Drug Profile

Do Not Use: This drug is no more effective than older drugs for schizophrenia and causes irregular heartbeat.

Ziprasidone (GEODON, ZELDOX) was approved by the Food and Drug Administration (FDA) for the treatment of schizophrenia in February 2001. In 2007 it was also approved for the treatment of manic and mixed episodes associated with bipolar disorder.[5] Refer to the drug product label for additional approved uses of ziprasidone.

Ziprasidone is not approved for the treatment of patients with dementia-related psychosis.

Ziprasidone belongs to a class of drugs called atypical, or second-generation, antipsychotics. Although all antipsychotics usually improve symptoms such as agitation, delusions, hallucinations and suspiciousness, atypical antipsychotics claim to improve “negative” symptoms, such as apathy, disorientation, emotional withdrawal and lack of pleasure, better than older antipsychotics do. However, there is no clear evidence that atypical antipsychotics are more effective or better tolerated than the older, conventional antipsychotics.[6]

Adverse effects

One of the known adverse effects of ziprasidone is QTc interval prolongation. The QTc interval is the length of time it takes the large chambers of the heart (ventricles) to electrically discharge and recharge. A prolongation of the QTc interval can lead to a type of heart rhythm disturbance known as torsades de pointes, which can lead to sudden death. Ziprasidone should not be used with any drug that prolongs the QTc interval. An extensive list of drugs that have this effect can be found on the site of the Arizona Center for Education and Research on Therapeutics.

Neuroleptic malignant syndrome (NMS) is a rare yet severe adverse effect of antipsychotic drugs. The symptoms of NMS can include fever; confusion; disorientation or other cognitive (thinking) function changes; muscle rigidity; profuse sweating; and unstable blood pressure, heart rate and gastrointestinal function. NMS can be life threatening; rapid recognition and treatment are important.[7]

Interactions

Ziprasidone should be used with caution when it is taken in combination with other drugs that work on the central nervous system.

Taking ziprasidone can cause low blood pressure, so it may enhance the effects of blood pressure-lowering drugs.

Ziprasidone may antagonize the effects of levodopa (LARODOPA). It also interacts with carbamazepine (CARBATROL, TEGRETOL) and ketoconazole (NIZORAL).

Studies show ...

Ziprasidone manufacturer Pfizer presented the results of five clinical trials to the FDA in support of ziprasidone’s approval. Four of these tested the effect of the drug in the management of acute symptoms of schizophrenia.

In one of these trials, ziprasidone was compared with a fixed dose of 15 milligrams of an old and relatively inexpensive antipsychotic drug called haloperidol (HALDOL). Pfizer estimated that the treatment effect on schizophrenic patients for haloperidol was greater than for any of the dosages of ziprasidone.[8] However, Pfizer did not determine whether the difference between the drugs was statistically significant and failed to provide sufficient information to make this determination.

In April 2011, the Office of Inspector General of the Department of Health and Human Services released a study, “Medicare Atypical Antipsychotic Drug Claims for Elderly Nursing Home Residents,” with dismal results. The study was conducted at the request of Sen. Charles Grassley (R-Iowa) and evaluated the extent to which elderly nursing home residents receive newer, more expensive atypical antipsychotic drugs and the associated cost to the Medicare system. It also assessed the extent to which dangerous, off-label prescribing of these drugs was occurring. Click here to read the August 2011 Worst Pills, Best Pills News article on the report.

On May 24, 2013, the Centers for Medicare and Medicaid Services, as part of the National Partnership to Improve Dementia Care in Nursing Homes, issued new guidelines discouraging the use of antipsychotic drugs to treat dementia in nursing home patients. The recommendations belatedly follow the May 2011 report by the Inspector General of the Department of Health and Human Services, which found that 14% of nursing home residents had Medicare claims filed on their behalf for atypical antipsychotic medications, which have never been approved by the FDA for managing dementia.

A study published in the British Medical Journal evaluated the risk of death associated with specific antipsychotic medications used in elderly residents in nursing homes. The study reviewed information relating to the risk of death when using different drug therapies and found that the risk of death varied according to the specific drug used. The authors of the study concluded:

“The evidence accumulated so far implies that use of haloperidol in this vulnerable population cannot be justified because of the excess harm.  Quetiapine might be somewhat safer than other atypical drugs, but these findings will require replication in other studies.”[9]

In 2015, JAMA Internal Medicine published an article showing that use of atypical antipsychotic drugs was associated with an increased risk of falls and fractures in patients 65 and older.[10]

Regulatory actions surrounding ziprasidone

1998: Pfizer submitted a New Drug Application to the FDA for ziprasidone in March. Three months later, the agency sent the company a "not-approvable" letter based on “the judgment that ziprasidone prolongs the QTc and that this represents a risk of potentially fatal ventricular arrhythmias [heart rhythm disturbances] that is not outweighed by a demonstrated and sufficient advantage of ziprasidone over already marketed antipsychotic drug products.”[11]

2003: In September, the FDA ordered that the product labeling for certain antipsychotic drugs warn that patients using them should be monitored for symptoms of diabetes. The drugs requiring this warning were risperidone (RISPERDAL), aripiprazole (ABILIFY), clozapine (CLOZARIL), olanzapine (ZYPREXA), quetiapine (SEROQUEL) and ziprasidone.[12]

2005: The FDA issued a public health advisory to warn that atypical antipsychotic drugs are associated with an increased risk of death when used to treat dementia in elderly patients. The drugs affected by this advisory were ziprasidone, aripiprazole, olanzapine, quetiapine, risperidone and clozapine. None of these drugs are approved for the treatment of behavioral disorders in patients with dementia.[13]

2009: The FDA updated the product label of ziprasidone to include information that the agency had received reports of leukopenia/neutropenia (low white blood cell count) in users of this drug. These reports were received in clinical trial and/or post-marketing reports, and the FDA called them short-term events “related to antipsychotic agents.” A more serious condition, agranulocytosis (failure of the bone marrow to make enough white blood cells), also had been reported in patients taking ziprasidone.[14]

2011: The FDA updated the information for all antipsychotic drugs to state that when mothers are treated with these drugs during the third trimester of pregnancy, there is a potential risk of abnormal muscle movements (extrapyramidal signs, or EPS) and withdrawal symptoms in their newborns.[15]

2014: The FDA updated the product label for ziprasidone to include a rare but serious condition known as drug reaction with eosinophilia and systemic symptoms. This condition, a severe skin reaction to a drug, appears as a rash that can spread to all parts of the body. It also can affect internal organs and is sometimes fatal.[16]

2016: Health Canada, an agency similar to the FDA, updated the product label of atypical antipsychotics to warn that the drugs are associated with an increased risk of sleep apnea (a disorder that causes breaks in breathing or very shallow breathing during sleep).[17]

2017: The FDA approved a new warning in the product label of ziprasidone that stated that the drug may cause excessive sleepiness, low blood pressure upon sitting up or standing (postural hypotension) and problems with balance, all of which may increase the risk of falls and fractures in patients taking the drug.[18]