

Hypersensitivity to ganciclovir or acyclovir or to any other ingredients of the product.

4.4 Special Warnings And Precautions For Use

The following special warnings and precautions for use should be borne in mind, although systemic effects after ocular instillation are very unlikely. In preclinical testing ganciclovir given systemically caused aspermatogenesis, mutagenicity, teratogenicity, carcinogenicity and suppression of female fertility. These effects in animal studies have been observed at plasma concentrations far exceeding those being seen in humans after therapeutic use of Virgan Eye Gel (see also 5.3). However, ganciclovir should be considered a potential carcinogen and teratogen in humans.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In case of any additional local ocular treatment there should be an application interval of at least 5 minutes between the two medications. VIRGAN Eye Gel should be the last medication instilled.

Although the quantities of ganciclovir passing into the general circulation after ophthalmic use are small, the risk of drug interactions cannot be ruled out. Interactions with ganciclovir administered systemically have been observed.

Binding of ganciclovir to plasma proteins is only about 1-2% and drug interactions involving binding site displacement are not anticipated.

It is possible that drugs which inhibit replication of rapidly dividing cell populations such as bone marrow, spermatogonia and germinal layers of skin and gastrointestinal mucosa might have combined additive toxic effects when used concomitantly with, before, or after ganciclovir. Because of the possibility of additive toxicity with co-administration of drugs such as dapsone, pentamidine, flucystosine, vincristine, vinblastine, adriamycin, amphotericin B, trimethoprim/sulpha combinations or other nucleoside analogues, combination with ganciclovir therapy should be used only if the potential benefits outweigh the risks.

Since both zidovudine and ganciclovir can result in neutropenia, it is recommended that these two drugs should not be given concomitantly during induction treatment with ganciclovir. Maintenance ganciclovir treatment plus zidovudine at the recommended dose resulted in severe neutropenia in most patients studied to date.

Generalised seizures have been reported in patients taking ganciclovir and imipenem-cilastatin concomitantly.

It is also possible that probenecid, as well as other drugs which inhibit renal tubular secretion or resorption, may reduce renal clearance of ganciclovir and could increase the plasma half-life of ganciclovir.

4.6 Pregnancy And Lactation

Teratogenicity has been observed in animal studies with systemic ganciclovir. There is no experience regarding the safety of VIRGAN eye gel in human pregnancy or lactation. Administration during pregnancy and lactation is therefore not recommended, except for compelling reasons.

4.7 Effects On Ability To Drive And Use Machines

Patients should refrain from driving a vehicle or operating machines on the occurrence of any visual disturbance or other visual symptomatology.

4.8 Undesirable Effects

In some cases, adverse events which did not result in a treatment interruption were observed in relation to the use of VIRGAN eye gel; burning sensations or brief tingling sensations, superficial punctate keratitis, visual disturbance on application.

4.9 Overdose

There is practically no risk of adverse events due to accidental oral ingestion since a tube of 5g contains 7.5mg ganciclovir compared to the daily adult i.v dose of 500-1000mg.

In the unlikely event of overdose, dialysis and hydration may be of benefit in reducing drug plasma levels.

Toxic manifestations seen in animals given very high single intravenous doses of ganciclovir (500mg/kg) included emesis, hypersalivation, anorexia, bloody diarrhoea, inactivity, cytopenia, abnormal liver function tests and BUN, testicular atrophy and death.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

VIRGAN^®is a formulation of 0.15% ganciclovir in a transparent aqueous gel with a hydrophilic polymer base.

Ganciclovir, 9-(1,3-dihydroxy-2-propoxymethyl)guanine or DHPG, is a broad-spectrum virustatic agent which inhibits the replication of viruses, including viruses of the herpes group, both in vivo and in vitro: herpes simplex types 1 and 2 (HSV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes zoster (HZV).

The mean effective dose (ED50) in vitro of ganciclovir on ocular clinical isolates of the herpes simplex virus is on average 0.23μg/ml (0.06 - 0.50). Ganciclovir inhibits in vitro the replication of various adenovirus serotypes. The ED50 is 1.8 to 4.0μg/ml for Ad 8 and Ad 19, those most frequently seen in ophthalmology.

Herpetic viruses induce one or more cellular kinases in the host cells, which phosphorylise the ganciclovir into its triphosphate derivative. This phosphorylation is carried out mainly in infected cells, as the concentrations of ganciclovir-triphosphate in non-infected cells are 10 times lower.

Ganciclovir-triphosphate works as an antiviral agent by inhibiting the synthesis of viral DNA in two ways: competitive inhibition of viral DNA-polymerases and direct incorporation into viral DNA which has the effect of stopping its elongation.

5.2 Pharmacokinetic Properties

Studies of ocular pharmacokinetics in rabbits have shown a rapid and relevant penetration of ganciclovir into the cornea and the anterior segment of the eye, allowing concentrations higher than the effective antiviral concentrations over several hours. In fact, after instillation of one drop of ganciclovir gel, the concentrations (Cmax) of ganciclovir measured in the cornea (17μg/g), the conjunctiva (160μg/g), the aqueous humour (1μg/g) and the iris/ciliary body (4μg/g), are higher than the inhibitory concentrations for herpes simplex viruses 1 and 2 (<0.5μg/ml) over more than 4 hours.

The repeated instillation 4 times a day for 12 days in rabbits with herpetic keratitis does not result in an accumulation of ganciclovir in the plasma.

In man, after daily ocular instillations repeated 5 times a day for 11 to 15

days in the course of treatment of superficial herpetic keratitis, plasma levels determined by means of a precise analytical method (quantification

limit: 0.005μg/ml) are very low: on average 0.013μg/ml (0 - 0.037) which is

640 times lower than levels following a one hour i.v infusion of 5mg/kg

(Cmax=8.0μg/ml). The oral bioavailability of ganciclovir is approximately

6% when taken with food. Ganciclovir has a half life of 2.9 hours, the

systemic clearance is 3.64ml/min/kg and the major route of excretion of

ganciclovir is via glomerular filtration of unchanged drug.

5.3 Preclinical Safety Data

Animal data indicate that a side-effect of systemic ganciclovir is inhibition of spermatogenesis which is reversible at lower doses and irreversible at higher doses. Animal data have also indicated that permanent suppression of fertility in women may occur.

Ganciclovir had no effect on developing mouse foetuses at daily intravenous doses of 36mg/kg, but caused maternal/foetal toxicity and embryo death at daily doses of 108mg/kg. In rabbits, ganciclovir had no effect on developing foetuses at daily intravenous doses of 6mg/kg, but caused foetal growth retardation, embryo death, teratogenicity and/or maternal toxicity at daily doses of 20 or 60mg/kg.

Ganciclovir did not cause point mutations in bacterial or yeast cells or dominant lethality in mice, but caused point mutations and chromosomal damage in mammalian cells in vitro and in vivo. Ganciclovir was positive in these tests at thousands of times the concentration in plasma of patients undergoing therapy with VIRGAN eye gel.

Ganciclovir was carcinogenic in the mouse after daily oral doses of 20 and 1000mg/kg/day. No carcinogenic effect occurred at the dose of 1mg/kg/day. Tumour incidence was slightly increased at plasma levels of ganciclovir approximately 50 times human levels following VIRGAN eye gel treatment.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Benzalkonium chloride, Carbomer 974P, Sorbitol, Sodium hydroxide

Purified water

6.2 Incompatibilities

None known to date.

6.3 Shelf Life

In the unopened container: 3 years.

In the opened container: 4 weeks.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

5g tube (polyethylene-aluminium) with dropper nozzle (polyethylene) and screw cap (polyethylene) fitted with a detachable plastic base. This base allows the tube to be placed vertically, with the dropper nozzle pointing downwards, thus avoiding an accumulation of air around the opening, which would inhibit the correct formation of drops.

