Clozaril (Clozapine)

Denzapine 25, 50,100 and 200 mg tablets. Clozapine

The use of Denzapine is restricted to those patients registered with the Denzapine Monitoring Services.

What Denzapine is and what it is used for

Denzapine contains clozapine, which belongs to a group of medicines called atypical antipsychotics. Antipsychotics are mainly used to treat schizophrenia. Schizophrenia is a psychiatric disorder that affects the way a person thinks and behaves.

Denzapine is used:

• to treat schizophrenia when other antipsychotic medicines have not worked or have caused severe side effects
• to treat psychotic disorders occurring in patients with Parkinson’s disease, when standard treatment has failed

Denzapine is available only with a doctor’s prescription. Ask your doctor if you have any questions about why this medicine has been prescribed for you

Before you take Denzapine

Denzapine must not be given to anyone who is unconscious or in coma.

Do NOT take Denzapine if:

You are allergic (hypersensitive) to clozapine or to any of the other ingredients of the Denzapine tablets. It is important to tell your doctor if you think you have ever had an allergic reaction to any of these ingredients.

Symptoms of an allergic reaction can include:

• swelling of the face and mouth itchy skin rashes or hives difficulty breathing faintness If you are unable to digest lactose (milk sugar), due to one of the following conditions: galactose intolerance Lapp-lactase deficiency glucose-galactose malabsorption
• You are unable to undergo regular blood tests
• You have a low number of white cells in the blood (granulocytopenia/agranulocytosis)
• You have ever had a low white blood cell count that was unexplained or was caused by
• medicinal treatment (except anticancer treatment)
• You are receiving treatment with other medicines that can cause a fall in the number of white
• blood cells
• You have suffered from a very low white blood cell count (agranulocytosis) caused by
• previous treatment with Denzapine
  

You have any of the following diseases:

• Disorders of the bone marrow (when the bone marrow does not make enough blood cells)
• Uncontrolled epilepsy (fits or seizures)
• Acute mental illness caused by alcohol, medicines or other substances
• Poisoning caused by other medicines
• Circulatory collapse (a very pronounced fall in the blood pressure that may lead to unconsciousness)
• Disorders affecting the brain that can lead to drowsiness or unconsciousness
• Severe kidney disease
• Heart disease (such as myocarditis, pericarditis or cardiomyopathy)
• Active liver disease with jaundice (yellow colouration of the skin and eyes), feeling sick and loss of appetite
• Liver failure (very serious liver disease)
• Paralytic ileus (a disorder of the small intestine)

Take special care with Denzapine

Please tell your doctor if you have or have had any medical conditions or illnesses, especially the following:

• Low number of white blood cells (leukopenia, neutropenia, granulocytopenia, agranulocytosis)
• High number of a certain type of white blood cells called eosinophil granulocytes (eosinophilia)
• Low number of platelets in the blood (thrombocytopenia)
• Pericarditis or pericardial effusion (inflammation of the membranes around the heart)

If you or any member of your family have changes on the heart trace (ECG)

• Orthostatic hypotension (a fall in the blood pressure on standing up)
• Epilepsy or fits, even if they are well controlled
• Liver disease
• Enlargement of the prostate
• Glaucoma (raised pressure in the eye)
• Constipation, paralytic ileus, disease of the large bowel or operations on the abdomen
• Fever

• Neuroleptic Malignant Syndrome, a serious reaction to some anti-psychotic medicines.
• Symptoms include a sudden increase in body temperature, sweating, a fast heart beat, muscle
• stiffness and a fluctuating blood pressure. It can lead to coma.
• Diabetes
• Stroke
• Blood clots in your veins (thromboembolism). If you are not mobile you are at increased risk of developing blood clots while taking Denzapine.

If you or someone else in your family has a history of blood clots, as medicines like these have been associated with formation of blood clots

Also tell your doctor if you are taking any other antipsychotic medicines.

Denzapine may lower the number of your white blood cells, making you more prone to infections. Before and during your treatment with Denzapine, your doctor will monitor your blood count closely to make sure that the number of your white blood cells do not fall under a certain level. Please tell your doctor if you develop any signs of infection, such as fever, sore throat or flu-like symptoms.

If this medicine makes you feel dizzy, light-headed or faint, be careful when getting up from a sitting or lying position. Denzapine may lower your blood pressure, especially at the start of treatment. These symptoms can usually be prevented by getting up slowly and flexing leg muscles and toes to get the blood circulating. When getting out of bed, dangle your legs over the side for a minute or two before standing up.

Be careful when drinking alcohol or when taking antihistamines (medicines used for hay fever, allergies or colds), sleeping tablets or tablets to relieve pain while taking this medicine. Denzapine can increase drowsiness caused by alcohol and by medicines affecting your nervous system.

Denzapine may affect the way your body controls temperature, and it may prevent sweating even in very hot weather. Exercise, hot baths or saunas may make you feel dizzy or faint while you are taking this medicine.

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.

Some medicines must NOT be used when you are taking Denzapine. These include:

Medicines that affect the bone marrow. These can decrease the number of blood cells produced by the bone marrow. They include:

some antibiotics (e.g. co-trimoxazole, chloramphenicol, sulphonamides) certain pain-killers (e.g. phenylbutazone, oxybutazone, antipyrine, dipyrone) penicillamine (for rheumatoid arthritis)

carbamazepine (for epilepsy and for neuralgic pain) cytotoxic (anticancer) medicines

Other antipsychotic medicines (neuroleptics), especially when given as a depot (for long-term treatment)

Other medicines can be affected by Denzapine or may affect how well Denzapine works. Your doctor will tell you what medicines you can take and their doses. Please also consult your doctor if you are taking any of the medicines listed below:

Medicines that can make you drowsy e.g. morphine (for pain), benzodiazepines (sleeping pills) and antihistamines (for allergies) such as loratadine, chlorpheniramine

Anticholinergic medicines, which are used to relieve stomach cramps, spasms and travel sickness

Medicines used to treat high blood pressure, e.g. metoprolol, captopril, enalapril.

Medicines used to treat a fast or irregular heart beat (antiarrhythmics, e.g. flecainide, pilsicainide)

Medicines that can cause changes on the heart trace (ECG). Your doctor will know which these medicines are

Medicines that can cause constipation, particularly certain medicines to treat psychosis, depression or Parkinson’s disease. Your doctor will know which these medicines are Atropine, a medicine which may be used in some eye drops or cough preparations

Medicines which may cause excessive salt loss, such as diuretics (water tablets) Adrenaline (epinephrine), a medicine used in emergency situations Warfarin, a medicine to prevent blood clots

• Digoxin (for heart diseases)
• Cimetidine, used for stomach ulcers
• Erythromycin and rifampicin (antibiotics)
• Medicines to treat fungal infections, such as ketoconazole, itraconazole and miconazole
• Medicines to treat epilepsy e.g. phenytoin, carbamazepine, valproic acid
• Medicines for depression, such as fluvoxamine, fluoxetine, paroxetine, sertraline, citalopram,
• amitriptyline, phenelzine, moclobemide, chlorpromazine, mesoridazine or fluphenazine
• Lithium (for mental disorders)
• Medicines which affect how your body eliminates clozapine. Your doctor will know which these medicines are.
• Omeprazole (a drug used to treat excess stomach acid)

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking Denzapine.

