Clozaril

Clozaril (Azaleptin, Leponex, Fazaclo, Froidir; Denzapine, Zaponex; Klozapol, Clopine)

Generic name: lozaril

Brand names: Azaleptin, Leponex, Fazaclo, Froidir; Denzapine, Zaponex; Klozapol, Clopine

What is Clozaril (Azaleptin, Leponex, Fazaclo, Froidir; Denzapine, Zaponex; Klozapol, Clopine)?

Clozaril is taken to remedy schizophrenia. This pharmaceutical is only taken when others have not worked. It has a risk of serious side effects and is only available through a monitoring and dispensing system that includes special pediatrician, and laboratories. For the first few months of treatment, you will be required to have routine blood testing before your prescription can be refilled. This pharmaceutical may be taken for other objective; ask your doctor if you have questions.

What should I report to my pediatrician before I take this pill?

They need to know if you have any of these conditions:

• being treated for cancer
• blood disease or disorder, like leukemia
• constipation, fecal impaction, or a history of an obstruction of the intestine
• dementia
• diabetes
• heart disease-kidney disease
• liver disease
• low blood counts, like low white cell, platelet, or red cell counts
• lung or breathing disease, like asthma
• Parkinson’s disease
• seizures
• an unusual or allergic reaction to clozapine, other medicines, foods, dyes, or preservatives
• pregnant or trying to get pregnant
• breast-feeding
  

How should I take this pill?

Take this remedy by mouth with a drink of water. Follow the directions on the prescription label. This medicine may be used with or without food. Take your doses at regular intervals. Do not take your drug more often than directed. Do not suddenly stop using this pill. You may need to gradually reduce the dose. Stop taking this drug on the advice of your pediatrician only.

Talk to your pediatrician regarding the use of this pharmaceutical in children. Special medication may be needed.

Overdosage:

If you think you have used too much of this drug contact a poison control center or emergency room at once.

Note: This medicine is only for you. Do not share this drug with others.

What if I miss a dose?

If you miss a dose, use it as soon as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses. If you miss your drug for more than 2 days, you should not restart your remedy at the same dose. Contact your health care provider for instructions.

What may interact with this remedy?

Do not use this remedy with any of the following:

• cisapride
• medicines for treating cancer
• mibefradil
• olanzapine
• phenothiazines like perphenazine, thioridazine and chlorpromazine
• pimozide
• ziprasidone

This pharmaceutical may also interact with the following:

• caffeine
• carbamazepine
• cimetidine
• ciprofloxacin
• erythromycin or clarithromycin
• lithium
• medicines for anxiety or sleeping problems, such as diazepam or temazepam
• medicines for colds, hay fever, and other allergies
• medicines for high blood pressure
• medicines for mental depression, anxiety, or other mood problems
• nicotine
• phenytoin
• rifampin or rifabutin
• some medicines used to treat irregular heartbeats

This register may not report all possible interactions. Give your pediatrician a catalogue of all the pharmaceuticals, herbs, non-prescription remedies, or dietary supplements you take. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your pill.

What side effects may I notice from this pill?

Side effects that you should tell your physician as soon as possible:

• allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue
• breathing problems
• changes in vision
• chest pain, fast or irregular heartbeat
• confusion
• difficulty sleeping, nightmares
• excessive thirst and/or hunger
• feeling faint or lightheaded, falls
• fever, chills, sore throat, or mouth sores
• muscle and joint aches and pains
• nausea, vomiting, or severe loss of appetite
• restlessness
• seizures
• stiffness, spasms, trembling
• trouble passing urine or change in the amount of urine
• trouble with balance, talking, walking
• uncontrollable tongue or chewing movements, smacking lips or puffing cheeks
• unusually weak or tired
• yellowing of the eyes, skin

Side effects that usually do not require medical attention ( report to your physician if they continue or are bothersome):

• constipation
• dry mouth
• headache
• increased watering of the mouth, drooling
• weight gain

This catalogue may not report all possible side effects.

What should I watch for while using this specific?

Visit your health care provider for regular checks on your progress. It may be several weeks before you see the full effects of this medicine. Contact your doctor if your syndromes get worse or if you have new prodromes.

You must have a weekly blood test when you first begin this pill. If your blood counts stay in the right range, your tests may be abated after 6 months to every other week. Your name will go on a national registry of patients that take this pharmaceutical, to make sure that you have never had a serious reaction to it.

You may get drowsy or dizzy. Do not drive, use machinery, or do anything that needs mental alertness until you know how this drug affects you. Do not stand or sit up quickly, especially if you are an older patient. This reduces the risk of dizzy or fainting spells. Alcohol can make you more drowsy and dizzy. Avoid alcoholic drinks.

Do not heal yourself for colds, fever, diarrhea or allergies. Ask your doctor for advice, some nonprescription specific may increase possible side effects.

If you are going to have surgery speak to your doctor that you are using this pill.

Where should I store this pharmaceutical?

Store out of the reach of children.
Store at room temperature below 30 degrees C (86 degrees F). Throw away any unused remedies after the expiration date.

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.