6.6 Special Precautions For Disposal And Other Handling

The package remains sterile until the original closure is broken. Do not use

VIRGAN eye gel for more than 28 days after first opening.

Administrative Data

7. Marketing Authorisation Holder

Chauvin Pharmaceuticals Ltd

Ashton Road

Harold Hill

Romford

Essex

RM3 8SL

United Kingdom

8. Marketing Authorisation Number(S)

PL 00033/0158

9. Date Of First Authorisation/Renewal Of The Authorisation

21 July 2000

10. Date Of Revision Of The Text

February 2002

Viramune 50mg / 5ml oral Suspension

Viramune 50 mg/5 ml oral suspension

nevirapine

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 further questions, please 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 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 VIRAMUNE is and what it is used for


• 2. Before you take VIRAMUNE


• 3. How to take VIRAMUNE


• 4. Possible side effects


• 5 How to store VIRAMUNE


• 6. Further information

What Viramune Is And What It Is Used For

VIRAMUNE belongs to a group of medicines called antiretrovirals, used in the treatment of Human Immunodeficiency Virus (HIV-1) infection.

The active ingredient of your medicine is called nevirapine. The active ingredient is the substance in this medicine that reduces the amount of viruses in the blood thus improving your medical condition. Nevirapine belongs to a class of anti-HIV medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs). Reverse transcriptase is an enzyme that HIV needs in order to multiply. Nevirapine stops reverse transcriptase from working. By stopping reverse transcriptase from working, VIRAMUNE helps control HIV-1 infection.

You must take VIRAMUNE together with other antiretroviral medicines. Your doctor will recommend the best medicines for you.

If Viramune has been prescribed for your child, please note that all information in this leaflet is addressed to your child (in this case please read “your child” instead of “you”).

Before You Take Viramune

Do not take VIRAMUNE

• if you are allergic (hypersensitive) to nevirapine or any of the other ingredients of VIRAMUNE See Section 6 of this leaflet for a list of other ingredients (“What VIRAMUNE contains”).


• if you have taken VIRAMUNE before and had to stop the treatment because you suffered from:
  
  
  • severe skin rash
  • skin rash with other symptoms for example:
    
    
    • fever
    • blistering
    • mouth sores
    • inflammation of the eye
    • swelling of the face
    • general swelling
    • shortness of breath
    • muscle or joint pain
    • general feelings of illness
    • abdominal pain
  • hypersensitivity (allergic) reactions
  • inflammation of the liver (hepatitis)


• if you have severe liver disease


• if you have had to stop VIRAMUNE treatment in the past because of changes in your liver function


• if you are taking a medicine containing the herbal substance St John’s Wort (Hypericum perforatum). This herbal substance may stop VIRAMUNE from working properly.

Take special care with VIRAMUNE

During the first 18 weeks of treatment with VIRAMUNE it is very important that you and your doctor watch out for signs of liver or skin reactions. These can become severe and even life threatening. You are at greatest risk of such a reaction during the first 6 weeks of treatment.

If you experience severe rash or hypersensitivity (allergic reactions that may appear in the form of rash) accompanied by other side effects such as

• 
  fever,
  


• 
  blistering,
  


• 
  mouth sores,
  


• 
  inflammation of the eye,
  


• 
  swelling of the face,
  


• 
  general swelling,
  


• 
  shortness of breath,
  


• 
  muscle or joint pain,
  


• 
  general feelings of illness,
  


• 
  or abdominal pain
  

YOU SHOULD DISCONTINUE TAKING VIRAMUNE AND YOU MUST CONTACT your doctor IMMEDIATELY as such reactions can be potentially life-threatening or lead to death.

If you ever have only mild rash symptoms without any other reaction please inform your doctor immediately, who will advise you whether you should stop taking VIRAMUNE.

If you experience symptoms suggesting damage of the liver, such as

• 
  loss of appetite,
  


• 
  feeling sick (nausea),
  


• 
  vomiting,
  


• 
  yellow skin (jaundice),
  


• 
  abdominal pain
  

you should discontinue taking VIRAMUNE and must contact your doctor immediately.

If you develop severe liver, skin or hypersensitivity reactions whilst taking VIRAMUNE, NEVER TAKE VIRAMUNE again without referring to your doctor.

You must take the dosage of Viramune as prescribed by your doctor. This is especially important within the first 14 days of treatment (see more information in “How to take VIRAMUNE”).

The following patients are at increased risk of developing liver problems:

• women


• infected with hepatitis B or C


• abnormal liver function tests


• higher CD4 cell counts at start of Viramune therapy (women more than 250 cells per cubic millimetre, men more than 400 cells per cubic millimetre)
  
  

In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection (AIDS-defining illness), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body’s immune response, enabling the body to fight infections that may have been present with no obvious symptoms. If you notice any symptoms of infection, please inform your doctor immediately.

Changes of body fat may occur in patients receiving combination antiretroviral therapy. Contact your doctor if you notice changes in body fat (see section 4 “POSSIBLE SIDE EFFECTS”).

Some patients taking combination antiretroviral therapy may develop a bone disease called osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). The length of combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe weakness of the immune system and higher body mass index may be some of the many risk factors for developing this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty in movement. If you notice any of these symptoms please inform your doctor.

VIRAMUNE is not a cure for HIV infection. Therefore, you may continue to develop infections and other illnesses associated with HIV infection. You should, therefore, remain in regular contact with your doctor. In addition, VIRAMUNE does not prevent the risk of passing on HIV to others through blood or sexual contact. Use appropriate precautions to prevent passing on HIV to other people. Please refer to your doctor.

Use in children:

VIRAMUNE oral suspension can be taken by children of all age groups. Always follow the exact instructions given by your child’s doctor.

VIRAMUNE is also available as tablets. VIRAMUNE tablets can be taken by:

• children 16 years of age or older


• children under 16 years of age who:
  
  
  • weigh 50 kg or more
  • or have a body surface area above 1.25 square meters.

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. Inform your doctor about all other medicines you are taking before you start taking VIRAMUNE. Your doctor might need to monitor whether your other medicines are still working and adjust doses. Carefully read the package leaflet of all other HIV medicinal products you are taking in combination with VIRAMUNE.

It is particularly important that you tell your doctor if you are taking or have recently taken:

• St John’s Wort (Hypericum perforatum, medicine to treat depression)


• rifampicin (medicine to treat tuberculosis)


• rifabutin (medicine to treat tuberculosis)


• macrolides e.g. clarithromycin (medicine to treat bacterial infections)


• fluconazole (medicine to treat fungal infections)


• ketoconazole (medicine to treat fungal infections)


• itraconazole (medicine to treat fungal infections)


• methadone (medicine used for treatment of opiate addicts)


• warfarin (medicine to reduce blood clotting)


• hormonal contraceptives (e.g. the “pill”)


• atazanavir (another medicine to treat HIV-infection)


• lopinavir/ritonavir (another medicine to treat HIV-infection)


• fosamprenavir (another medicine to treat HIV-infection)


• efavirenz (another medicine to treat HIV-infection)

Your doctor will carefully monitor the effect of VIRAMUNE and any of these medicines if you are taking them together.

If you are undergoing kidney dialysis, your doctor may consider a dose adjustment of VIRAMUNE. This is because VIRAMUNE can be partly washed out of your blood by dialysis.

Taking VIRAMUNE with food and drink

There are no restrictions on taking VIRAMUNE with food and drink.

Pregnancy and breast-feeding

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

You should stop breast-feeding if you are taking VIRAMUNE. It is in general recommended that you do not breast-feed if you have HIV infection because it is possible that your baby can become infected with HIV through your breast milk.

Driving and using machines

There are no specific studies on the ability to drive vehicles and use machinery. If you feel that your ability to drive or use machines may be affected you should not drive or use machines.