Taking Denzapine with food and drink

You can take your Denzapine tablet with or without food.

Denzapine  may increase the effect of alcohol. Therefore, you should not drink alcohol during treatment.

Coffee can affect the levels of clozapine (the active substance of  Denzapine ) in your blood.

You may drink coffee. However, if you stop drinking coffee suddenly, the levels of clozapine in your blood may fall. This will make the medicine less effective. Equally, if you start drinking coffee, the levels may rise, increasing the risk of side effects.

Smoking

Smoking can affect the levels of clozapine in your blood. If you stop smoking suddenly, the levels of clozapine in your blood may rise. This may increase in the risk of side effects.

Children

Denzapine  is not recommended for use in children.

Pregnancy

Tell your doctor if you are or think you may be pregnant or if you are planning to become pregnant.

There is limited information on the safety of Denzapine tablets in pregnancy. Your doctor will discuss with you the risks and benefits of taking this medicine during pregnancy.

Some women taking antipsychotic medicines have irregular or no periods. If you have been affected in this way, your periods may return when your medication is changed to  Denzapine .

In these circumstances you should be sure to take adequate contraceptive precautions.

Breast-feeding

If you are breast-feeding, Denzapine can reach your baby through your breast milk. Denzapine should not be used when breast-feeding.

Driving and using machines

You may feel tired, drowsy, dizzy or you may feel faint while taking  Denzapine , especially during the early stages of treatment. If you have any of these symptoms, do not drive, operate machinery or do any tasks where you need to be alert.

How to take Denzapine

Your dose of Denzapine has been determined by your doctor. The dose will depend on how well you respond to the medicine. It will also depend on the other medicines you are taking and other medical conditions you may have. The dose may be altered from time to time.

If you have heart, kidney or liver disease, epilepsy or are elderly, or if you are taking any other medicines that may affect the way Denzapine works, your doctor may start you on a lower dose to prevent unwanted effects. The dose will be increased slowly.

When changing from a previous antipsychotic treatment to Denzapine , the first treatment should be gradually withdrawn before starting Denzapine .

Carefully follow all the instructions given to you by your doctor and pharmacist. Their instructions may differ from the information contained in this leaflet. If you do not understand the instructions on the label, ask your doctor or pharmacist for help. Take Denzapine exactly as prescribed by your doctor to prevent unwanted side effects.

Do not take more or less Denzapine than your doctor has prescribed. If you think the dose is too weak or too strong, talk to your doctor.

Dosage

The total amount of Denzapine you take each day is usually divided into two doses. If you have to divide your dose, you should take the larger dose at bed time. However, if your total daily dose is not over 200 mg, it is not necessary to divide the dose. In this case, it is usually taken in the evening.

Swallow Denzapine tablets with a full glass of water or other liquid. Taking the tablets at the same time each day will have the best effect and will help you remember to take them.

Schizophrenic patients resistant to other treatments

When you first start taking  Denzapine , the usual dose is half a 25 mg tablet (12.5 mg) taken once or twice on the first day, followed by one or two 25 mg tablets taken on the second day. If this dose is well tolerated, it may be increased gradually, usually to between 200 mg and 450 mg per day.

However, some people may need a higher dose. The maximum permissible dose is 900 mg per day. Once the maximum benefit is achieved, your doctor may reduce the dose gradually to a lower level. Your doctor will determine the most appropriate dose for you.

Parkinsonian patients with psychotic disorders that do not respond to standard treatment.

The initial dose is of 12.5 mg (half a 25 mg tablet) taken in the evening. The dose is gradually increased to a maximum of 50 mg per day, taken in the evening. The effective dose is usually between 25 mg and 37.5 mg (one to one-and-a-half 25 mg tablets). If the 50 mg dose is not effective, it can be increased to 100 mg in some patients. This dose (100 mg) must not be exceeded.

Elderly patients:

Denzapine  tablets can be used in the elderly (over 65 years of age). Treatment usually begins with a lower dose (e.g. 12.5 mg daily), which is then gradually increased.

Duration of treatment:

You should take Denzapine for at least 6 months. Do not stop taking this medicine without first talking to your doctor.

While taking Denzapine

Tell all of the doctors and pharmacists who are treating you that you are taking  Denzapine . You must have regular blood tests while taking  Denzapine .

Blood tests

Before starting Denzapine you will have a blood test to make sure that you can take this medicine.

Denzapine  can cause agranulocytosis. In this condition, the number of white blood cells (which are necessary to fight infection) is too low. If this occurs, you are at risk of suffering infections which may be life-threatening. Warning signs include flu-like symptoms, a sore throat or fever. If you develop these or any other signs suggestive of infection, you should contact your doctor immediately.

There is no way of knowing who is at risk of developing agranulocytosis. Deaths have occurred in severe cases of agranulocytosis, although with regular blood tests, agranulocytosis can be detected early. If Denzapine is stopped as soon as a problem is detected, the white blood cell numbers should return to normal. You must understand the importance of regular blood tests by your doctor while taking Denzapine .

After starting treatment with Denzapine , you will have a blood test once a week for the first 18 weeks. The risk of agranulocytosis is highest in this period. For the rest of the first year of treatment, blood tests will be performed every 2 weeks. After the first year, tests will be performed every 4 weeks for as long as you continue to take Denzapine . Tests will also be performed for one month after stopping the medicine. These tests will tell the doctor if there is any problem with number of white cells in your blood. There are some situations where you may need to have blood tests more often (e.g. twice a week). Your doctor will talk to you about this.

If the number of your white blood cells falls below a critical level, Denzapine must be stopped immediately and you must never take any medicines containing clozapine again.

Things which I must not do

Do not stop taking Denzapine or lower the dosage even if you are feeling better, unless your doctor tells you to do so. Your condition may worsen if you suddenly stop taking it. Your doctor will gradually reduce the amount you take each day before stopping the medicine completely.

Do not give Denzapine to anyone else even if they have the same symptoms as you. It may harm them even if their condition seems similar to yours.

Do not use Denzapine to treat other complaints unless your doctor tells you to.

If you take more Denzapine than you should

If you suspect that you or someone else has taken too many Denzapine tablets, contact a doctor immediately or go to the Accident and Emergency Department at your nearest hospital. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention. Keep the telephone numbers for these places handy.

The most common signs and symptoms of overdose include:

• drowsiness
• confusion and coma
• delirium
• agitation
• light-headedness
• a fall in the blood pressure
• collapse
• shallow or slow breathing or sometimes shortness of breath
• fast or irregular heartbeat
• dribbling –   fits.

If you forget to take Denzapine

If it is almost time for your next dose (within four hours), forget the dose you missed and take your next dose at its normal time. Otherwise take it as soon as you remember, and then go back to taking your tablets as you would normally.

If you miss a dose of Denzapine do not take a double dose to make up for the missed dose.

If you have stopped taking Denzapine for more than two days, you must contact your doctor before starting to take it again. In this case, the medicine must be started again at a low dose and then increased.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If your doctor tells you to stop taking Denzapine

If the medicine needs to be stopped abruptly due to side effects, you will be monitored closely for psychotic symptoms. Other symptoms can also arise, including increased sweating, headache, nausea (feeling sick), vomiting and diarrhoea.

