Pocket Drug Guide

Posts Tagged ‘Germany’

Lipostat 10mg, 20mg and 40mg tablets

Pravastatin sodium

1. What Lipostat is and what it is used for

Lipostat belongs to a group of medicines called statins (or HMG-CoA reductase inhibitors). It prevents the production of cholesterol by the liver and consequently reduces the levels of cholesterol and other fats (triglycerides) in your body. When there are excessive levels of cholesterol in the blood, the cholesterol accumulates on the walls of blood vessels and blocks them.

This condition is called hardening of the arteries or atherosclerosis and it may lead to:

•   chest pain (angina pectoris), when a blood vessel in the heart is partially blocked,

•   a heart attack (myocardial infarction), when a blood vessel in the heart is completely blocked,

•   a stroke (cerebrovascular accident), when a blood vessel in the brain is completely blocked.

This medicine is used in 3 situations:

In the treatment of high levels of cholesterol and fats in the blood

Lipostat is used to lower high levels of “bad” cholesterol and to raise the levels of “good” cholesterol in the blood when changes to diet and exercise have failed to adequately do this.

In the prevention of heart and blood vessel diseases

•   If you have high levels of cholesterol in your blood and risk factors favouring these diseases (if you smoke, are overweight, if you have high blood sugar levels or high blood pressure, if you take little exercise), Lipostat is used to reduce the risk of you having heart and blood vessel diseases and to lower your risk of dying from these diseases.

•   If you have already had a stroke or if you have pains in the chest (unstable angina), and even if you have normal cholesterol levels, Lipostat is used to reduce the risk of you having another heart attack or stroke in the future, and to lower your risk of dying from these diseases.

After organ transplants

If you have had an organ transplant and receive medication to prevent your body rejecting the transplant,

Lipostat is used to reduce increased levels of fats in the blood.

2. Before you take Lipostat

Do not take Lipostat

•   if you are allergic (hypersensitive) to pravastatin or any of the other ingredients of this medicine (see Further Information);

•   if you are pregnant, trying to become pregnant or if you are breast-feeding (see Pregnancy and breast-feeding);

•   if you have a liver disease (active liver disease);

•   if several blood tests have shown abnormal functioning of your liver (increased levels of liver enzymes in the blood).

Take special care with Lipostat

Before you take this treatment, you should tell your doctor if you have or have had any medical problems such as:

•   kidney disease;

•   an underactive thyroid (hypothyroidism);

3. How to take Lipostat

Your doctor will advise you on a lowfat diet which you should continue over the full treatment period. Always take this treatment exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. Lipostat can be taken with or without food, with half a glass of water.

Dosage

Adults:

•   In the treatment of high levels of cholesterol and fats in the blood: the usual dose is 10 40 mg once a day, preferably in the evening.

•   In the prevention of heart and blood vessel diseases: the usual dose is 40 mg once a day, preferably in the evening.

The maximum daily dose of 40 mg of pravastatin should not be exceeded. Your doctor shall tell you which dose suits you.

Children (8 13 years) and adolescents (14 18 years) with a hereditary disease which increases the level of cholesterol in the blood:

The usual dose is 10 20 mg once a day between 8 and 13 years and from 10 to 40 mg once a day between 14 and 18 years.

After organ transplant:

Your doctor may prescribe a starting dose of 20 mg once a day. The dose may be adjusted up to 40 mg by your doctor.

If you are also taking a medicine which lowers the body’s immune system (ciclosporin), your doctor may prescribe a starting dose of 20 mg once a day. The dose may be adjusted up to 40 mg by your doctor.

If you suffer from kidney or severe liver disease, your doctor may prescribe a lower dose of Lipostat to you.

If you have the impression that the effect of this treatment is too strong or too weak, talk to your doctor or pharmacist.

Duration of treatment

Your doctor will indicate the duration of your treatment with Lipostat. This medicine must be used very regularly and for as long as your doctor advises, even if it is for a very long time. Do not stop your treatment by yourself.

If you take more Lipostat than you should

If you have taken too many tablets, or if someone accidentally swallows some, contact your doctor or the nearest hospital for appropriate advice.

If you forget to take Lipostat

If you miss a dose, simply take your usual dose when it is next due.

Do not take a double dose to make up for a forgotten dose.

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

4. Possible side effects

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

Stop taking Lipostat and tell your doctor immediately if you develop any unexplained or persistent muscle pain, tenderness, weakness, or cramps, especially, if at the same time you feel unwell or have a high temperature.

In very rare cases, muscle problems can be serious (rhabdomylosis) and can lead to a serious, life-threatening kidney disease.

Sudden severe allergic reactions including swelling of the face, lip, tongue or wind pipe which can cause great difficulty in breathing. This is a very rare reaction which can be serious if it occurs. You should tell your doctor immediately if it happens.

The following side effects are uncommon and may affect more than 1 out of 1 000 persons:

•   Effects on nervous system: dizziness, tiredness, headache or sleep disturbances, including insomnia;

•   Effects on vision: blurred or double vision;

•   Digestive effects: indigestion, nausea, vomiting, stomach pain or discomfort, diarrhoea or constipation and wind;

•   Effects on skin and hair: itching, pimples, hives, rashes, scalp and hair problems (including hair loss);

•   Urinary and genital effects: bladder problems (painful or more frequent urination, having to pass water at night) and sexual difficulties;

•   Effects on muscles and joints: muscle and joint pain.