Important information about some of the ingredients of VIRAMUNE

VIRAMUNE oral suspension contains 150 mg sucrose and 162 mg sorbitol per ml of VIRAMUNE oral suspension. This should be taken into account in patients with diabetes mellitus. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

VIRAMUNE oral suspension contains methyl parahydroxybenzoate and propyl parahydroxybenzoate. These ingredients can cause allergic reactions over time.

How To Take Viramune

You should not use VIRAMUNE on its own. You must take it with at least two other antiretroviral medicines. Your doctor will recommend the best medicines for you.

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

VIRAMUNE oral suspension is in a liquid suspension form and should only be taken by mouth. Shake the bottle well before you take your medicine.

The usual dose is the same for all adults (20 ml).

Your child’s doctor will calculate the dose for your child.

The calculation will include your child’s age and bodyweight, or body surface area. Make sure that your child’s doctor clearly tells you what dose you must give to your child.

Measure the exact dose using the measuring syringe and adapter supplied as follows:

• 1. Shake the bottle gently.


• 2. Open the bottle.


• 3. Fit the plastic adapter onto the open bottle neck by first pressing and then screwing the adapter. Make sure that the adapter is fitted tightly.


• 4. Insert the syringe into the adapter. Make sure that the syringe is tightly inserted.


• 5. Turn the bottle upside down and gently draw out the required amount of VIRAMUNE oral suspension.


• 6. The most that you can withdraw is 5 ml at a time. If you need a higher dose, repeat steps 4-5 above.

The bottle can be kept sealed with the lid of the plastic adapter.

If you are an adult and choose to use another measuring device (e.g. cup or teaspoon) please make sure that you take the whole dose. This is because some VIRAMUNE can remain in the cup or spoon.

For adults

The dose for adults is 20 ml (200 mg) once a day for the first 14 days of treatment (“lead in” period). After 14 days, the usual dose is 20 ml (200 mg) twice a day.

It is very important that you take only 20 ml of VIRAMUNE a day for the first 14 days (“lead-in” period). If you have any rash during this period, do not increase the dose but consult your doctor.

VIRAMUNE is also available as 200 mg tablets for adults (16 years of age and older).

For children

The dose for children is 4 mg/kg bodyweight or 150 milligrams per square metre body surface area once a day for the first 14 days of treatment (“lead-in period”). Thereafter your child will be switched to a twice daily dosing schedule and your child’s doctor will decide the right dose based either on your child’s weight or body surface area.

It is very important that your child takes VIRAMUNE only once a day for the first 14 days (“lead-in” period). If your child develops any rash during this period, do not increase the dose but consult your child’s doctor.

VIRAMUNE is also available as 200 mg tablets for older children, particularly adolescents, weighing more than 50 kg or having a body surface area of more than 1.25 square metres. Your child’s doctor will inform you exactly of the correct dose for your child. Your child’s doctor will continually check your child’s weight or body surface area to ensure the correct dose.

If you are uncertain please be sure to ask your child’s doctor or pharmacist.

The 14-day ”lead-in” period has been shown to lower the risk of skin rash.

As VIRAMUNE must always be taken together with other HIV antiretroviral medicines, you should follow the instructions for your other medicines carefully. These are supplied in the package leaflets for those medicines.

You should continue to take VIRAMUNE for as long as instructed by your doctor.

As explained in ‘Take special care with VIRAMUNE’, above, your doctor will monitor you with liver tests or for undesirable effects such as rash. Depending on the outcome your doctor may decide to interrupt or stop VIRAMUNE treatment. Your doctor might then decide to restart you on a lower dose.

If you take more VIRAMUNE than you should

Do not take more VIRAMUNE than prescribed by your doctor and described in this leaflet. There is at present little information on the effects of VIRAMUNE overdose. Consult your doctor if you have taken more VIRAMUNE than you should.

If you forget to take VIRAMUNE

Try not to miss a dose. If you notice that you have missed a dose within 8 hours, take the next dose as soon as possible.

If you notice it more than 8 hours later, take the next dose at the usual time.

If you stop taking VIRAMUNE

Taking all doses at the appropriate times:

• greatly increases the effectiveness of your combination antiretroviral medicines


• reduces the chances of your HIV infection becoming resistant to your antiretroviral medicines.

It is important that you continue taking VIRAMUNE correctly, as described above, unless your doctor instructs you to stop.

If you stop taking VIRAMUNE for more than 7 days your doctor will instruct you to start the 14-day ‘lead in’ period (described above) once again, before returning to the twice daily dose.

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

Possible Side Effects

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

As mentioned in ‘Take special care with VIRAMUNE’, above, the most important side effects of VIRAMUNE are severe and life threatening skin reactions and serious liver damage. These reactions occur mainly in the first 18 weeks of treatment with VIRAMUNE. This is therefore an important period which requires close monitoring by your doctor.

If you ever observe any rash symptoms, inform your doctor immediately.

When rash occurs it is normally mild to moderate. However, in some patients a rash, which appears as a blistering skin reaction, can be severe or life-threatening (Stevens-Johnson syndrome and toxic epidermal necrolysis) and deaths have been recorded. Most of the cases of both severe rash and mild/moderate rash occur in the first six weeks of treatment.

If rash occurs and you also feel sick, you must stop treatment and visit your doctor immediately. Pay special attention to any rashes that your child develops. Although these may appear normal (for example nappy rash), they might be rashes due to VIRAMUNE. If in doubt ask your child’s doctor.

Hypersensitivity (allergic) reactions can occur. Such reactions may appear in the form of anaphylaxis (a severe form of allergic reaction) with symptoms such as:

• rash


• swelling of the face


• difficulty breathing (bronchial spasm),


• anaphylactic shock

Hypersensitivity reactions can also occur as rash with other side effects such as:

• fever


• blistering of your skin


• mouth sores


• inflammation of the eye


• swelling of the face


• general swelling


• shortness of breath


• muscle or joint pain


• a reduction in the number of your white blood cells (granulocytopaenia)


• general feelings of illness


• severe problems with liver or kidneys (liver or kidney failure).

Tell your doctor immediately if you experience rash and any of the other side effects of a hypersensitivity (allergic) reaction. Such reactions can be life-threatening.

Abnormal liver functioning has been reported with the use of VIRAMUNE. This includes some cases of inflammation of the liver (hepatitis), which can be sudden and intense (fulminant hepatitis), and liver failure, which can be both fatal.

Tell your doctor if you experience any of the following clinical symptoms of liver damage:

• loss of appetite


• feeling sick (nausea)


• vomiting


• yellow skin (jaundice)


• abdominal pain.

Evaluation of the side effects is based on the following frequencies:

Very common: in at least 1 out of 10 patients treated

Common: in at least 1 out of 100 and less than 1 out 10 patients treated

Uncommon: in at least 1 out of 1000 and less than 1 out 100 patients treated

Rare: in at least 1 out of 10,000 and less than 1 out 1000 patients treated

The side effects described below have been experienced by patients given VIRAMUNE:

Very common:

• rash

Common:

• decreased number of white blood cells (granulocytopenia)


• allergic reactions (hypersensitivity)


• headache


• feeling sick (nausea)


• vomiting


• abdominal pain


• loose stools (diarrhoea)


• inflammation of the liver (hepatitis)


• muscle pain (myalgia)


• feeling tired (fatigue)


• fever


• abnormal liver function tests

Uncommon:

• decreased numbers of red blood cells (anaemia)


• yellow skin (jaundice)


• severe and life-threatening skin rashes (Stevens Johnson Syndrome/toxic epidermal necrolysis)


• hives (urticaria)


• fluid under the skin (angioneurotic oedema)


• joint pain (arthralgia)

Rare:

• sudden and intense inflammation of the liver (fulminant hepatitis)

Not Known:

• drug rash with systemic symptoms (drug rash with eosinophilia and systemic symptoms)


• allergic reaction characterised by rash, swelling of the face, difficulty breathing (bronchial spasm) or anaphylactic shock

Combination antiretroviral therapy may cause changes in body shape due to changes in fat distribution. These may include loss of fat from legs, arms and face, increased fat in the abdomen (belly) and other internal organs, breast enlargement and fatty lumps on the back of the neck (‘buffalo hump’). The cause and long-term health effects of these conditions are not known at this time. Combination antiretroviral therapy may also cause raised lactic acid and sugar in the blood, hyperlipaemia (increased fats in the blood) and resistance to insulin.