Possible side effects

Blood clots in the veins especially in the legs (symptoms include swelling, pain and redness in the leg), which may travel through blood vessels to the lungs causing chest pain and difficulty in breathing. If you notice any of these symptoms seek medical advice immediately.

Like all medicines, Denzapine can cause side effects although not everybody gets them. The frequency of side effects is based on the following:

Very common:	In more than 1 in 10 patients treated
Common:	In less than 1 in 10, but more than 1 in 100 patients treated
Uncommon:	In less than 1 in 100, but more than 1 in 1,000 patients treated
Rare:	In less than 1 in 1,000, but more than 1 in 10,000 patients treated
Very rare:	In less than 1 in 10,000 patients treated, including single reports

The following side effects have been associated with  Denzapine :

Very common:

• Drowsiness
• Dizziness
• A fast heart beat (tachycardia)
• Constipation
• Hypersalivation (forming a large volume of saliva)

Common:

• A fall in the number of white cells in the blood (leukopenia, neutropenia, granulocytopenia, agranulocytosis)
• Eosinophilia (an increase in the number of a certain type of white blood cells called eosinophil granulocytes)
• Leukocytosis (an increase in the number of white blood cells)
• Weight gain
• Blurred vision
• Headache
• Tremor
• Stiffness of the limbs (rigidity)
• Restlessness (akathisia)
• Problems of coordination
• Epileptic fits (localised or generalised)
• Changes on the heart trace (ECG)
• High blood pressure (hypertension)
• A fall in the blood pressure on standing up (orthostatic hypotension)
• Fainting
• Nausea (feeling sick)
• Vomiting
• Loss of appetite (anorexia)
• Dry mouth
• Changes in the blood tests that assess how the liver is working
• Urinary incontinence
• Urinary retention (the inability to pass urine)
• Fatigue
• Fever
• Benign hyperthermia (drug fever; changes in body temperature caused by certain medicines)
• Alterations in the body’s control of temperature
• Alterations of sweating

Uncommon:

• Agranulocytosis (a very low number of white cells in the blood) Neuroleptic malignant syndrome (fever, sweating, a fast heart beat, muscle stiffness and changes in the blood pressure)

Rare:

• Impaired glucose tolerance (excess sugar levels in the blood)
• Diabetes mellitus
• Restlessness (agitation)
• Confusion
• Delirium
• Circulatory collapse (a very low blood pressure that can lead to unconsciousness)
• Irregular heart beat (arrhythmia)
• Ventricular arrhythmias (life-threatening disorders of the heart. These are medical emergencies.)
• Inflammation of the heart muscle (myocarditis)
• Pericarditis (inflammation of the membranes around the heart)
• Pericardial effusion (a collection of liquid in the membranes around the heart)
• Inhaling of food into the lungs (aspiration)
• Difficulty swallowing (dysphagia)
• Inflammation of the liver (hepatitis)
• Jaundice (yellow colouration of the skin and eyes)
• Inflammation of the pancreas (pancreatitis)
• A rise in the CPK values (a blood test)
• A low number of red blood cells (anaemia)

Very rare:

• A fall in the number of platelets in the blood (thrombocytopenia)
• Complications of excessive sugar in the blood (severe hyperglycaemia, ketoacidosis, hyperosmolar coma)
• Excessive fat in the blood (hypertriglyceridaemia)
• Tardive dyskinesia (slow, abnormal movements of the face, tongue and limbs)
• Disease of the heart muscle (cardiomyopathy)
• Cardiac arrest
• Torsades de pointes (a life-threatening disorder of the heart. This is a medical emergency.)
• Very slow or shallow breathing (respiratory depression)
• Absence of breathing (respiratory arrest)
• Enlargement of the parotid glands (salivary glands)
• Altered bowel movement (intestinal obstruction, paralytic ileus, faecal impaction)
• Death of the liver (fulminant hepatic necrosis)
• Skin reactions
• Inflammation of the kidney (interstitial nephritis)
• A persistent and possibly painful erection (priapism)
• Sudden unexplained death

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 Denzapine

Keep Denzapine out of the reach and sight of children.

A locked cupboard at least one and a half metres from the ground is a good place to store medicines.

Do not take Denzapine after the expiry date shown on the outer carton or on the blister strip. The expiry date refers to the last day of that month.

Do not take Denzapine if the packaging is damaged or shows signs of tampering.

Do not store above 30°C. Store in the original packaging. Keep in the outer carton to protect from light

Keep your tablets in the original container until it is time to take them. Do not store Denzapine or any medicine in the bathroom or near a sink. Do not leave it in a car or on a window sill. Heat and dampness can destroy medicines. If your tablets appear to change in their appearance or show any other apparent signs of deterioration, do not take the tablets but refer immediately to the pharmacist.

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

Further information

What Denzapine contains

The active substance is clozapine.

One Denzapine 25 mg tablet contains 25 mg clozapine. One Denzapine 50 mg tablet contains 50 mg clozapine. One Denzapine 100 mg tablet contains 100 mg clozapine. One Denzapine 200 mg tablet contains 200 mg clozapine.

The other ingredients are

• Microcrystalline cellulose
• Lactose monohydrate
• Povidone
• Sodium starch glycolate
• Magnesium stearate

What Denzapine looks like and contents of the pack

Denzapine  25 mg tablets are small, round, yellow tablets with “25″ embossed over a breakline on one face, the other side is plain.

Denzapine  50 mg tablets are small, round, yellow tablets with “50″ embossed over a breakline on one face, the other side is plain.

Denzapine  100 mg tablets are small, round, yellow tablets with “100″ embossed over a breakline on one face, the other side is plain.

Denzapine  200 mg tablets are large, oval shaped, yellow tablets with “200″ on one side and a breakline on the other side..

The breakline allows the tablet to be broken for easier swallowing.

Denzapine  25 and 100 mg tablets are supplied in bottles of 100 tablets and in blister packs containing 28 or 84 tablets.

Denzapine  50 mg tablets are supplied in bottles of 100 tablets and in blister packs containing 20 or 50 tablets.

Denzapine  200 mg tablets are supplied in blister packs containing 50 tablets.

The quantity provided to you by the pharmacy will be determined by your doctor.

Precautions

Chlorpromazine and other phenothiazines are contra-indicated in patients with pre-existing CNS depression or coma, bone-marrow suppression, phaeochromocytoma, or prolactin-dependent tumours. They should be used with caution or not at all in patients with impaired liver, kidney, cardiovascular, cerebrovascular, and respiratory function and in those with angle-closure glaucoma, a history of jaundice, parkinsonism, diabetes mellitus, hypothyroidism, myasthenia gravis, paralytic ileus, prostatic hyperplasia, or urinary retention.

Care is required in patients with epilepsy or a history of seizures as phenothiazines may lower the seizure threshold. Debilitated patients may be more prone to the adverse effects of phenothiazines as may the elderly, especially those with dementia. For precautions of phenothiazines in pregnancy, see below. The sedative effects of phenothiazines are most marked in the first few days of treatment affected patients should not drive or operate machinery.

The effects of phenothiazines on the vomiting centre may mask the symptoms of overdosage of other drugs, or of disorders such as gastrointestinal obstruction. Use at extremes of temperature may be hazardous since body temperature regulation is impaired by phenothiazines.