The following side effects are very rare and may affect less than 1 out of 10 000 persons:

•   Effects on nervous system: problems with touch including burning or tingling sensations or numbness which may indicate damage to nerves;

•   Effects on skin: a severe skin disease (lupus erythematous-like syndrome);

•   Effects on liver: inflammation of the liver or pancreas; jaundice (recognisable by a yellowing of the skin and of whites of the eyes; very rapid death of liver cells (fulminant hepatic necrosis);

•   Effects on muscles and bones: inflammation of one or more muscles leading to pain or weakness in muscles (myositis or polymyositis); pain or weakness in muscles, inflammation of tendons which may be complicated by rupture of tendons.

•   Abnormal blood tests: increases in transaminases (a group of enzymes occurring naturally in the blood) which may be a sign of liver problems. Your doctor may want to perform tests periodically to check these.

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.

Possible side effects

•   Nightmares

•   Memory loss

•   Depression

•   Breathing problems including persistant cough and/or shortness of breath or fever.

•   a liver disease or alcohol problems (drinking large amounts of alcohol);

•   muscle disorders caused by a hereditary disease;

•   muscle problems caused by another medicine belonging to the statins group (HMG-CoA reductase inhibitor drugs) or one belonging to the group known as fibrates.

If you have suffered from any of these problems, or if you are older than 70 years, your doctor will need to carry out a blood test before and possibly during your treatment. These blood tests will be used to evaluate your risk of muscle-related side effects. If you feel any unexplained cramps or muscle pains during treatment, tell your doctor immediately.

Check with your doctor or pharmacist before taking Lipostat if you:

•   Have severe respiratory failure

Using other medicines

When combined with this treatment, the medicines stated below may result in an increased risk of developing muscle problems. It is important that you inform your doctor whether you are already being treated with:

•   a medicine which lowers the cholesterol level in the blood (fibrates, e.g. gemfibrozil, fenofibrate);

•   a medicine which lowers the body’s immune defences (ciclosporin);

•   a medicine which treats the infections caused by bacteria (an antibiotic such as erythromycin or clarithromycin);

•   another medicine which lowers the level of cholesterol in your blood (nicotinic acid).

If you are also using a medicine which lowers the level of fat in your blood (of the resin-type such as colestyramine or colestipol), this treatment should be taken at least one hour before or four hours after you have taken the resin. This is because the resin can affect the absorption of Lipostat if the two medicines are taken too closely together.

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

Taking Lipostat with food and drink

This treatment can be taken with or without food, with half a glass of water.

You should always keep your alcohol intake to a minimum. If you are concerned about how much alcohol you can drink while you are taking this medicine, you should discuss this with your doctor.

Pregnancy

Do not take Lipostat during pregnancy. If you discover that you are pregnant, you should inform your doctor immediately.

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

Breast-feeding

Do not take Lipostat if you intend to breast-feed as this treatment passes into the mother’s milk.

Driving and using machines

Lipostat does not usually affect your ability to drive or use machines. If you experience any dizziness, blurred or double vision during treatment, make sure you are fit to drive and use machines before attempting to do so.

Important information about some of the ingredients of Lipostat

Lipostat contains lactose.

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

5. How to store Lipostat

Keep out of the reach and sight of children.

Do not use this treatment after the expiry date which is stated on the carton and blister. The expiry date refers to the last day of that month.

Do not store above 25°C.

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

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.

6. Further information

What Lipostat contains:

•   The active substance is pravastatin sodium. Each tablet contains 10mg, 20mg or 40mg of pravastatin sodium.

•   The other ingredients are lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, magnesium stearate, heavy magnesium oxide, yellow iron oxide (E172).

What Lipostat looks like and contents of the pack

Lipostat 10mg is a yellow, capsule-shaped, biconvex, scored tablet with a “10″ engraved on one side. Lipostat 20mg is a yellow, capsule-shaped, biconvex, scored tablet with a “20″ engraved on one side. Lipostat 40mg is a yellow, capsule-shaped, biconvex, scored or unscored tablet with a “40″ engraved on one side. They come in blister packs in boxes of 28 tablets.

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

Name of the Member States	Name of the medicinal product
Belgium	Pravasine
Denmark	Pravachol
Finland	Pravachol
France	Elisor
Germany	Pravasin protect
Greece	Pravachol
Iceland	Pravachol
Ireland	Lipostat
Italy	Selectin
Luxembourg	Pravasine
Netherlands	Selektine
Norway	Pravachol
Portugal	Pravacol
Spain	Lipemol
Sweden	Pravachol
UK	Lipostat

 

 

Lescol XL 80 mg prolonged-release tablets

Fluvastatin

1. WHAT LESCOL XL IS AND WHAT IT IS USED FOR

Lescol XL contains the active fluvastatin sodium which belongs to a group of medicines known as statins, which are lipid-lowering medicines: they lower the fat (lipids) in your blood. They are used in patients whose conditions cannot be controlled by diet and exercise alone.

- Lescol XL is a medicine used to treat raised levels of fats in the blood in adults, in

particular total cholesterol and so called “bad” or LDL cholesterol, which is associated with an increased risk of heart disease and stroke.