The following events have also been reported when VIRAMUNE has been used in combination with other antiretroviral agents:

• decreased numbers of red blood cells or platelets


• inflammation of the pancreas


• decrease in or abnormal skin sensations.

These events are commonly associated with other antiretroviral agents and may be expected to occur when VIRAMUNE is used in combination with other agents; however, it is unlikely that these events are due to treatment with VIRAMUNE.

Use in children

A reduction in white blood cells (granulocytopenia) can occur, which is more common in children. A reduction in red blood cells (anaemia), which may be related to nevirapine therapy, is also more commonly observed in children. As with rash symptoms, please inform your doctor of any 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 Viramune

Keep out of the reach and sight of children.

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

VIRAMUNE should be used within 6 months of opening the bottle.

This medicinal product does not require any special storage conditions.

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 VIRAMUNE contains

• The active substance is nevirapine. Each ml contains 10 mg of the active substance nevirapine (as nevirapine hemihydrate).


• The other ingredients are:
  
  
  • carbomer
  • methyl parahydroxybenzoate
  • propyl parahydroxybenzoate
  • sorbitol
  • sucrose
  • polysorbate 80
  • sodium hydroxide
  • water

What VIRAMUNE looks like and contents of pack

VIRAMUNE oral suspension is a white to off-white homogenous suspension.

VIRAMUNE oral suspension is supplied in plastic bottles of suspension for oral use, with 240 ml suspension per bottle.

A plastic measuring syringe is included for measuring the correct dose.

VIRAMUNE is also supplied as 200 mg tablets for older children and adults.

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH

Binger Strasse 173

55216 Ingelheim am Rhein

Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG

Binger Strasse 173

55216 Ingelheim am Rhein

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 05/2009

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

10004576/06

Vinorelbine 10mg / ml concentrate for solution for infusion (Actavis UK Ltd)

Vinorelbine 10mg/ml Concentrate For Solution For Infusion

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 Vinorelbine is and what it is used for


• 2. Before you use Vinorelbine


• 3. How to use Vinorelbine


• 4. Possible side effects


• 5. How to store Vinorelbine


• 6. Further information

What Vinorelbine Is And What It Is Used For

Vinorelbine is used in the treatment of cancer and belongs to a group of medicines known as Vinca alkaloids.

Vinorelbine is used to treat certain types of lung cancer and breast cancer.

Before You Use Vinorelbine

Do not use Vinorelbine

• if you are allergic (hypersensitive) to vinorelbine or other Vinca alkaloids


• if you have or recently had serious infection or severe decrease in white blood cells (neutropenia)


• if you have severe decrease in blood platelets.


• if you are pregnant


• if you are breast-feeding


• if you are a women of childbearing potential not using effective contraception


• if you have a severe liver disease not caused by cancer


• in combination with yellow fever vaccine

This medicine is strictly for intravenous use only and should not be injected into the spine.

Take special care with Vinorelbine

• if you have had a heart disease involving lack of blood supply to the heart (ischaemic heart disease, angina)


• if you are having radiotherapy and the treatment field includes the liver


• if you present signs or symptoms suggestive of infection (such as fever, chills, sore throat), let your doctor know immediately, so that he/she can carry out any tests which may be needed


• if you have impaired liver function


• if you need a vaccination. You should inform your doctor of the treatment before any vaccination.


• if you receive a cancer medicine named mitomycin C

Vinorelbine must not get into contact with the eye as there is a risk of severe irritation and even corneal ulceration. If this occurs, immediately rinse the eye with normal saline solution and contact an ophthalmologist.

Men and women who are treated with Vinorelbine should use an effective contraception during treatment. Men and women should BOTH read the information under pregnancy and breast-feeding below.

Before each administration of Vinorelbine, a blood sample will be taken for analysis of its components. If the results of this analysis are not satisfactory, your treatment may be delayed and further checks made until these values return to normal.

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 especially important if you are using any of the following medicines:

• other medicines which can affect the bone marrow e.g. cancer medicines


• carbamazepine, phenytoin and phenobarbital (medicines for the treatment of epilepsy)


• antibiotics such as rifampicin, erythromycin, clarithromycin, telithromycin


• St John’s Wort (Hypericum perforatum)


• ketoconazole and itraconazole (medicines for the treatment of fungal infections)


• antiviral medicines to treat HIV-infection e.g. ritonavir (HIV protease inhibitors).


• nefazodon (medicines for the treatment of depression)


• cyclosporine and tacrolimus (medicine which decrease the activity of the immune system)


• verapamil, quinidine (medicines for the treatment of heart diseases)


• other medicines for the treatment of cancer e.g. mitomycin C, cisplatin


• blood thinning medicines e.g. warfarin


• yellow fever vaccine and other live vaccines

Pregnancy and breast-feeding

Vinorelbine should not be given to pregnant women, because it can cause serious birth defects.

If you are a woman of childbearing age you must use an effective method of contraception during treatment. If pregnancy occurs during your treatment you must immediately inform your doctor. If you are or become pregnant during treatment with Vinorelbine, genetic counselling is recommended.

If you are a man, you should avoid fathering a child during treatment with Vinorelbine and for 6 months after treatment has stopped. There is also a risk that treatment with Vinorelbine will lead to male infertility and you may wish to seek advice about sperm storage before the treatment starts.

You must discontinue breast-feeding before treatment with Vinorelbine starts as it is not known whether it might pass into breast milk thereby affecting the baby.

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

Driving and using machines

No studies of the effects on the ability to drive and use machines have been performed.

How To Use Vinorelbine

Vinorelbine will be given to you under the supervision of a doctor specialized in this type of treatment.

The dosage depends on the condition you are being treated for, your response to the therapy and other medication you are being given. Your general condition and your response to the treatment will be closely observed before, during and after the vinorelbine treatment.

The usual dosage of vinorelbine is 25-30mg/metres squared of body surface area given once a week.

The medicine should be diluted before use with a solution of sodium chloride or glucose and given into a vein as an injection over 5-10 minutes or by infusion (drip) over 20-30 minutes. Following your treatment, a solution of sodium chloride will be used to flush the vein.

Dosage will be reduced if you have severe liver problems.

The safety and efficacy in children have not been determined.

If you use more Vinorelbine than you should

As this medicine will be given to you whilst you are in hospital it is unlikely that you will be given too little or too much, however, tell your doctor or pharmacist if you have any concerns.

Possible Side Effects

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

Frequency:

Very common: likely to affect more than 1 of every 10 people.

Common: likely to affect more than 1 of every 100 but less than 1 of every 10 people.

Uncommon: likely to affect more than 1 of every 1,000 but less than 1 of every 100 people.

Rare: likely to affect more than 1 of every 10,000 but less than 1 of every 1,000 people.

Very rare: likely to affect less than 1 of every 10,000 people.

Serious side effects – if any of the following side effects occur, immediately contact your doctor:

Common: Narrowing of the airways (bronchospasm), shortness of breath, respiratory reactions due to allergy.

Rare: Chest pain which spreads to the back of the neck and arm, due to lack of blood supply to the heart. Heart attack, lung disease.

These are very serious side effects. You may need immediate medical care.