Regular eye examinations are advisable for patients receiving long-term phenothiazine therapy and avoidance of undue exposure to direct sunlight is recommended. Phenothiazines should be used with caution in the presence of acute infection or leucopenia. Blood counts are advised if the patient develops an unexplained infection or fever.

Patients should remain supine for at least 30 minutes after parenteral doses of chlorpromazine blood pressure should be monitored.

Abrupt withdrawal of phenothiazine therapy is best avoided.

AIDS

Isolated reports’ have suggested that patients with AIDS may be particularly susceptible to antipsychotic-induced extrapyramidal effects.

Asthma

Findings of a retrospective case-control study appeared to indicate that asthmatic patients given antipsychotics were at an increased risk of death or near death from asthma.

Breast feeding

The American Academy of Pediatrics considers that the use of chlorpromazine by mothers during breast feeding may be of concern, since there have been reports of galactorrhoea in the mother and of drowsiness, lethargy, and declines in developmental scores in the infant. The BNF considers that the use of antipsychotics such as chlorpromazine should be avoided by breast-feeding mothers unless absolutely necessary. Chlorpromazine was detected in all milk samples from 4 women at concentrations ranging from 7 to 98 nanograms/mL. Two of the women breast-fed their infants, but one infant showed no effects while the other was noted to be drowsy and lethargic milk-chlorpromazine concentrations were 7 and 92 nanograms/mL, respectively.

Children

Few phenothiazines are recommended for use in children in particular there have been concerns about the use of phenothiazine derivatives in infants (see Sudden Infant Death Syndrome). For reference to the use of chlorpromazine in infants suffering neonatal abstinence syndrome see Substance Dependence, Opioids, under Uses and Administration, below. References.

Contact sensitisation

The BNF warns that because of the risk of contact sensitisation, health workers should avoid direct contact with chlorpromazine tablets should not be crushed and solutions should be handled with care.

The elderly

The risk of hip fracture has been reported to be increased in elderly patients given antipsychotics. A large case-control study in patients over 65 found that current users of antipsychotics had a twofold increase in the risk of hip fractures. The effect was dose-related and the increased risk was similar for chlorpromazine, haloperidol, and thioridazine. It was suggested that antipsychotic-induced sedation or orthostatic hypotension could increase the risk of falls in elderly persons.

A study in 12 schizophrenic patients receiving antipsychotics plus other drugs such as antimuscarinics or benzodiazepines has suggested that long-term treatment with antipsychotics may decrease bone mineralisation. A later study suggested that any increased risk of falls might be due to an effect of antipsychotics on balance as thioridazine was found to increase sway in elderly but not young subjects. A meta-analysis of 40 studies concluded that there was a small, but consistent, association between the use of most classes of psychotropic drugs, including antipsychotics, and falls. However, the evidence from these studies was based solely on observational data, with minimal adjustment for confounders, dosage, or duration of therapy.

There is some evidence to suggest that the use of antipsychotics to manage behavioural complications of dementia may increase the rate of cognitive decline. Elderly patients with dementia, especially Lewy-body dementia, are reported to be highly susceptible to the extrapyramidal adverse effects of antipsychotic drugs, and the reaction can be extremely serious, even fatal. If these drugs are to be used in elderly patients with dementia, then very low doses should be used, and special care should be taken if the dementia is suspected to be of the Lewy-body type since sudden life-threatening deterioration may occur.

Depot preparations should not be used and, since dopamine D₂ receptors may be involved, it has been suggested that consideration could be given to using an antipsychotic such as clozapine that does not principally antagonise those receptors however, the FDA now recommends that atypical antipsychotics should not be used in such patients because of evidence of an increased death rate (see Dementia).

An increased risk of death has also been noted in elderly patients given classical antipsychotics. A retrospective cohort study, involving nearly 23 000 patients given atypical or classical antipsychotics, found that classical antipsychotics were at least as likely as the atypicals to increase the risk of death in the elderly. The authors also suggested that the greatest increase in risk occurred soon after starting therapy and with higher doses of classical antipsychotics. A similar increase in risk with use of classical antipsychotics was also seen in a large retrospective population-based study in elderly patients with dementia when compared with that seen with use of atypicals in this patient group.

For further discussion of the problems associated with the use of antipsychotics in disturbed behaviour in the elderly.

Epilepsy

See Convulsions under Adverse Effects, above.

Folic acid deficiency

Concentrations of folate in serum and erythrocytes were reduced in 15 patients receiving long-term treatment with chlorpromazine or thioridazine. All the patients had significant induction of hepatic microsomal enzymes. It was suggested that folate deficiency due to the induction of microsomal enzymes might subsequently limit enzyme induction and hence reduce drug metabolism, which could lead to symptoms of toxicity in patients apparently stabilised for a number of years. The dietary intake of patients on long-term treatment with enzyme-inducing drugs might be inadequate.

Hypoparathyroidism

There have been rare reports’ of acute dystonic reactions associated with the use of phenothiazines in patients with untreated hypoparathyroidism. Caution was recommended in giving phenothiazine derivatives to patients with hypoparathyroidism and it was suggested that any acute reaction to such a drug should prompt investigation for some form of latent tetany.

Pregnancy

Licensed product information generally does not recommend the use of phenothiazines in late pregnancy such use may be associated with intoxication of the neonate. Chlorpromazine may prolong labour and should be withheld until the cervix is dilated 3 to 4 cm. Overall, however, it has been suggested that the criteria for the selection of an antipsychotic for use in pregnant women do not differ from those used in non-pregnant women. It was also concluded that the benefits of continuing antipsychotic treatment at the minimum effective dose would usually outweigh any risks to the fetus.

A review of the use of phenothiazines in pregnancy concluded that there was no clear evidence that these drugs caused a significant increase in fetal malformations. Nevertheless it was considered advisable that if pregnant patients required such treatment, then a single phenothiazine should be used and that it should be one of the established drugs.

A subsequent review of the literature reported that women with schizophrenia are generally at increased risk for poor obstetric outcomes including preterm delivery, low birth-weight, and ne-onates who are small for their gestational age. It was also considered that there was an increased risk of congenital malformation when the fetus was exposed to phenothiazines during weeks 4 to 10 of gestation but this conclusion and the methods used to select the data to review have been criticised

See also for the use of phenothiazines as antiemetics during pregnancy.

Renal impairment

Although there do not seem to be specific indications for dosage adjustment of phenothiazines in renal impairment, the BNF considers that cerebral sensitivity to antipsychotics may be increased in severe renal impairment. Phenothiazine-induced toxic psychosis occurred in 4 patients with chronic renal failure who had been given chlorpromazine.

Interactions

The most common interactions encountered with phenothiazines such as chlorpromazine result from use with drugs that have similar pharmacological actions. Symptoms of CNS depression may be enhanced by other drugs with CNS-depressant properties including alcohol, general anaesthetics, hypnotics, anxiolytics, and opioids. When given with other drugs that produce orthostatic hypotension, dosage adjustments may be necessary. However, it should be noted that phenothiazines have been reported to reduce the antihypertensive action of guanethidine and other adrenergic neurone blockers.

As many phenothiazines possess antimuscarinic actions they can potentiate the adverse effects of other drugs with antimuscarinic actions, including tricyclic antidepressants and the antimuscarinic antiparkinsonian drugs that may be given to treat phenothiazine-induced extrapyramidal effects. In theory, antipsychotics with dopamine-blocking activity and dopaminergic drugs such as those used to treat parkinsonism may be mutually antagonistic. Use with metoclopramide may increase the risk of antipsychotic-induced extrapyramidal effects.