-  in adult patients with high blood levels of cholesterol

-  in adult patients with high blood levels of both cholesterol and triglycerides (another sort of blood lipid)

- Your doctor can also prescribe Lescol XL to prevent further serious cardiac events (e.g. heart attack) in patients after they already went through a heart catheterisation, with an intervention in the heart vessel.

2.BEFORE YOU TAKE LESCOL XL

Follow all instructions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

Read the following explanations before you take Lescol XL.

Do not take Lescol XL

1. if you are allergic (hypersensitive) to fluvastatin or any of the other ingredients of Lescol XL listed in section 6 of this leaflet.
2. if you currently have liver problems, or if you have unexplained, persistently high level of certain liver enzymes (transaminases).
3. if you are pregnant or breast-feeding.

If any of these apply to you, do not take Lescol XL and tell your doctor.

Take special care with Lescol XL

1. if you previously had a liver disease. Liver function tests will normally be done before you start Lescol XL, when your dose is increased and at various intervals during treatment to check for side effects.
2. if you have a kidney disease.
3. if you have a thyroid disease (hypothyroidism).
4. if you have a medical history of muscle diseases yourself or in your family.
5. if you had muscle problems with another lipid-lowering medicine.
6. if you regularly drink large amounts of alcohol.

Check with your doctor or pharmacist before taking Lescol XL:

if you have severe respiratory failure

If any of these apply to you, tell your doctor before you take Lescol XL. Your doctor will take a blood test before prescribing Lescol XL.

Lescol XL and people over 70 years

If you are over 70 years your doctor may want to check if you have risk factors for muscular diseases. You may need specific blood tests.

Lescol XL and children/adolescents

Lescol XL has not been investigated and is not intended for the use in children below 9 years. For dose information in children and adolescents over 9 years, see section 3.

There is no experience with the use of Lescol in combination with nicotinic acid, cholestyramine or fibrates in children and adolescents.

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.

Lescol XL can be taken on its own or with other cholesterol-lowering medicines prescribed by your doctor.

After intake of a resin, e.g. cholestyramine (primarily used to treat high cholesterol) wait at least 4 hours before taking Lescol XL.

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

1. Ciclosporin (a medicine used to suppress the immune system).
2. Fibrates (e.g. gemfibrozil), nicotinic acid or bile acid sequestrants (medicines used to
3. lower bad cholesterol levels).
4. Fluconazole (a medicine used to treat fungal infections).
5. Rifampicin (an antibiotic).
6. Phenytoin (a medicine used to treat epilepsy).
7. Oral anticoagulants like warfarin (medicines used to reduce blood clotting).
8. Glibenclamide (a medicine used to treat diabetes).
9. Colchicines (used to treat gout).

Taking Lescol XL with food and drink

You can take Lescol XL with or without food.

Pregnancy and breast-feeding

Do not take Lescol XL if you are pregnant or breast-feeding as the active ingredient may lead to harm to your unborn child, and it is not known whether the active ingredient is excreted in human breast milk. If you are pregnant, consult your doctor or pharmacist before taking Lescol XL. Use reliable contraception for the whole time that you are taking Lescol XL.

If you become pregnant while taking this medicine, stop taking Lescol XL and see your doctor.

Driving and using machines

There is no information on the effects of Lescol XL on your ability to drive and use machines.

3. HOW TO TAKE LESCOL XL

Follow your doctor’s instructions carefully. Do not exceed the recommended dose.

Your doctor will recommend you to follow a low-cholesterol diet. Stay on this diet while taking Lescol XL.

How much Lescol XL to take

- The dose for adults is 80 mg per day. Dose adjustments may be made by your doctor at 4-week or longer intervals.

- For children (aged 9 years and older) the maximum daily dose is 80 mg. Dose adjustments may be made by your doctor at 6-week intervals.

Your doctor will tell you exactly how many tablets of Lescol XL to take.

Depending on how you respond to the treatment, your doctor may suggest a higher or lower dose.

• When to take Lescol XL

You can take your Lescol XL dose at any time of the day.

Lescol XL can be taken with or without meals. Swallow whole with a glass of water.

• If you take more Lescol XL than you should

If you have accidentally taken too much Lescol XL, talk to your doctor straight away. You may need medical attention.

• If you forget to take Lescol XL

Take one dose as soon as you remember. However, do not take it if there is less than 4 hours before your next dose. In this case take your next dose at the usual time. Do not take a double dose to make up for the one that you missed.

• If you stop taking Lescol XL

To maintain the benefits of your treatment, do not stop taking Lescol XL unless your doctor tells you to. You must continue to take Lescol XL as directed to keep the levels of your ‘bad’ cholesterol down. Lescol XL will not cure your condition but it does help control it. Your cholesterol levels need to be checked regularly to monitor your progress. If you have any further questions on the use of this product, ask your doctor or pharmacist.