Other side effects – if any of the following side effects occur, contact your doctor as soon as possible:

Very common: Low count of white blood cells, which may increase the risk of infection. Low count of red blood cells (anaemia), which may make you feel tired. Inflammation of the mouth or the gullet. Nausea and vomiting. Anorexia (decreased appetite), constipation, diarrhoea. Hair loss. Oedema, tenderness, pain and/or rash on the injection site. Fatigue, fever, pain, weakness, abnormal results of liver function tests, loss of deep tendon reflexes.

Common: Numbness (paraesthesia). Pain in joints and muscles. Increased creatinine values (change in renal function). Symptoms of infection e.g. fever, pain. Skin reactions. Low count of a special type of white blood cells, which can cause fever. Low count of blood platelets (risk of bleeding).

Rare: Inflammation of the pancreas, paralytic intestinal blockage (ileus). Weakness of lower extremities. Low levels of sodium in the blood. Changes in the activity of the heart (ECG changes). Jaw pain. Injection site necrosis.

Very rare: Guillain-Barrés syndrome (inflammation in peripheral nerves which may cause weakness). SIADH syndrome, which may include symptoms of increased weight, nausea (feeling sick), vomiting, muscle cramps, confusion and seizures (fits).

As changes in the blood may occur, your doctor may order blood samples to be taken to control this (low count of white blood cells, anaemia and/or low count of blood platelets, influence on the liver- or kidney function and the electrolyte balance in your body).

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 Vinorelbine

Keep out of the reach and sight of children.

Store in a refrigerator (2°C – 8°C). DO NOT FREEZE. Keep the vial in the outer carton in order to protect from light.

Do not use Vinorelbine after the expiry date which is stated on the vial label and carton.

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 Vinorelbine contains

The active substance is vinorelbine. One ml concentrate for solution for infusion contains 10 mg vinorelbine (as tartrate).

Each 1ml vial contains 10mg of vinorelbine (as tartrate).

Each 5ml vial contains 50mg of vinorelbine (as tartrate).

The other ingredient is water for injections.

What Vinorelbine looks like and contents of the pack

Vinorelbine 10mg/ml Concentrate For Solution For Infusion is a clear, colourless to slightly yellow solution.

Pack-sizes:

1 x 1ml vial

10 x 1ml vial

1 x 5ml vial

10 x 5ml vial

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Actavis Group PTC ehf.

Reykjavikurvegur 76-78

220 Hafnarfjordur

Iceland

Manufacturers

Actavis Nordic A/S

Ørnegardsvej 16

2820 Gentofte

Denmark

S.C Sindan-Pharma S.R.L.

11^th, Ion Mihalache Blvd.

Bucharest, 011171

Romania

This leaflet was last revised in October 2008

If you would like a leaflet with larger text, please contact 01271 311257.

Actavis

Barnstaple

EX32 8NS

UK

SINPL022

Vibramycin 50 CAPSULES

1. Name Of The Medicinal Product

VIBRAMYCIN 50

2. Qualitative And Quantitative Composition

Active Ingredient: doxycycline.

Vibramycin 50 Capsules contain 50mg doxycycline as doxycycline hyclate Ph. Eur.

3. Pharmaceutical Form

Vibramycin 50 capsules are green and ivory, coded 'Pfizer' and 'VBM 50'.

4. Clinical Particulars

4.1 Therapeutic Indications

Vibramycin has been found clinically effective in the treatment of a variety of infections caused by susceptible strains of Gram-positive and Gram-negative bacteria and certain other micro-organisms.

Respiratory tract infections Pneumonia and other lower respiratory tract infections due to susceptible strains of Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae and other organisms. Mycoplasma pneumoniae pneumonia. Treatment of chronic bronchitis, sinusitis.

Urinary tract infections caused by susceptible strains of Klebsiella species, Enterobacter species, Escherichia coli, Streptococcus faecalis and other organisms.

Sexually transmitted diseases Infections due to Chlamydia trachomatis including uncomplicated urethral, endocervical or rectal infections. Non-gonococcal urethritis caused by Ureaplasma urealyticum (T-mycoplasma). Vibramycin is also indicated in chancroid, granuloma inguinale and lymphogranuloma venereum. Vibramycin is an alternative drug in the treatment of gonorrhoea and syphilis.

Skin infections Acne vulgaris, when antibiotic therapy is considered necessary.

Since Vibramycin is a member of the tetracycline series of antibiotics, it may be expected to be useful in the treatment of infections which respond to other tetracyclines, such as:

Ophthalmic infections Due to susceptible strains of gonococci, staphylococci and Haemophilus influenzae. Trachoma, although the infectious agent, as judged by immunofluorescence, is not always eliminated. Inclusion conjunctivitis may be treated with oral Vibramycin alone or in combination with topical agents.

Rickettsial infections Rocky Mountain spotted fever, typhus group, Q fever, Coxiella endocarditis and tick fevers.

Other infections Psittacosis, brucellosis (in combination with streptomycin), cholera, bubonic plague, louse and tick-borne relapsing fever, tularaemia glanders, melioidosis, chloroquine-resistant falciparum malaria and acute intestinal amoebiasis (as an adjunct to amoebicides).

Vibramycin is an alternative drug in the treatment of leptospirosis, gas gangrene and tetanus.

Vibramycin is indicated for prophylaxis in the following conditions: Scrub typhus, travellers' diarrhoea (enterotoxigenic Escherichia coli), leptospirosis and malaria. Prophylaxis of malaria should be used in accordance to current guidelines, as resistance is an ever changing problem.

4.2 Posology And Method Of Administration

Adults

The usual dosage of Vibramycin for the treatment of acute infections in adults is 200mg on the first day (as a single dose or in divided doses) followed by a maintenance dose of 100mg/day. In the management of more severe infections, 200mg daily should be given throughout treatment.

Capsules are for oral administration only.

Vibramycin capsules should be administered with adequate amounts of fluid. This should be done in the sitting or standing position and well before retiring at night to reduce the risk of oesophageal irritation and ulceration. If gastric irritation occurs, it is recommended that Vibramycin be given with food or milk. Studies indicate that the absorption of Vibramycin is not notably influenced by simultaneous ingestion of food or milk.

Exceeding the recommended dosage may result in an increased incidence of side effects. Therapy should be continued for at least 24 to 48 hours after symptoms and fever have subsided.

When used in streptococcal infections, therapy should be continued for 10 days to prevent the development of rheumatic fever or glomerulonephritis.

Dosage recommendations in specific infections:

Acne vulgaris 50mg daily with food or fluid for 6 to 12 weeks.

Sexually transmitted diseases 100mg twice daily for 7 days is recommended in the following infections: uncomplicated gonococcal infections (except anorectal infections in men); uncomplicated urethral, endocervical or rectal infection caused by Chlamydia trachomatis; non-gonococcal urethritis caused by Ureaplasma urealyticum. Acute epididymo-orchitis caused by Chlamydia trachomatis or Neisseria gonorrhoea 100mg twice daily for 10 days. Primary and secondary syphilis: Non-pregnant penicillin-allergic patients who have primary or secondary syphilis can be treated with the following regimen: doxycycline 200mg orally twice daily for two weeks, as an alternative to penicillin therapy.

Louse and tick-borne relapsing fevers A single dose of 100 or 200mg according to severity.

Treatment of chloroquine-resistant falciparum malaria 200mg daily for at least 7 days. Due to the potential severity of the infection, a rapid-acting schizonticide such as quinine should always be given in conjunction with Vibramycin; quinine dosage recommendations vary in different areas.

Prophylaxis of malaria 100mg daily in adults and children over the age of 12 years. Prophylaxis can begin 1-2 days before travel to malarial areas. It should be continued daily during travel in the malarial areas and for 4 weeks after the traveller leaves the malarial area. For current advice on geographical resistance patterns and appropriate chemoprophylaxis, current guidelines or the Malaria Reference Laboratory should be consulted, details of which can be found in the British National Formulary (BNF).

For the prevention of scrub typhus 200mg as a single dose.