There is an increased risk of arrhythmias when antipsychotics are used with drugs that prolong the QT interval, including certain antiarrhythmics, other antipsychotics, some non-sedating antihistamines, antimalarials, and cisapride use with diuretics that cause electrolyte imbalance (particularly hypokalaemia) may also have the same effect. There is also an increased risk of arrhythmias when tricyclic antidepressants are used with antipsychotics that prolong the QT interval. Because of an increased risk of seizures US licensed product information for chlorpromazine recommends withdrawal before the use of metrizamide for radio-graphic procedures.

Most interactions with antipsychotics are as a result of additive pharmacological effects. Since tolerance develops to many of these adverse effects, interactions are likely to be most important in the early stages of combination therapy.

Alcohol

Phenothiazines may increase the CNS depressant effects of alcohol. There has been a report of akathisia and dy stonia after consumption of alcohol by patients taking antipsychotics alcohol might lower the threshold of resistance to neurotoxic adverse effects.

Antacids

Studies in 6 patients showed that chlorpromazine plasma concentrations were significantly lower after giving chlorpromazine with an aluminium hydroxide and magnesium trisilicate antacid gel (Gelusil) than after chlorpromazine alone. In-vitro studies indicated that chlorpromazine was highly bound to the gel.

Antiarrhythmics

There is an increased risk of arrhythmias when antipsychotics are given with other drugs that prolong the QT interval. It has been recommended that the use of pimozide or thioridazine with antiarrhythmics (especially amiodarone, disopyramide, procainamide, and quinidine) should be avoided. Use of haloperidol with amiodarone is also not recommended. A study in healthy subjects has suggested that quinidine might increase plasma concentrations of haloperidol.

Antibacterials

Seven schizophrenic patients whose antituber-cular therapy included rifampicin (in addition to isoniazid, and in some cases also ethambutol) had lower serum concentrations of haloperidol compared with tuberculotic schizophrenic patients receiving no antimycobacterials and with non-tuberculotic schizophrenics. Pharmacokinetic studies involving some of these patients indicated accelerated haloperidol clearance in the presence of rifampicin. Abnormally high serum-haloperidol concentrations were observed in 3 of 18 patients treated with isoniazid alone.

Black galactorrhoea occurred in a patient receiving minocycline, perphenazine, amitriptyline hydro chloride, and diphenhydramine hydrochloride. Simultaneous occurrence of phenothiazine-induced galactorrhoea and tetracycline-induced pigmentation was considered responsible.

Sudden cardiac deaths have been reported in patients given clarithromycin and pimozide. Elevated pimozide plasma concentrations were recorded after pretreatment with clarithromycin. The manufacturer of pimozide has recommended that pimozide should not be used with macrolide antibacterials.

Anticoagulants

For reference to the effects of some antipsychotics on the activity of anticoagulants, see under Warfarin.

Antidepressants

Interactions between antipsychotics and tricyclic antidepressants are generally of two forms: additive pharmacological effects such as antimuscarinic effects or hypotension or pharmacokinetic interactions. Although not commonly reported in the literature, additive antimuscarinic activity may be a significant risk especially in the elderly. Careful drug selection might help to prevent the development of serious adverse effects. Mutual inhibition of liver enzymes involved in the metabolism of both the antipsychotic and the tricyclic antidepressant might result in increased plasma concentrations of either drug. In one study, addition of nortriptyline to chlorpromazine therapy produced an increase in plasma concentrations of chlorpromazine but this resulted in a paradoxical increase in agitation and tension.

There is an increased risk of arrhythmias when tricyclic antidepressants are given with other drugs that prolong the QT interval. It has been recommended that the use of pimozide or thioridazine with tricyclic antidepressants should be avoided. Increased serum concentrations of haloperidol have occurred when patients were also given fluoxetine, fluvoxamine or nefazodone. Isolated reports of extrapyramidal symptoms, psychoneuromotor syndrome, stupor, bradycardia, and urinary retention associated with use of fluoxetine with antipsychotics suggest that fluoxetine might exacerbate the adverse effects of antipsychotics or produce additive toxicity.

Similar CNS effects have been noted in subjects given perphenazine and paroxetine® There has also been an isolated report of a patient who complained of amenorrhoea and galactorrhoea after fluvoxamine was added to loxapine therapy. Significant increases in the plasma concentrations of thioridazine have occurred after use with fluvoxamine. Paroxetine may also inhibit the metabolism of thioridazine, resulting in increased thioridazine plasma concentrations UK licensed product information for paroxetine contra-indicates their concomitant use. The US licensed product information for paroxetine states that giving paroxetine with pimozide was associated with a mean increase of 151 % in the area under the concentration-time curve of pimozide and 62% in its mean maximum plasma concentration. Due to the narrow therapeutic index of pimozide concomitant use of these 2 drugs is contra-indicated.

Combinations of antipsychotics and lithium should be used with care. Lithium can reduce plasma-chlorpromazine concentrations and there is a report of ventricular fibrillation on withdrawal of lithium from a patient also taking chlorpromazine. Chlorpromazine has also been reported to enhance the excretion of lithium. Neurotoxic or extrapyramidal symptoms have been reported rarely in patients taking antipsychotics and lithium these may be atypical cases of lithium toxicity or neuroleptic malignant syndrome. The above issues are discussed in detail, and references given.

A patient on long-term trifluoperazine treatment developed neuroleptic malignant syndrome after a single dose ofvenlafaxine The authors noted that the manufacturers of venlafaxine have received a small number of similar reports after introduction of venlafaxine in patients receiving antipsychotics including molindone.

There have been occasional reports of sexual disinhibition in patients taking tryptophan with phenothiazines.

Antidiabetic drugs

Since chlorpromazine may cause hyperglycaemia or impair glucose tolerance the dose of oral hypoglycaemics or of insulin may need to be increased in diabetics.

Antiepileptics

Carbamazepine, phenobarbital, and phenyioin are potent enzyme inducers and use may decrease plasma concentrations of antipsychotics or their active metabolites. The clinical effect of any interaction has not been consistent worsening, improvement, or no change in psychotic symptoms have all been noted. Delirium has been reported in a patient given haloperidol and carbamazepine. Phenytoin might also exacerbate antipsychotic-induced dyskinesia. Care should be taken when withdrawing enzyme-inducing antiepileptics as this may result in a rise in antipsychotic serum concentrations. The effect of antipsychotics on antiepileptic concentrations is discussed on carbamazepine and phenytoin. It should also be remembered that antipsychotics may lower the seizure threshold.

Antihistamines

For the effect of a preparation containing chlorphenamine maleate and phenylpropanolamine hydrochloride on thioridazine, see Sympathomimetics (below). There is an increased risk of arrhythmias when antipsychotics are given with other drugs that prolong the QT interval. It has been recommended that the use of pimozide or thioridazine with antihistamines such as astemizole or terfenadine should be avoided.

Antihypertensives

For discussion of the interaction between phenothiazines and drugs with hypotensive properties, see Interactions, above. For a report of chlorpromazine enhancing the hyperglycaemic effect of diazoxide. For reports of hypertension or dementia in patients given meihyldopa and antipsychotics.