4. POSSIBLE SIDE EFFECTS

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

Some rare or very rare effects could be serious: get medical help immediately.

if you have unexplained muscle pain, tenderness or weakness. These might be early signs of a potentially severe muscle degradation. This can be avoided if your doctor stops your treatment with fluvastatin as quickly as possible. These side effects have also been found with similar medicines of this class (statins).

if you have unusual tiredness or fever, yellowing of the skin and eyes, dark coloured urine (signs of hepatitis).

if you have signs of skin reactions such as skin rash, hives, redness, itching, swelling of  the face, eyelids, and lips.

if you have skin swelling, difficulty in breathing, dizziness (signs of severe allergic reaction).

if you bleed or bruise more easily than normal (signs of decreased number of blood platelets).

if you have red or purple skin lesions (signs of blood vessel inflammation).

if you have red blotchy rash mainly on the face which may be accompanied by fatigue, fever, nausea, loss of appetite (signs of lupus erythematous-like reaction).

if you have severe upper stomach pain (signs of inflamed pancreas). If you experience any of these, tell your doctor straight away.

Other side effects: tell your doctor if they worry you.

Common:

• Difficulty in sleeping, headache, stomach discomfort, abdominal pain, nausea.

Very rare:

• Tingling or numbness of the hands or feet, disturbed or decreased sensitivity.

Other possible side effects

• Sleep disturbances, including insomnia and nightmares
• Memory loss
• Sexual difficulties
• Depression
• Breathing problems including persistent cough and/or shortness of breath or fever

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

5. HOW TO STORE LESCOL XL

Keep your tablets in their original pack at a temperature below 30°C. Keep Lescol XL out of the reach and sight of children.

Do not use Lescol XL after the expiry date which is stated on the carton and blister. 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.

6. FURTHER INFORMATION

• What Lescol XL contains

The active substance is fluvastatin sodium

Each Lescol XL 80 mg tablet contains 84.24 mg fluvastatin sodium equivalent to 80 mg fluvastatin free acid.

The tablets also contain the inactive ingredients microcrystalline cellulose, hypromellose, hydroxypropyl cellulose, potassium hydrogen carbonate, povidone, magnesium stearate, yellow iron oxide (E172), titanium dioxide (E171) and macrogol 8000.

• What Lescol XL looks like and contents of the pack

Lescol XL 80 mg prolonged release tablets are round, yellow tablets marked ‘LE’ on one side and ‘NVR’ on the other. They come in packs of 28 tablets.

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

Member State	Medicinal Product
Estonia, Bulgaria, Cyprus, Czech Republic, Greece, Hungary, Ireland, Latvia, Lithuania, Malta, Netherlands, Poland, Portugal, Romania, Slovak Republic, Slovenia, United Kingdom	Lescol XL
Demark, Finland, Iceland, Norway, Sweden	Lescol Depot
Austria, Germany	Fluvastatin Novartis
Austria	Lescol MR
Belgium	Lescol Exel
France	Lescol LP
Germany, Luxembourg	Locol
Italy	Lescol, Lipaxin, Primesin
Portugal	Cardiol XL, Canef
Spain	Lescol Prolib, Leposit Prolib, Vaditon Prolib, Digaril Prolib

 

 

Despite relatively good long-term survival rates, chronic lymphocytic leukemia  is considered incurable. For many years, first-line therapy was dominated by the oral alkylating agent chlorambucil (GlaxoSmithKline’s Leukeran). The introduction of purine analogues as monotherapy or in combination with alkylating agents into current treatment strategies has vastly improved response rates, although no improvement in overall survival has yet been noted.

Patients with chronic lymphocytic leukemia do not have a wide choice of therapy options. The overall population is elderly and has a low tolerance for toxic chemotherapy regimens. Once patients have failed both chlorambucil and fludarabine (Schering AG and Berlex’s Fludara), the disease becomes extremely difficult to treat. The aim of current drug regimens is to obtain the highest possible rate and duration of remission while balancing the associated toxicity and infection rate in these patients. TABLE. Current Regimens Used for Chronic Lymphocytic Leukemia describes the current regimens used to treat chronic lymphocytic leukemia.