For the prevention of travellers' diarrhoea in adults 200mg on the first day of travel (administered as a single dose or as 100mg every 12 hours) followed by 100mg daily throughout the stay in the area. Data on the use of the drug prophylactically are not available beyond 21 days.

For the prevention of leptospirosis 200mg once each week throughout the stay in the area and 200mg at the completion of the trip. Data on the use of the drug prophylactically are not available beyond 21 days.

Use for children See under “Contra-indications”.

Use in the elderly Vibramycin may be prescribed in the elderly in the usual dosages with no special precautions. No dosage adjustment is necessary in the presence of renal impairment.

Use in patients with impaired hepatic function See under “Special warnings and precautions for use”.

Use in patients with renal impairment Studies to date have indicated that administration of Vibramycin at the usual recommended doses does not lead to accumulation of the antibiotic in patients with renal impairment see under “ Special warnings and precautions for use”.

4.3 Contraindications

Persons who have shown hypersensitivity to doxycycline, any of its inert ingredients or to any of the tetracyclines.

The use of drugs of the tetracycline class during tooth development (pregnancy, infancy and childhood to the age of 12 years) may cause permanent discolouration of the teeth (yellow-grey-brown). This adverse reaction is more common during long-term use of the drugs but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Vibramycin is therefore contra-indicated in these groups of patients.

Pregnancy Vibramycin is contra-indicated in pregnancy. It appears that the risks associated with the use of tetracyclines during pregnancy are predominantly due to effects on teeth and skeletal development. (See above about use during tooth development).

Nursing mothers Tetracyclines are excreted into milk and are therefore contra-indicated in nursing mothers. (See above about use during tooth development).

Children Vibramycin is contra-indicated in children under the age of 12 years. As with other tetracyclines, Vibramycin forms a stable calcium complex in any bone-forming tissue. A decrease in the fibula growth rate has been observed in prematures given oral tetracyclines in doses of 25mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. (See above about use during tooth development).

4.4 Special Warnings And Precautions For Use

Use in patients with impaired hepatic function Vibramycin should be administered with caution to patients with hepatic impairment or those receiving potentially hepatotoxic drugs.

Abnormal hepatic function has been reported rarely and has been caused by both the oral and parenteral administration of tetracyclines, including doxycycline.

Use in patients with renal impairment Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with normal renal function. This percentage excretion may fall to a range as low as 1-5%/72 hours in individuals with severe renal insufficiency (creatinine clearance below 10ml/min). Studies have shown no significant difference in the serum half-life of doxycycline in individuals with normal and severely impaired renal function. Haemodialysis does not alter the serum half-life of doxycycline. The anti-anabolic action of the tetracyclines may cause an increase in blood urea. Studies to date indicate that this anti-anabolic effect does not occur with the use of Vibramycin in patients with impaired renal function.

Photosensitivity Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines, including doxycycline. Patients likely to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs and treatment should be discontinued at the first evidence of skin erythema.

Microbiological overgrowth The use of antibiotics may occasionally result in the overgrowth of non-susceptible organisms including Candida. If a resistant organism appears, the antibiotic should be discontinued and appropriate therapy instituted.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including doxycycline, and has ranged in severity from mild to life-threatening. It is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of antibacterial agents.

Oesophagitis Instances of oesophagitis and oesophageal ulcerations have been reported in patients receiving capsule and tablet forms of drugs in the tetracycline class, including doxycycline. Most of these patients took medications immediately before going to bed or with inadequate amounts of fluid.

Bulging fontanelles in infants and benign intracranial hypertension in juveniles and adults have been reported in individuals receiving full therapeutic dosages. These conditions disappeared rapidly when the drug was discontinued.

Porphyria There have been rare reports of porphyria in patients receiving tetracyclines.

Venereal disease When treating venereal disease, where co-existent syphilis is suspected, proper diagnostic procedures including dark-field examinations should be utilised. In all such cases monthly serological tests should be made for at least four months.

Beta-haemolytic streptococci infections Infections due to group A beta-haemolytic streptococci should be treated for at least 10 days.

Myasthenia gravis Due to a potential for weak neuromuscular blockade, care should be taken in administering tetracyclines to patients with myasthenia gravis.

Systemic lupus erythematosus Tetracyclines can cause exacerbation of SLE.

Methoxyflurane Caution is advised in administering tetracyclines with methoxyflurane. See section 4.5.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The absorption of doxycycline may be impaired by concurrently administered antacids containing aluminium, calcium, magnesium or other drugs containing these cations; oral zinc, iron salts or bismuth preparations. Dosages should be maximally separated.

Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving Vibramycin in conjunction with penicillin.

There have been reports of prolonged prothrombin time in patients taking warfarin and doxycycline. Tetracyclines depress plasma prothrombin activity and reduced doses of concomitant anticoagulants may be necessary.

The serum half-life of doxycycline may be shortened when patients are concurrently receiving barbiturates, carbamazepine or phenytoin. An increase in the daily dosage of Vibramycin should be considered.

Alcohol may decrease the half-life of doxycycline.

A few cases of pregnancy or breakthrough bleeding have been attributed to the concurrent use of tetracycline antibiotics with oral contraceptives.

Doxycycline may increase the plasma concentration of cyclosporin. Co-administration should only be undertaken with appropriate monitoring.

The concurrent use of tetracyclines and methoxyflurane has been reported to result in fatal renal toxicity. See section 4.4

Laboratory test interactions

False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.

4.6 Pregnancy And Lactation

See “Contra-indications”.

4.7 Effects On Ability To Drive And Use Machines

The effect of doxycycline on the ability to drive or operate heavy machinery has not been studied. There is no evidence to suggest that doxycycline may affect these abilities.

4.8 Undesirable Effects

The following adverse reactions have been observed in patients receiving tetracyclines, including doxycycline.

Autonomic nervous system Flushing.

Body as a whole Hypersensitivity reactions, including anaphylactic shock, anaphylaxis, anaphylactoid reaction, anaphylactoid purpura, hypotension, pericarditis, angioneurotic oedema, exacerbation of systemic lupus erythematosus, dyspnoea, serum sickness, peripheral oedema, tachycardia and urticaria.

Central and Peripheral nervous system Headache. Bulging fontanelles in infants and benign intracranial hypertension in juveniles and adults have been reported in individuals receiving full therapeutic dosages of tetracyclines. In relation to benign intracranial hypertension, symptoms included blurring of vision, scotomata and diplopia. Permanent visual loss has been reported.

Gastro-intestinal Gastro-intestinal symptoms are usually mild and seldom necessitate discontinuation of treatment. Abdominal pain, anorexia, nausea, vomiting, diarrhoea, dyspepsia and rarely dysphagia. Oesophagitis and oesophageal ulceration have been reported in patients receiving Vibramycin. A significant proportion of these occurred with the hyclate salt in the capsule form. (See 'Special warnings and precautions for use' section).

Hearing/Vestibular Tinnitus.

Haemopoietic Haemolytic anaemia, thrombocytopenia, neutropenia, porphyria, and eosinophilia have been reported with tetracyclines.

Liver/Biliary Transient increases in liver function tests, hepatitis, jaundice, hepatic failure and pancreatitis have been reported rarely.

Musculo-Skeletal Arthralgia and myalgia.

Skin Rashes including maculopapular and erythematous rashes, exfoliative dermatitis, erythema multiforme, Steven-Johnson syndrome and toxic epidermal necrolysis. Photosensitivity skin reactions (see 'Special warnings and precautions for use' section).

Superinfection As with all antibiotics, overgrowth of non-susceptible organisms may cause candidiasis, glossitis, staphylococcal enterocolitis, pseudomembranous colitis (with Clostridium difficile overgrowth) and inflammatory lesions (with candidal overgrowth) in the anogenital region. Similarly there have been reports for products in the tetracycline class of stomatitis and vaginitis.