Antimalarials

Pretreatment with single doses of chloroquine sulfate, amodiaquine hydrochloride, or sulfadoxine with pyrimeihamine increased the plasma concentrations of chlorpromazine and 7-hydroxychlorpromazine, but not of chlorpromazine sulfoxide, in schizophrenic patients maintained on chlorpromazine. The raised plasma concentrations appeared to be associated with a greater level of sedation. There is an increased risk of arrhythmias when antipsychotics are given with other drugs that prolong the QT interval. It has been recommended that the use of antipsychotics, and pimozide in particular, with antimalarials such as halofantrine, mefloquine, or quinine should be avoided. For the possible effects of the use of quinidine with antipsychotics see Antiarrhythmics, above.

Antimigraine drugs

A report of a patient receiving loxapine who had a dystonic reaction within 15 minutes of subcutaneous sumatriptan suggests that these two drugs might interact or potentiate each other’s adverse effects. However, the patient had a previous history of dystonic reactions associated with haloperidol and was receiving benzatropine prophylactic ally. Furthermore, the dose of loxapine had been increased 2 days before the event and this may have predisposed the patient to dystonia.

Antiparkinsonian drugs

Antiparkinsonian drugs are sometimes given with antipsychotics for the management of antipsychotic-induced adverse effects including extrapyramidal disorders (see under Adverse Effects, above). Theoretically, dopaminergics such as levodopa and bromocriptine might induce or exacerbate psychotic symptoms. A study in 18 subjects and review of the literature suggested that bromocriptine can be used safely in patients at risk of psychotic illness provided they are clinically stable and maintained on antipsychotics. Conversely, antipsychotics might antagonise the effects of dopaminergics diminished therapeutic effects of levodopa have been noted with several antipsychotics and thioridazine has been reported to oppose the prolactin-lowering action of bromocriptine.

Additive antimuscarinic adverse effects are obviously a risk when antimuscarinic antiparkinsonian drugs are given with antipsychotics. Although these are generally mild, serious reactions have occurred. Trihexyphenidyl and orphenadrine have both been reported to decrease plasma concentrations of chlorpromazine, possibly by interfering with absorption from the gastrointestinal tract. Reports suggesting that antimuscarinics may antagonise the antipsychotic effects of antipsychotics at the neurotransmitter level require substantiating.

Antipsychotics

Elevated plasma levels of haloperidol were reported in a patient being treated for schizophrenia when chlorpromazine or clozapine were also given.

Antivirals

Ritonavir may increase the plasma concentration of some antipsychotics. The increases expected for pimozide were considered in licensed product information for ritonavir to be large enough to recommend that these drugs should not be used together. Other classical antipsychotics predicted to have increases include haloperidol, perphenazine, and thioridazine it was recommended that monitoring of drug concentrations and/or adverse effects were required when used with ritonavir.

Beta blockers

Chlorpromazine andpropranololmay mutually inhibit each other’s hepatic metabolism. Propranolol has been reported to increase plasma concentrations of chlorpromazine and thioridazine, andpindolol to increase plasma-thioridazine concentrations. Neither beta blocker tested had a significant effect on haloperidol concentrations, although there is a report of severe hypotension or cardiopulmonary arrest occurring on 3 occasions in a schizophrenic patient given haloperidol with propranolol. The clinical significance of antipsychotic-beta blocker interactions is unclear.

For the effect of chlorpromazine on propranolol, see Anxiolytics and Antipsychotics, under Interactions of Beta Blockers. There is an increased risk of arrhythmias when antipsychotics are given with other drugs that prolong the QT interval. The use of antipsychotics, and pimozide in particular, with sotalol should be avoided.

Buspirone

The use of haloperidol with buspirone has resulted in increased serum haloperidol concentrations. However, while some found the mean rise in serum-haloperidol concentrations to be 26%, that observed by others was not statistically significant.

Cimetidine

Despite expectations that cimetidine might reduce the metabolism of chlorpromazine, mean steady-state plasma concentrations of chlorpromazine fell rather than rose in 8 patients given cimetidine for 7 days in addition to regular chlorpromazine therapy. The explanation was probably that cimetidine interfered with chlorpromazine absorption. Excessive sedation, necessitating a reduction in chlorpromazine dosage, has been reported after addition of cimetidine to the drug therapy of 2 chronic schizophrenics.

Cocaine

The risk of antipsychotic-induced dystonic reactions may be increased in cocaine abusers. Dystonia occurred in 6 of 7 cocaine abusers treated with haloperidol.

Desferrioxamine

Loss of consciousness lasting 48 to 72 hours occurred in 2 patients given prochlorperazine during desferrioxamine therapy. Prochlorperazine may enhance the removal of transition metals from brain cells by desferrioxamine.

Disulfiram

A psychotic patient, previously maintained with plasma-perphenazine concentrations of 2 to 3 nanomol/mL on a dose of 8 mg twice daily by mouth, was readmitted with subtherapeutic plasma-perphenazine concentrations of less than 1 nanomol/mL, despite unchanged dosage, after disulfiram therapy. The concentration of the sulfoxide metabolite of perphenazine was much increased. After a change from oral to intramuscular perphenazine therapy there was a substantial clinical improvement associated with a return to therapeutic plasma concentrations of perphenazine and a fall in concentration of the metabolite. Disulfiram appears to greatly enhance biotransforma-tion of oral perphenazine to inactive metabolites, but parenteral administration avoids the ‘first-pass’ effect in the liver.

General anaesthetics

A schizophrenic patient without a history of epilepsy who was receiving oral chlorpromazine and fiupentixol depot injection had a convulsive seizure when given enflurane anaesthesia.

Naltrexone

Two patients maintained on thioridazine experienced intense sleepiness and lethargy after receiving 2 doses of naltrexone.

NSAIDs

A report of severe drowsiness and confusion in patients given haloperidol with indometacin.

Opioid analgesics

For reference to the effects of phenothiazines onpethidine.

Piperazine

There has been an isolated report of convulsions associated with the use of chlorpromazine in a child who had received piperazine several days earlier. Subsequent animal studies produced conflicting evidence for an interaction and it was suggested that an interaction would only be clinically significant when high concentrations of piperazine were reached in the body.

Sympathomimetics

For reference to the possible interaction between phenothiazines and adrenaline, see Treatment of Adverse Effects, above.

A 27-year-old woman with schizophrenia and T-wave abnormality of the heart, receiving thioridazine 100 mg daily withprocyclidine 2.5 mg twice daily, died from ventricular fibrillation within 2 hours of also taking a single dose of a preparation reported to contain chlorphenamine maleate 4 mg with phenylpropanolamine hydrochloride 50 mg (Contac C).

Tobacco smoking

Smoking has been shown to decrease the incidence of chlorpromazine-induced sedation and orthostatic hypotension. Studies indicate that the clearance of chlorpromazine, fluphenazine, tiotixene, haloperidol, and thioridazine may be increased in patients who smoke. It has been suggested that some of the components of smoke may act as liver-enzyme inducers. The clinical significance of this effect is unclear but the possible need to use increased doses in smokers should be borne in mind.

Vitamins

Giving ascorbic acid, for vitamin C deficiency, to a patient receiving fluphenazine for bipolar disorder was associated with a fall in serum concentrations of fluphenazine and a deterioration of behaviour.