TABLE. Current Regimens Used for Chronic Lymphocytic Leukemia

	Regimen Components		Dose
Regimen	Agent	Availability		Common Toxicities
Chlorambucil (single agent)	Chlorambucil (GlaxoSmith-Kline’s Leukeran)	US ,France,  Germany,  Italy, S, UK	Chlorambucil: 10 mg/m2/d on days 1 -7. Cycle repeated every 28 days.	•  Myelosuppression •  Mild gastrointestinal disturbances •  Increased risk of secondary malignancy
Fludarabine (single agent)	Fludarabine (Berlex’s Fludara, Schering’s Fludara/Fludar/ Bebeflur, generics)	US ,France,  Germany,  Italy, Spain,  UK, Japan	Fludarabine (oral): 40 mg/m2/d on days 1-5, (IV) 25 mg/m2/d on days 1 -5. Cycle repeated every 28 days.	•  Myelosuppression •  Increased infection •  Neurotoxicity •  Malaise/fatigue •  Nausea/vomiting •  Anorexia
Fludarabine/ cyclophosphamide (FC)	Fludarabine (Berlex’s Fludara, Schering’s Fludara/Fludar/ Bebeflur, generics)	US ,France,  Germany,  Italy, Spain,  UK, Japan	Fludarabine (oral): 40 mg/m2/d on days 1-3, (IV) 25 mg/m2/d on days 1 -3. Cycle repeated every 28 days.	•  Myelosuppression •  Increased infection •  Neurotoxicity (fludarabine) •  Alopecia (more common with cyclophosphamide)
	Cyclophosphamide (Bristol-Myers Squibb’s Cytoxan/ Endoxan/ Endoxana, Baxter’s Endoxan/ Endoxana, Shionogi’s Endoxan, Pfizer’s Neosar/Cyclostin, generics)	US ,France,  Germany,  Italy, Spain,  UK, Japan	Cyclophosphamide: 250 mg/m2/d on days 1 -3. Cycle repeated every 28 days.	•  Malaise/fatigue •  Nausea/vomiting •  Anorexia •  Hemorrhagic cystitis (cyclophosphamide) •  Neutropenia
Fludarabine/ cyclophosphamide/ mitoxantrone (FCM)	Fludarabine (Berlex’s Fludara, Schering’s Fludara/Fludar/ Bebeflur, generics)	US ,France,  Germany,  Italy, Spain,  UK, Japan	Fludarabine (oral): 40 mg/m2/d on days 1-3, (IV) 25 mg/m2/d on days 1 -3. Cycle repeated every 28 days.	•  Myelosuppression •  Increased infection •  Neurotoxicity (fludarabine) •  Alopecia (more common with cyclophosphamide)
	Cyclophosphamide (Bristol-Myers Squibb’s Cytoxan/ Endoxan/ Endoxana, Baxter’s Endoxan/ Endoxana, Shionogi’s Endoxan, Pfizer’s Cyclostin, generics) Mitoxantrone (Serono Lab/Wyeth/ Takeda’s Novantrone, Baxter’s Onkotrone, generics)	US ,France,  Germany,  Italy, Spain,  UK, Japan US ,France,  Germany,  Italy, Spain,  UK, Japan	Cyclophosphamide: 200 mg/m2/d on days 1 -3. Cycle repeated every 28 days. Mitoxantrone: 6 mg/m2/d on day 1. Cycle repeated every 28 days.	•  Malaise/fatigue •  Nausea/vomiting •  Anorexia •  Hemorrhagic cystitis (cyclophosphamide •  Cardiac toxicity (mitoxantrone)
CHOP	Cyclophosphamide (Bristol-Myers Squibb’s Cytoxan/ Endoxan/ Endoxana, Baxter’s Endoxan/ Endoxana, Shionogi’s Endoxan, Pfizer’s Neosar/Cyclostin, generics)	US ,France,  Germany,  Italy, Spain,  UK, Japan	Cyclophosphamide: 750 mg/m2/d on day 1. Cycle repeated every 28 days.	•  Myelosuppression •  Increased infection •  Alopecia •  Malaise/fatigue •  Nausea/vomiting •  Anorexia •  Hemorrhagic cystitis (cyclophosphamide)
	Doxorubicin (Pfizer’s Adriamycin/ Adriblastine, Bristol-Myers Squibb’s Rubex, Kyowa’s Adriacin, generics)	US ,France,  Germany,  Italy, Spain,  UK, Japan	Doxorubicin: 50 mg/m2/d on day 1. Cycle repeated every 28 days.
	Vincristine (Eli Lilly/EG Labo/Lilly-Shionogi’s Oncovin, generics)	US ,France,  Germany,  Italy, Spain,  UK, Japan	Vincristine: 1.4 mg/m2/d on day 1. Cycle repeated every 28 days.
	Prednisone3 (generics)	US ,France,  Germany,  Italy, Spain	Prednisone/ Prednisolone: 50 mg/m2 on days 1-5. Cycle repeated every 28 days.
	Prednisolone (generics)	US ,France,  Germany,  Italy, Spain,  UK, Japan
Cyclophosphamide, Vincristine, Prednisone	Cyclophosphamide (Bristol-Myers Squibb’s Cytoxan/ Endoxan/ Endoxana, Baxter’s Endoxan/ Endoxana, Shionogi’s Endoxan, Pfizer’s Neosar/Cyclostin. generics)	US ,France,  Germany,  Italy, Spain,  UK, Japan	Cyclophosphamide: 750 mg/m2/d on day. Cycle repeated every 28 days.	•  Myelosuppression •  Increased infection •  Alopecia •  Malaise/fatigue •  Nausea/vomiting •  Anorexia •  Hemorrhagic cystitis (cyclophosphamide)
	Vincristine (Eli Lilly/EG Labo/Lilly-Shionogi’s Oncovin, generics)	US ,France,  Germany,  Italy, Spain,  UK, Japan	Vincristine: 1 mg/m2/d on day 1. Cycle repeated every 28 days.
	Prednisone3 (generics)	US ,France,  Germany,  Italy,   S	Prednisone/ Prednisolone: 50 mg/m2 on days 1-5. Cycle repeated every 28 days.
	Prednisolone (generics)	US ,France,  Germany,  Italy, Spain,  UK, Japan
Pentostatin/ cyclophosphamide	Pentostatin (SuperGen/ Wyeth/ Pfizer’s Nipent, Nihonkayaku’s Coforin)	US ,France,  Germany,  Italy, Spain,  UK, Japan	Pentostatin: 4 mg/m2/d on day 1. Cycle repeated every 28 days.	•  Myelosuppression (mild) •  Increased infection •  Malaise/fatigue •  Fever •  Nausea/vomiting •  Anorexia •  Hemorrhagic cystitis (cyclophosphamide)
	Cyclophosphamide (Bristol-Myers Squibb’s Cytoxan/ Endoxan/ Endoxana, Baxter’s Endoxan/ Endoxana, Shionogi’s Endoxan, Pfizer’s Cyclostin, generics)	US ,France,  Germany,  Italy, Spain,  UK, Japan	Cyclophosphamide: 600 mg/m2/d on day 1. Cycle repeated every 28 days.
Cladribine (single agent)	Cladribine (Ortho-Biotech’s Leustatin, Japananssen-Cilag’s Leustatin/ Leustatine/ Leustat, generics)	US ,France,  Germany,  Italy, Spain,  UK, Japan	Cladribine: 0.14 mg/kg/d on days 1 -5.	•  Myelosuppression •  Increased infection •  Malaise/fatigue •  Fever •  Rash •  Headache
Alemtuzumab (single agent)	Alemtuzumab (Berlex’s Campath, Schering’s Mab Campath)	US ,France,  Germany,  Italy, Spain,  UK	Alemtuzumab: escalating dose of 3, 10,30 mg/d for week 1, followed by 30 mg/d for 3 days per week.	•  Myelosuppression •  Increased infection •  Anemia •  Fever •  Nausea/vomiting •  Rash •  Fatigue •  Urticaria •  Rigors • Transient Cytopenia