Urinary system Increased blood urea. (See 'Special warnings and precautions for use' section.)

Other When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discolouration of thyroid tissue. No abnormalities of thyroid function are known to occur.

Tetracyclines may cause discoloration of teeth and enamel hypoplasia, but usually only after long-term use.

4.9 Overdose

Acute overdosage with antibiotics is rare. In the event of overdosage discontinue medication. Gastric lavage plus appropriate supportive treatment is indicated.

Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Vibramycin is primarily bacteriostatic and is believed to exert its antimicrobial effect by the inhibition of protein synthesis. Vibramycin is active against a wide range of Gram-positive and Gram-negative bacteria and certain other micro-organisms.

5.2 Pharmacokinetic Properties

Tetracyclines are readily absorbed and are bound to plasma proteins in varying degrees. They are concentrated by the liver in the bile and excreted in the urine and faeces at high concentrations and in a biologically active form. Doxycycline is virtually completely absorbed after oral administration. Studies reported to date indicate that the absorption of doxycycline, unlike certain other tetracyclines, is not notably influenced by the ingestion of food or milk. Following a 200mg dose, normal adult volunteers averaged peak serum levels of 2.6 micrograms/ml of doxycycline at 2 hours decreasing to 1.45 micrograms/ml at 24 hours. Doxycycline has a high degree of lipid solubility and a low affinity for calcium. It is highly stable in normal human serum. Doxycycline will not degrade into an epianhydro form.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Vibramycin 50mg capsules: Maize Starch Ph.Eur., Lactose Ph.Eur., alginic acid, Magnesium Stearate NF, Sodium Lauryl Sulphate Ph Eur. In addition the capsule shell cap contains: Gelatin BP, titanium dioxide (E171), patent blue V (E131) and quinoline yellow (E104) and the body contains yellow iron oxide (E172), indigotine (E132) and titanium dioxide (E171).

6.2 Incompatibilities

None stated.

6.3 Shelf Life

Vibramycin 50mg capsules 48 months.

6.4 Special Precautions For Storage

Store below 25°C.

6.5 Nature And Contents Of Container

Vibramycin 50 Capsules 50mg are available as:

Calendar Packs of 28 Capsules. Aluminium/PVC blister strips, 14 capsules per strip, 2 strips in a carton box.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Pfizer Limited

Ramsgate Road

Sandwich

Kent CT13 9NJ

United Kingdom

8. Marketing Authorisation Number(S)

Vibramycin Capsules 50mg

0057/0238

9. Date Of First Authorisation/Renewal Of The Authorisation

Vibramycin Capsules 50mg

29/10/00

10. Date Of Revision Of The Text

May 2008

Legal Category

POM

Ref: VM 9_0

Visken Tablets 5 mg

1. Name Of The Medicinal Product

Visken Tablets 5 mg

2. Qualitative And Quantitative Composition

Each tablet contains 5 mg pindolol.

3. Pharmaceutical Form

Tablet.

4. Clinical Particulars

4.1 Therapeutic Indications

Essential hypertension: For reduction in blood pressure in essential hypertension. Onset of action of Visken is usually rapid, most patients showing a response within the first one to two weeks of treatment. However, maximum response may take several weeks to develop.

Prophylactic treatment of angina pectoris: Prophylactic treatment with Visken reduces the frequency and severity of anginal attacks and increases work capacity.

4.2 Posology And Method Of Administration

Adults

Hypertension: Initially one 5 mg tablet two or three times a day. According to the response of the patient the dose may be increased at weekly intervals to a maximum of 45 mg given in divided doses twice or three times daily.

Once daily dosage schedule: Further work shows that many patients respond to a once daily dosage regime. Initially 15 mg (3 tablets) should be taken once a day with breakfast and adjusted according to individual response up to a maximum of 45 mg (9 tablets). Most patients respond to a once daily dose of between 15-30 mg (3-6 tablets).

Angina pectoris: Usually 2.5 mg to 5 mg orally three times a day according to response.

Use in children

Experience with Visken in children is limited. Its use is therefore not recommended.

Use in the elderly

No evidence exists that elderly patients require different dosages or show different side-effects from younger patients.

Route of administration

Oral.

4.3 Contraindications

Untreated cardiac failure, cardiogenic shock, sick sinus syndrome, second and third degree heart block, Prinzmetals angina, history of bronchospasm and bronchial asthma (a warning stating "do not take this medicine if you have a history of wheezing or asthma" will appear on the label), untreated phaeochromocytoma, peripheral circulatory disease, pronounced bradycardia, obstructive pulmonary disease, history of cor pulmonale, metabolic acidosis, prolonged fasting, severe renal failure. Visken should not be taken in conjunction with agents which inhibit calcium transport e.g. verapamil.

4.4 Special Warnings And Precautions For Use

Patients with a poor cardiac reserve should be stabilised with digitalis before treatment with Visken to prevent impairment of myocardial contractility.

As for other beta-blockers, and especially in patients with ischaemic heart disease, treatment should not be discontinued suddenly. The dosage should gradually be reduced, i.e. over 1-2 weeks, if necessary at the same time initiating replacement therapy, to prevent exacerbation of angina pectoris.

As with all beta-blockers, Visken should be used with caution in patients with a history of non-asthmatic chronic obstructive lung disease or recent myocardial infarction. Caution must be exercised when beta-blocking agents are administered to patients with spontaneous hypoglycaemia or diabetes under treatment with insulin or oral hypoglycaemic agents, since hypoglycaemia may occur during prolonged fasting and some of its symptoms (tachycardia, tremor) may be masked. Beta-blockers may also mask the symptoms of thyrotoxicosis.

During treatment with Visken, patients should not undergo anaesthesia with agents causing myocardial depression (e.g. halothane, cyclopropane, trichloroethylene, ether, chloroform). Visken should be gradually withdrawn before elective surgery. In emergency surgery or cases where withdrawal of Visken would cause deterioration in cardiac condition, atropine sulphate 1 to 2 mg intravenously should be given to prevent severe bradycardia.

If a beta-blocker is indicated in a patient with phaeochromocytoma it must always be given in conjunction with an alpha-blocker. Pre-existing peripheral vascular disorders may be aggravated by beta-blockers.

In severe renal failure a further impairment of renal function following beta blockade has been reported in a few cases.

There have been reports of skin rashes and/or dry eyes associated with the use of beta-adrenoceptor blocking drugs. The reported incidence is small and in most cases the symptoms have cleared when treatment is withdrawn. Discontinuance of the drug should be considered if any such reaction is not otherwise explicable.

Cessation of therapy with a beta-blocker should be gradual.

Patients with known psoriasis should take beta-blockers only after careful consideration.

Beta-blockers may increase both the sensitivity towards allergens and the seriousness of anaphylactic reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Calcium-channel blocking agents: Visken should not be used with calcium-channel blockers with negative inotropic effects e.g. verapamil and to a lesser extent diltiazem. The concomitant use of oral beta-blockers and calcium antagonists of the dihydropyridine type can be useful in hypertension or angina pectoris. However, because of their potential effect on the cardiac conduction system and contractility, the i.v. route must be avoided. The concomitant use with dihydropyridines e.g. nifedipine may increase the risk of hypotension. In patients with cardiac insufficiency, treatment with beta-blocking agents may lead to cardiac failure.

Use of digitalis glycosides, in association with beta-adrenoceptor blocking drugs, may increase atrio-ventricular conduction time.

Clonidine: when therapy is discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blockers should be gradually discontinued several days before clonidine is discontinued, in order to reduce the potential risk of a clonidine withdrawal hypertensive crisis.

MAO inhibitors: concurrent use with beta-blockers is not recommended. Possibly significant hypertension may theoretically occur up to 14 days following discontinuation of the MAO inhibitor.

Caution should be exercised in the concurrent use of beta-blocking agents with class 1 antiarrhythmics (e.g. disopyramide, quinidine) and amiodarone.