Xanthine-containing beverages

Studies in vitro have shown precipitation of some antipsychotics from solution by addition of coffee and tea. However, in a study of 16 patients taking antipsychotics no correlation could be found between plasma-antipsychotic concentrations or behaviour and tea or coffee consumption.

Pharmacokinetics

Chlorpromazine is readily, although sometimes erratically, absorbed from the gastrointestinal tract peak plasma concentrations are attained 2 to 4 hours after ingestion. It is subject to considerable first-pass metabolism in the gut wall and is also extensively metabolised in the liver and is excreted in the urine and bile in the form of numerous active and inactive metabolites there is some evidence of enterohepatic recycling. Owing to the first-pass effect, plasma concentrations after oral doses are much lower than those after intramuscular doses.

Moreover, there is very wide intersubject variation in plasma concentrations of chlorpromazine no simple correlation has been found between plasma concentrations of chlorpromazine and its metabolites, and their therapeutic effect (see Administration under Uses and Administration, below). Paths of metabolism of chlorpromazine include hydroxylation and conjugation with glucuronic acid, N-oxidation, oxidation of a sulfur atom, and dealkylation.

Although the plasma half-life of chlorpromazine itself has been reported to be about 30 hours, elimination of the metabolites may be very prolonged. There is limited evidence that chlorpromazine induces its own metabolism. Chlorpromazine is about 95 to 98% bound to plasma proteins. Itis widely distributed in the body and crosses the blood-brain barrier to achieve higher concentrations in the brain than in the plasma. Chlorpromazine and its metabolites also cross the placenta and are distributed into breast milk.

Bioavailability.

Mean plasma concentration of clozapine increased from 329 to 629 nanograms/mL in 10 patients when switched from an extemporaneous liquid formulation to conventional tablets.

Uses and Administration

Clozapine is a dibenzodiazepine derivative and the prototype of the atypical antipsychotics. It has relatively weak dopamine receptor-blocking activity at D₁, D₂, D₃, and D₅ receptors but has a high affinity for the D₄ receptor. Clozapine possesses alpha-adrenergic blocking, antimuscarinic, antihistaminic, antiserotonergic, and sedative properties.

Clozapine is used for the management of schizophrenia however, because of the risk of agranulocytosis, it is reserved for patients who fail to respond to other antipsychotics, including other atypicals, or who experience severe neurological effects with such drugs. In the USA, it may also be used for reducing the risk of recurrent suicidal behaviour in those with schizophrenia or schizoaffective disorder who are at chronic risk for suicidal behaviour. In the UK, it is also used in the management of treatment-resistant psychoses associated with Parkinson’s disease.

Clozapine use must be accompanied by strict procedures for the monitoring of white blood cell counts (see Precautions, above). To minimise the incidence of adverse effects, clozapine therapy should be introduced gradually, beginning with low doses and increasing according to response.

In the treatment of schizophrenia, including reducing the risk of suicidal behaviour, the usual oral dose is 12.5 mg once or twice on the first day followed by 25 mg once or twice on the second day. Thereafter the daily dosage may be increased gradually in steps of 25 to 50 mg to achieve a daily dose of up to 300 mg within 14 to 21 days (in the USA, up to 450 mg daily is permitted by the end of 2 weeks). Subsequent increases in steps of 50 to 100 mg may be made once or twice weekly a daily dosage of 900 mg should not be exceeded.

Once a therapeutic response has been obtained, a gradual reduction of dosage to a suitable maintenance dose is recommended most patients respond to 200 to 450 mg daily. The total daily dose is given in divided doses a larger portion may be given at night. Daily maintenance doses of 200 mg or less may be given as a single dose in the evening. If clozapine is to be withdrawn, this should be done gradually over a 1- to 2-week period. However, immediate withdrawal with careful observation is essential if neutropenia develops or if myocarditis or cardiomyopathy is suspected (see Precautions, above).

Elderly patients may require lower doses of clozapine and it is recommended that treatment should start with a dose of 12.5 mg on the first day and that subsequent dose increments should be restricted to 25 mg. For patients who are restarting treatment after an interval of more than 2 days, 12.5 mg may be given once or twice on the first day. If this dose is well tolerated it may be possible to increase the dosage more quickly than when first starting.

However, patients who have had respiratory or cardiac arrest with initial dosing, but were then successfully titrated to a therapeutic dose, should be re-titrated with extreme caution after a break of even 24 hours. Additional monitoring of blood cell counts may also be required if treatment is interrupted, see Treatment Break, under Monitoring, above. It is recommended that oral therapy with other antipsychotics should be withdrawn gradually before treatment with clozapine is started. Clozapine has also been given by intramuscular injection.

In the management of treatment-resistant psychoses in Parkinson’s disease, the initial oral dose of clozapine is no more than 12.5 mg once daily in the evening. Thereafter, the daily dosage may be increased in increments of 12.5 mg up to twice a week a dose of 50 mg daily should not be reached before the end of the second week. The usual dose ranges from 25 to 37.5 mg daily. Increases in the daily dose above 50 mg should only be made in exceptional cases in increments of 12.5 mg at weekly intervals up to a maximum of 100 mg daily. The total daily dose should preferably be given as a single dose in the evening.

Dosage of anti-parkinsonian drugs may be increased when there has been complete remission of psychotic symptoms after at least 2 weeks of clozapine therapy. If psychotic symptoms recur after increases in antiparkinsonian therapy, the dose of clozapine may need to be increased in line with the above guidance. As in patients with schizophrenia, planned withdrawal of clozapine in patients with Parkinson’s disease should also be gradual in decrements of 12.5 mg over 1 to 2 weeks.

Action

Antipsychotics are thought to work through inhibition of dopamine D₂-receptors, but this hypothesis fails to explain the activity of the atypical antipsychotics such as clozapine. How clozapine produces its antipsychotic activity is not clear it has a high affinity for a number of different receptors.

Administration

There has been controversy over the bioequivalence or otherwise of different brands of clozapine. Although some reports indicate that it is perfectly possible to switch from branded to generic clozapine, the need for monitoring and concerns about any requirement for retitration of doses (because of potential lack of bioequivalence) have to be taken into account. There have been a few reports of exacerbation of psychotic symptoms in patients who were switched to a generic formulation.’

Bipolar disorder

Clozapine is of benefit for the treatment of mania in patients with bipolar disorder, and the use of atypical antipsychotics in the management of such patients is increasing. However, the adverse effects of clozapine may restrict its use.

Dementia

Although atypical antipsychotics such as clozapine have been tried in elderly patients with dementia, the licensing authorities in the USA now recommend against such use, see under Precautions, above. For further discussion of the management of disturbed behaviour.

Parkinsonism

Clozapine is used as an alternative to classical antipsychotics in the management of treatment-resistant psychoses in patients with Parkinson’s disease. Some neurologists even consider clozapine to be the antipsychotic of choice in these patients, although this remains to be determined. A review in 1994 considered that there was little evidence to support clozapine as first choice given the quality of the available studies and the need for extensive monitoring. However a subsequent double-blind, placebo-controlled study showed that low-dose clozapine treatment (up to 50 mg daily) significantly improved drug-induced psychosis without worsening parkinsonism. Adverse effects noted in this study were generally mild, although in the clozapine group of 30 patients, there was 1 report of leucopenia.