a. Prednisolone is used where prednisone is not available.

IV = Intravenous; MAB = Monoclonal antibody.

Chlorambucil (Single Agent)

Overview

For the past 40 years, first-line treatment of chronic lymphocytic leukemia has been limited mainly to the alkylating agent chlorambucil (GlaxoSmithKline’s Leukeran). Although newer agents are being used with increasing frequency, chlorambucil still garners a significant patient share in the United States, France, Germany, Italy, Spain, and the United Kingdom. This popularity is the result of its preferable toxicity profile, which is advantageous in chronic lymphocytic leukemia — a disease with an elderly population that is less able to cope with high toxicities.

Mechanism Of Action

Chlorambucil is an alkylating agent. Alkylation of DNA results in breaks in the DNA molecule as well as cross-linking of the twin strands, thus interfering with DNA replication and transcription of RNA and ultimately causing cell death.

Clinical Performance

A variety of schedules are in use. Chlorambucil is an agent that can be administered with or without the corticosteroids prednisone or prednisolone (both generic). No evidence from randomized trials exists to prove that adding a corticosteroid enhances the efficacy of chlorambucil or other alkylating agents. However, physicians often include them in cases of bulky disease requiring a rapid response or when chlorambucil produces severe hematologic toxicity.

First-line chlorambucil therapy (plus or minus prednisone) in untreated chronic lymphocytic leukemia patients produces complete response rates of 4-12% and overall response rates of approximately 40-60%. Recent trials have shown that first-line fludarabine therapy (discussed later) provides superior response rates compared with chlorambucil; however, the two compounds’ long-term survival rates are not significantly different.

Chlorambucil does have a less toxic side-effect profile and is therefore the preferred therapy in older patients (65 or older) and those with a poor performance status who are unable to tolerate the severe myelosuppression caused by fludarabine. Another well-established benefit of chlorambucil is its oral formulation, although an oral formulation of fludarabine has become available in some countries.

Drug Approvals

(BANM, US Adopted Name, rINNM)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish): Acetato de clormadinona; Chlormadinone, Acetate de; Chlormadinoni Acetas; NSC-92338.

6-Chloro-17-hydroxypregna-4,6-diene-3,20-dione acetate.

CAS — 1961-77-9 (chlormadinone); 302-22-7 (chlormadinone acetate).

ATC — C03DB06

Pharmacopoeias. In China, France, and Japan.

Adverse Effects and Precautions

As for progestogens in general (see Progesterone). See also under Hormonal Contraceptives.

Effects on the skin. A report of auto-immune dermatitis in a patient associated with chlormadinone acetate.

Interactions

As for progestogens in general (see Progesterone). See also under Hormonal Contraceptives.

Uses and Administration

Chlormadinone acetate is a progestogen structurally related to progesterone that has anti-androgenic activity. It is given either alone or with an oestrogen in the treatment of menstrual disorders such as menorrhagia and endometriosis in oral doses of 2 to 10 mg daily either cyclically or continuously. It may also be used as the progestogen component of combined oral contraceptives at a dose of 1 to 2 mg daily, particularly in women with androgen-dependent conditions such as acne and hirsutism. Chlormadinone acetate has been used in some countries in the management of prostatic hyperplasia and prostate cancer oral doses of 25 or 50 mg, respectively have been given twice daily.

Preparations

Proprietary Preparations

France: Luteran

Germany: Gestafortin

Japan: Prostal

Mexico: Lutoral.

Multi-ingredient

Chile: Belara Lovinda

Czech Republic: Belara

France: Belara

Germany: Balanca Belara Esticia Gestamestrol N Neo-Eunomin Ovosistoin

Hungary: Belara

Israel: Belara

Italy: Belara

Mexico: Belara Lutoral-E Secuentex-21

Portugal: Belara Libeli

Russia: Belara

Spain: Belara

Switzerland: Belara

Venezuela: Belara.