Concomitant use of beta-blockers may intensify the blood sugar lowering effect of insulin and other antidiabetic drugs. Use of beta-blockers may prevent appearance of the signs of hypocalcaemia (tachycardia).

Cimetidine, hydralazine and alcohol may induce increased plasma levels of hepatically metabolised beta-blockers.

Prostaglandin synthetase inhibiting drugs may decrease the hypotensive effects of beta-blockers.

Sympathomimetics with beta-adrenergic stimulant activity and xanthines: concurrent use with beta-blockers may result in mutual inhibition of therapeutic effects; in addition, beta-blockers may decrease theophylline clearance.

Concomitant use of beta-blockers with tricyclic antidepressants, barbiturates and phenothiazines as well as other anti-hypertensive agents may increase the blood pressure lowering effect.

Reserpine: concurrent use may result in an additive and possibly excessive beta-adrenergic blockade.

4.6 Pregnancy And Lactation

Visken is contraindicated in pregnancy and passes in small quantities into breast milk. Breastfeeding is therefore not recommended following administration.

4.7 Effects On Ability To Drive And Use Machines

Because dizziness or fatigue may occur during initiation of treatment with beta-adrenoceptor blocking drugs, patients driving vehicles or operating machinery should exercise caution until their individual reaction to treatment has been determined.

4.8 Undesirable Effects

Bradycardia, a slowed AV-conduction or increase of an existing AV-block, hypotension, heart failure, cold and cyanotic extremities, Raynaud's phenomenon, paraesthesia of the extremities, increase of an existing intermittent claudication. Fatigue, headaches, impaired vision, hallucinations, psychoses, confusion, impotence, dizziness, sleep disturbances, depression, nightmares. Gastrointestinal disturbances (including diarrhoea, nausea and vomiting). Bronchospasm in patients with bronchial asthma or a history of asthmatic complaints. Disorder of the skin, especially rash. Dry eyes. Beta-blockers may mask the symptoms of thyrotoxicosis or hypoglycaemia. An increase in ANA (anti-nuclear antibodies) has been seen; its clinical relevance is not clear.

4.9 Overdose

Treat by elimination of any unabsorbed drug and general supportive measures. Marked bradycardia as a result of overdosage or idiosyncrasy should be treated with atropine sulphate 1 or 2 mg intravenously. If necessary, isoprenaline hydrochloride can be administered by a slow intravenous injection, under constant supervision, beginning with 25 mcg (5 mcg/min) until the desired effect is achieved. A cardiac pacemaker may be required, i.v. glucagon (5-10 mg) has been reported to overcome some of the features of serious overdosage and may be useful.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Visken is a potent beta-adrenoceptor antagonist (beta-blocker). It blocks both B- and B2-adrenoceptors for more than 24 hours after administration. It has negligible membrane-stabilising activity. As a beta-blocker, Visken protects the heart from beta-adrenoceptor stimulation by acetecholamines during physical exercise and mental stress, and also reduces the sympathetic drive to the heart at rest. Its intrinsic sympathomimetic activity (ISA), however, provides the heart with basal stimulation similar to that elicited by normal resting sympathetic activity, with the result that heart rate and contractility at rest and intracardiac conduction are not unduly depressed. The risk of bradycardia is therefore small and normal cardiac output is not reduced.

Visken is a beta-blocker with clinically relevant vasodilator activity. This results from the ISA exerted on B2-adrenoceptors in blood vessels. The high vascular resistance of established hypertension is lowered by Visken; tissue and organ perfusion is not impaired, and may even be improved.

In contrast to the potentially adverse changes in blood lipoprotein profiles seen during treatment with other beta-blockers (a decrease in the HDL/LDL ratio), the ratio of high density lipoproteins (HDL) to low density (for further information see product licence file).

5.2 Pharmacokinetic Properties

The rapid, nearly complete absorption ( >95%) and the negligible hepatic first-pass effect (13%) of Visken result in a high bioavailability (87%). Maximum plasma concentration is reached within one hour after oral administration. Visken has a plasma protein binding of 40%, a volume of distribution of 2-3 l/Kg and a total clearance of 500 ml/min. The elimination half-life of Visken is 3-4 hours. 30-40% is excreted unchanged in the urine, while 60-70% is excreted via kidney and liver as inactive metabolites. Visken crosses the placental barrier and passes in small quantities into breast milk.

Patients with impaired kidney or liver function may usually be treated with normal doses. Only in severe cases may a reduction of the daily dose be necessary.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SmPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Microcrystalline cellulose, starch, colloidal anhydrous silica, magnesium stearate.

6.2 Incompatibilities

None.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

None.

6.5 Nature And Contents Of Container

PVC/PVDC clear blister packs in a cardboard carton containing 56, 60 or 100 tablets.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Amdipharm Plc

Regency House

Miles Gray Road

Basildon

Essex

SS14 3AF

United Kingdom

8. Marketing Authorisation Number(S)

PL 20072/0021

9. Date Of First Authorisation/Renewal Of The Authorisation

1 January 2005

10. Date Of Revision Of The Text

Vitamin B Compound Strong Tablets

Vitamin B Compound Strong 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 Vitamin B Compound Strong 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 Vitamin B Compound Strong tablets are and what they are used for

Vitamin B Compound Strong tablets may be used to treat:

• vitamin B deficiency. The effects of a vitamin B deficiency can include: swelling of the tongue, mouth or lips, swelling of nerves which can cause pain, tenderness or loss of function and the growth of new blood vessels in the eye which can affect vision.


• the effects on the heart which occur in beri beri (a condition caused by vitamin B₁ (thiamine) deficiency).


• the effects on the skin which occur in pellagra (a condition caused by nicotinamide deficiency).

Before you take

Do not take Vitamin B Compound Strong tablets and tell your doctor if you:

• are allergic (hypersensitive) to nicotinamide, pyridoxine hydrochloride, riboflavine, thiamine mononitrate or any other ingredients in Vitamin B Compound Strong tablets (see section 6).

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, especially levodopa (for Parkinson’s disease) or medicines obtained without a prescription.

Pregnancy and breast-feeding

If you are pregnant particularly in the first three months, planning to become pregnant or are breast-feeding, speak to your doctor or pharmacist before taking this medicine.

Important information on some ingredients in Vitamin B Compound Strong tablets

• If you have been told you have an intolerance to some sugars, contact your doctor before taking this medicine, as it contains lactose.

How to take

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

Swallow the tablets whole.

Doses:

Adults (including elderly) and children over 3 years

1-2 tablets to be taken three times a day.

Children under 3 years

Not recommended.

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.

Possible side effects

Vitamin B Compound Strong tablets are unlikely to cause side-effects as any excess vitamin B is excreted from the body. If you notice any unusual effects, tell your doctor immediately.

How to store

Keep out of the reach and sight of children.

Store below 25°C in a dry place.

Do not use Vitamin B Compound Strong 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 Vitamin B Compound Strong tablets contain

• Each tablet contains the active substances (the ingredients that make the tablets work) 20mg nicotinamide, 2mg pyridoxine hydrochloride, 2mg riboflavine and 4.85mg thiamine mononitrate.


• The other ingredients are stearic acid, magnesium stearate, lactose, maize starch, hypromellose, hydroxypropyl cellulose, medium chain triglycerides, macrogol 3350, pregelatinised maize starch, red and black iron oxides (E172), titanium dioxide (E171).

What Vitamin B Compound Strong tablets look like and the contents of the pack

Vitamin B Compound Strong tablets are brown, circular, biconvex, film-coated tablets.

Pack size is 28.

Marketing Authorisation Holder and Manufacturer

Actavis

Barnstaple

EX32 8NS

UK

This leaflet was last revised in March 2009.

Actavis

Barnstaple

EX32 8NS

UK

50301581