A similar study also reported benefit, although 7 of 32 patients noted some aggravation of parkinsonism, usually mild and transient, while receiving clozapine. Adverse effects reported from other individuals have also included a patient with parkinsonism who had worsening of psychotic symptoms when her dose of clozapine was increased, and the sudden return of psychosis in another patient with parkinsonism whose psychosis was successfully treated with clozapine for 5 years. Low-dose clozapine (about 40 mg daily) also appears to be of benefit in the management of levodopa-induced dyskinesias in patients with severe Parkinson’s disease.

Schizophrenia

Clozapine is an effective antipsychotic for the management of schizophrenia but its use is limited by its blood toxicity. Its effectiveness and superiority over classical antipsychotics was shown in a multicentre study. Patients refractory to at least 3 different antipsychotics and who failed to improve after a single-blind trial of haloperidol, were randomised, double-blind, to treatment for 6 weeks with either clozapine up to 900 mg daily, or chlorpromazine hydrochloride up to 1800mg daily with benzatropine mesilate up to 6 mg daily. Of the 267 patients included in the evaluation, 5 of 141 (4%) improved with chlorpromazine and benzatropine, and 38 of 126 (30%) improved with clozapine.

Clozapine was superior to chlorpromazine in the treatment of negative as well as positive symptoms. Reviews’ of clozapine indicate that these findings have been well replicated both in subsequent studies and in clinical practice. It is, however, unclear for how long clozapine should be tried: although 1 study identified new responses up to 12 months after starting therapy, others have indicated that if improvement was not seen within the first 6 to 24 weeks, it was unlikely to occur.

Clozapine is also used to reduce suicide risk in patients with refractory chronic schizophrenia. The reported suicide rate of 0.05% peryear in 6300 patients in the UK given clozapine since 1990 was considered to be tenfold less than expected. A subsequent study found it to be more effective than olanzapine in preventing suicide attempts in patients with schizophrenia or schizoaffective disorder at high risk.

Clozapine has shown consistent clinical benefit in schizophrenic patients with persistent aggressive or violent behaviour. Whether this is due to a sedative effect, a specific antiaggressive action, or just reflects an overall improvement in psychosis is unknown.

Clozapine has been advocated for use in schizophrenic patients with moderate to severe tardive dyskinesia. It is still unclear whether clozapine can itself cause tardive dyskinesia but some patients with established tardive dyskinesia have experienced improvement in their symptoms when using clozapine.’

FAQ

Question

I am a pharmacist who practices in a mental health hospital. We are seeing some levels of both clozapine and norclozapine that are beyond the generally accepted blood levels. My own research on the subject has indicated that 1) Clozaril level is generally equated with efficacy, norclozaril level with adverse effects, 2) the optimal ratio of Clozaril to norclozaril is 2:1, 3) if the levels are high, but the patient is doing well and is suffering from no adverse effects, then leave the dose alone, and 4) some SSRI’s and Tagamet can be used in rapid cyclers to even out the Clozaril/norclozaril ratios. What is your opinion on correct Clozaril levels?

Answer

Understanding the relationship of clozapine levels to clinical response is very much a work in progress. I will tell you my general sense of where things are, then try to answer some of the specific questions you raise.

First, I think there is fairly good evidence linking clozapine (Clozaril) blood levels to therapeutic response, and to some extent to side effects. Second, there seems to be much less conclusive data on the ratios you mention, though there are some data implicating norclozapine with hematologic problems. An excellent study on clozapine blood levels and therapeutic response by VanderZwaag et al appeared in the December 1996 American Journal of Psychiatry.

That group found that clozapine levels above 200 ng/ml led to better outcome than levels in the 50-150 ng/ml range; and that there was no real advantage for levels in the 350-450 ng/ml range over the 200-300 ng/ml range. Indeed, at week 6, sleepiness was correlated with increasing serum level and was most frequent in the group with clozapine (Clozaril) blood levels in the 350-450 ng/ml range. (Tachycardia and orthostasis, however, were not correlated with blood levels.) This study did not look at norclozapine levels.

An earlier study by Perry et al in the February 1991 American Journal of Psychiatry also found a correlation between total clozapine (Clozaril) plus norclozapine plasma levels and clinical response, but did not analyze the clozapine:norclozapine ratios. I did not find any studies showing the optimal ratio of clozapine (Clozaril) to norclozapine to be 2:1, but did find one study showing that norclozapine levels tend to be higher in adolescents (Piscitelli et al, Journal of Clinical Psychiatry, Sept. 1994:55, supplement B 94-7).

I also found a study linking norclozapine/clozapine ratio to reduced neutrophil count (Mauri et al, Psychopharmacology [Berlin] June 1998; 137(4):341-4). By the way, in Parkinson’s disease patients with L-dopa induced psychosis, the plasma levels of clozapine (Clozaril) and norclozapine needed for therapeutic response may be much lower than in schizophrenic patients (clozapine between 4.5 and 16 ng/ml, norclozapine between 2.6 and 6 ng/ml), according to Meltzer et al in Neuropsychopharmacology, Feb. 1995, 12(1):39-45.

I generally agree that doses should be left alone if the patient is doing well, even if the clozapine (Clozaril) level is high – we are treating people, not laboratory values. However, since there is a correlation between clozapine (Clozaril) dose and seizure risk, and between dose and plasma levels, I might try to see if the patient could do as well on somewhat lower clozapine (Clozaril) doses/levels. For example, I might try a very gradual reduction in clozapine (Clozaril) dose over many months, measuring levels and clinical response as I reduced the dose. If the patient showed any signs of relapse, I would re-start the previous dose. (Some patients may require adjunctive valproate to “cover” break-through seizures.)

I’ve seen no studies on the use of SSRIs or Tagamet (cimetidine) for purposes of “evening out” the clozapine (Clozaril) to norclozapine ratio, but would have very serious reservations about using any antidepressant in a rapid cycler, with or without clozapine, since antidepressants often worsen the cycling rate. Until I see some controlled studies, I am not yet prepared to consider the clozapine/norclozapine ratio as a critical factor in response.

Preparations

The United States Pharmacopeia 31, 2008: Clozapine Tablets.

Proprietary Preparations

Argentina: Lapenax Sequax

Australia:: Clopine Clozaril

Austria: Lanolept Leponex

Belgium: Leponex

Brazil: Leponex Zolapin

Canada: Clozaril

Chile: Leponex

Czech Republic: Leponex

Denmark: Leponex

Finland: Froidir Leponex

France: Leponex

Germany: Elcrit Leponex

Greece: Leponex

Hong Kong: Clozaril

Hungary: Leponex

India: Lozapin Sizopin

Indonesia: Clozaril Sizoril

Ireland: Clozaril

Israel: Leponex Lozapine

Italy: Leponex

Malaysia: Clozaril Zapine

Mexico: Clopsine Leponex

The Netherlands: Leponex

Norway: Leponex

New Zealand: Clopine Clozaril

Philippines: Leponex

Poland: Klozapol Leponex

Portugal: Leponex Ozapim

Russia: Leponex

South Africa: Cloment Leponex

Singapore Clozaril

Spain: Leponex

Sweden: Leponex

Switzerland: Clopin Leponex

Thailand: Cloril Clozaril

Turkey: Leponex

UK: Clozaril Denzapine Zaponex

USA: Clozaril FazaClo Fazalco

Venezuela: Leponex