Drug Approvals

(British Approved Name, rINN)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish): CG; Choriogonadotrophin; Chorionic Gonadotropin; Chorioninis gonadotropinas; Gonadotrofina coridnica; Gonadotrophine Chorionique; Gonadotrophinum Chorionicum; Gonadotropin choriovy; Gonadotropine chorionique; Gonadotropinum chorionicum; hCG; Human Chorionic Gonadotrophin; Koriongonadotropiini; Koriongonadotropin; Korion-gonadotropin; Koriyonik Gonadotrofin; Pregnancy-urine Hormone; PU.

CAS — 9002-61-3

ATC — G03GA01

Pharmacopoeias. In China, Europe, Japan, and US.

European Pharmacopoeia, 6th ed. (Gonadotrophin, Chorionic). A dry preparation of placental glycoproteins extracted from the urine of pregnant women. The potency is not less than 2500 units/mg. A white to yellowish-white, amorphous powder. Soluble in water. Store at 2° to 8° in airtight containers. Protect from light.

The United States Pharmacopeia 31, 2008 (Chorionic Gonadotropin). A gonad-stimulating polypeptide hormone obtained from the urine of pregnant women. It has a potency of not less than 1500 USP units/mg. A white or practically white, amorphous powder. Freely soluble in water. Store in airtight containers at 2° to 8°.

Choriogonadotropin Alfa

Drug Approvals

(British Approved Name, US Adopted Name, rINN)

INNs in main languages (French, Latin, and Spanish): Choriogonadotropine Alfa; Choriogonadotropinum Alfa; Coriogonadotropina alfa.

CAS — 177073-44-8 (choriogonadotropin alfa); 56832-30-5 (α subumt) 56832-34-9 (β subunit).

ATC — G03GA08.

Adverse Effects and Precautions

Adverse effects that have been reported with chorionic gonadotrophin include headache, tiredness, changes in mood, depression, restlessness, oedema (especially in males), and pain on injection. Treatment for cryp-torchidism may produce premature epiphyseal closure or precocious puberty. Gynaecomastia has been reported. Ovarian hyperstimulation may occur, with marked ovarian enlargement or cyst formation, acute abdominal pain, ascites, pleural effusion, hypovolaemia, shock, and thromboembolic disorders in severe cases. Chorionic gonadotrophin should be given with care to patients in whom androgen-induced fluid retention might be a hazard as in asthma, epilepsy, migraine, or cardiovascular disorders, including hypertension, or renal disorders. Hypersensitivity reactions may occur and it is recommended that patients suspected to be susceptible should be given skin tests before treatment. It should not be given to patients with disorders that might be exacerbated by androgen release such as carcinoma of the prostate or precocious puberty. Use should also be avoided in the presence of breast, uterine, ovarian, and testicular tumours, as well as tumours of the hypothalamus, pituitary, thyroid, and adrenal glands.

Pharmacokinetics

Peak concentrations of chorionic gonadotrophin occur about 6 hours after an intramuscular dose and 16 to 20 hours after a subcutaneous injection. It is distributed primarily to the gonads. Blood concentrations decline in a biphasic manner, with half-lives of about 6 to 11 hours and 23 to 38 hours, respectively. Chorionic gonadotrophin is metabolised mainly in the kidneys. About 10 to 12% of an intramuscular dose is excreted in urine within 24 hours.

After subcutaneous doses, choriogonadotropin alfa has a bioavailability of about 40%. It is metabolised and excreted similarly to chorionic gonadotrophin.

Uses and Administration

Chorionic gonadotrophin is a hormone produced by the placenta and obtained from the urine of pregnant women. Its effects are mainly those of the gonadotrophin, luteinising hormone, which is responsible for triggering ovulation and formation of the corpus luteum in women, and stimulates the production of testosterone by the testes in men. It is usually given by intramuscular injection although the subcutaneous route has also been used. Choriogonadotropin alfa is a recombinant form of chorionic gonadotrophin.

In women with anovulatory infertility due to absent or low concentrations of gonadotrophins, chorionic gonadotrophin is given to induce ovulation after follicular development has been stimulated with follicle-stimulating hormone or human menopausal gonadotrophins. A single dose of 5000 to 10 000 units of chorionic gonadotrophin is given by intramuscular injection to mimic the midcycle peak of luteinising hormone which normally stimulates ovulation. Up to 3 repeat injections of up to 5000 units each may be given within the next 9 days to prevent insufficiency of the corpus luteum. Chorionic gonadotrophin is also given with menotrophin as an adjunct to IVF procedures and other assisted conception techniques involving superovula-tion and oocyte collection.

Choriogonadotropin alfa is used similarly to induce ovulation in the treatment of anovulatory infertility, or as an adjunct to IVF procedures and other assisted conception techniques. A single dose of 250 micrograms is given, by subcutaneous injection, when optimal stimulation of follicular growth is achieved.

In males, chorionic gonadotrophin has been used in the treatment of prepubertal cryptorchidism. Regimens vary widely, but doses usually range from 500 to 4000 units three times weekly by intramuscular injection. Treatment should continue for 1 to 2 months after testicular descent.

Chorionic gonadotrophin is also given for male infertility associated with hypogonadotrophic hypogonadism. Again, there is considerable variation in the dosage regimen, and doses have varied from 500 to 4000 units two or three times weekly by intramuscular injection. A drug with follicle-stimulating activity such as menotrophin is often added to enable normal sper-matogenesis.

In the treatment of delayed puberty associated with hypogonadism in males, an initial dose of chorionic gonadotrophin 500 to 1500 units is given twice weekly by intramuscular injection the dose should be titrated against plasma-testosterone concentration.

Cryptorchidism. Although surgery remains the treatment with the best success rate, primary hormonal therapy with chorionic gonadotrophin is widely used for cryptorchidism (p.2079). Systematic reviews’ suggest a success rate of about 20% overall, although this may be reduced when care is taken to exclude retractile testes. There is some suggestion that medical treatment given either before or after surgery can improve the patient’s fertility index, a predictor of future fertility. Chorionic gonadotrophin may also be used as an adjuvant before surgery, to render the testes palpable, but changes suggestive of inflammation in the testis have been reported following such treatment.

Delayed pu berty. Use of chorionic gonadotrophin may be appropriate in boys with delayed puberty due to hypogonadotrophic hypogonadism.

Infertility. In women with anovulatory infertility chorionic gonadotrophin and choriogonadotropin alfa can be used to provoke ovulation and provide luteal support once maturation of a suitable number of follicles has been stimulated by other means. They are used similarly in the various protocols for assisted reproduction. However, use is not recommended for assisted reproduction in patients at risk of ovarian hyperstimulation, such as those with poly cystic ovary syndrome. In men with hypogonadotrophic hypogonadism chorionic gonadotrophin is used to stimulate and maintain spermatogenesis. The management of male and female infertility, including the role of chorionic gonadotrophin, is discussed on p.2080.

Malignant neoplasms. Control of Kaposi’s sarcoma has been reported in a few patients given high-dose intramuscular chorionic gonadotrophin, but regrowth occurred when dosage was reduced or withdrawn. Another study, using lower doses, was stopped due to toxicity and lack of benefit, but others have confirmed benefit after intralesional injection. There is some suggestion that preparations vary in their activity against the tumour and that it is not chorionic gonadotrophin itself, but some impurity (perhaps a ribonuclease or the degradation product of the β-subunit), that is the active principle. Some contaminants may have a stimulant effect on the neoplasm, which might also contribute to the variable results.

Obesity. A meta-analysis involving 24 studies concluded that there was no evidence that chorionic gonadotrophin was effective in the treatment of obesity.

Testicular function. Chorionic gonadotrophin is used in the assessment of testicular function in suspected primary hypogonadism and incomplete masculinisation. The BNFC states that for children 1 month to 18 years of age a dose of 1500 to 2000 units may be given once daily for 3 days (short stimulation test) or twice weekly for 3 weeks (prolonged test).

Preparations

British Pharmacopoeia 2008: Chorionic Gonadotrophin Injection

The United States Pharmacopeia 31, 2008: Chorionic Gonadotropin for Injection.

Proprietary Preparations

Argentina: Dinaron Endocorion Gonacor Ovidrel Pregnyl Profasi †

Australia: Ovidrel Pregnyl Profasi

Austria: Pregnyl Profasi

Belgium: Choragon Ovitrelle Pregnyl

Brazil: Choragon † Ovidrel Pregnyl Profasi HP

Canada: Pregnyl Profasi HP

Chile: APL † Gonacor Ovidrel Pregnyl Profasi †

Czech Republic: Ovitrelle Praedynf Pregnyl Profasi †

Denmark: Ovitrelle Pregnyl Profasi †

Finland: Ovitrelle Pregnyl Profasi †

France: Ovitrelle

Germany: Choragon Ovitrelle Predalon Pregnesin+ Primogonyl †

Greece: Ovitrelle Pregnyl Profasi †

Hong Kong: Choragon Choriomon Ovidrel Pregnyl Profasi

Hungary: Choragon Ovitrelle Pregnyl Profasi †

India: Corion Profasi Proligon † Provigil Pubergen

Indonesia: Ovidrel Pregnyl

Ireland: Ovitrelle Pregnyl Profasi

Israel: Chorigon † Ovitrelle Pregnyl

Italy: Gonasi HP Ovitrelle Pregnyl Profasi HP †

Malaysia: Choragon Ovidrel Pregnyl Profasi †

Mexico: Choragon Choriomon Gonadotropyl Op, Ovidrel Pregnyl Profasi †

The Netherlands: Choragon Ovitrelle Pregnyl Profasi †

Norway: Ovitrelle Pregnyl Profasi †

New Zealand: Ovidrel Profasi

Philippines: Ovidrel Pregnyl

Poland: Choragon Ovitrelle Pregnyl

Portugal: Ovitrelle Pregnyl Profasi HP †

Russia: Choragon Ovitrelle Pregnyl

South Africa: APL Pregnyl Profasi

Singapore Ovidrel Pregnyl Profasi †

Spain: Ovitrelle Profasi HP †

Sweden: Ovitrelle Pregnyl Profasi †

Switzerland: Choriomon Ovitrelle Pregnyl Profasi †

Thailand: IVF-C Ovidrel Pregnyl Profasi †

Turkey: Choragon Ovitrelle Pregnyl

United Kingdom: Choragon Ovitrelle Pregnyl

USA: Chorexf Choron Gonic Novarel Ovidrel Pregnyl Profasi

Venezuela: Ovidrel Pregnyl Profasi.

Multi-ingredient

Germany: NeyNormin N (Revitorgan-Dilutionen N Nr 65)

Mexico: Gonakor

The symbol † denotes a preparation no longer actively marketed.