Risperdal

Risperdal

At its peak, Risperdal was the number one antipsychotic medication used in the US.  It was developed to eclipse an older antipsychotic, Haldol (haloperidol) which was a very popular antipsychotic used for schizophrenia in both a fast-acting tablet and a monthly injection. Haldol was also frequently used as a “chemical restraint” in elderly care environments, a practice that was never approved by the FDA and received massive criticism.

Risperdal was said to be an improvement over Haldol as it reportedly has milder “extrapyramidal” side effects.  Extrapyramidal side effects include some of the permanent movement disorders that have caused long term impairment in Risperdal users.  Consequently, it appears that though the intent was to lessen these side effects, the plan has not worked as Risperdal is prescribed for a greater number of disease conditions, some of which involve children.

Risperdal Case Review

The second generation antipsychotic medication, Risperdal (risperidone) has made billions of dollars for its manufacturer, Johnson & Johnson.  The medication is effective for many people but has been linked to a number of serious side effects including breast development in boys and irreversible movement disorders.

Risperdal was approved in 1994 by the Food and Drug Administration (FDA) for the treatment of schizophrenia.  Despite reports of side effects being suffered by children subjected to off-label prescribing of Risperdal, Bipolar disorder was added as an approved treatment in 2002, in 2006 for autism in children and for use in children with schizophrenia and bipolar disorder in 2007.

Risperdal has been a “blockbuster” drug for the Johnson & Johnson subsidiary, Janssen.  In 2007, annual sales of the medication peaked at over $4.5 billion.  After the patent expired and the drug became available generically, profits declined but were still estimated at $1.5 billion in 2013 for the name brand Risperdal products.

In addition, Johnson & Johnson came out with another, similar medication Invega (paliperidone) which is indicated for schizophrenia and schizoaffective disorder.  It is available as an extended release tablet and as Invega Sustenna – a 1 month injection which is known as Xeplion in Europe.  A 3 month injection formulation is in development.  Sales of Invega products have been reported at 1.8B for 2013.

Janssen and its parent company, Johnson & Johnson face a multi-billion dollar settlement with the U.S. government due to accusations of illegal marketing practices.  Similar settlements with numerous state goverments total nearly $2 billion as well.  The companies were accused of marketing the medication for off-label use in children ranging back to the 1990s.  Off-label use is allowed for physicians, however federal and state regulations ban the marketing or disseminating of any related information by the company.  The company is not allowed to discuss anything other than FDA approved uses.

The manufacturers of Risperdal products have also had a history with recalls due to contamination or packaging problems.  In 2011, two manufacturing lots of Risperdal were recalled due to possible contamination with chemicals used in shipping containers.  In 2013, one manufacturing lot of Risperdal Consta (sustained release formulation) was recalled due to concerns of mold contamination.

Invega Sustenna has also faced recall concerns as in 2011 it was discovered that there were cracks in prefilled syringes containing the medication which could lead to infection or dosing concerns.

Risperdal has been subject to a number of news reports and investigations of adverse effects including gynecomastia (breast tissue development) in boys, irreversible movement disorders and reports of diabetes complications.  Multiple personal injury lawsuits have already been settled but there are still hundreds that remain to face trial or settlement. To date, well over $5 billion in damages and fines have been paid to plaintiffs and state and local government agencies by the manufacturer.

What is Risperdal

Risperdal is an antipsychotic medication which is approved for the treatment of schizophrenia in adults and adolescents.  It is also approved to treat bipolar disorder in adults and adolescents as well as autism spectrum disorders (ASD) in adolescents and children.

It has also been used “off-label” for the treatment of attention deficit disorder (ADHD), schizoaffective disorder, anxiety, sleep disorders, and depressive disorders.  Off-label use means that the medication has not been approved for treatment of a specific disease and there is no research that has proven the medication safe; however physicians are allowed and routinely use medications for purposes other than that listed on the label.

Risperdal works by targeting neurotransmitter receptors in the brain.  The neurotransmitters serotonin and dopamine (along with others) are released by nerve cells to signal other cells along the chain.  Neurotransmitters help control mood states and emotional well-being in certain areas of the brain but are sometimes overactive.  Risperdal works to block some of the receptors that in areas of the brain where too much stimulation can trigger psychotic and aggressive behavior.  Blocking of the dopamine and serotonin receptors can minimize the symptoms of schizophrenia and other psychotic behavior disorders.  Risperdal also has effect on adrenergic and histamine receptors which result in some of the sedating and hypotensive effects.

Risperdal is known as an “atypical” antipsychotic because unlike other antipsychotics, it targets both dopamine and serotonin receptors where other drugs target only dopamine activity.  This makes it more effective for some disorders that involve mood states as well such as bipolar disorder, ADHD, schizoaffective disorder and ASD.  Other members of the atypical category include Abilify (aripiprazole), Seroquel (quetiapine fumarate) and Zyprexa (olanzapine) and are also used for disorders other than schizophrenia as well.  The medications may be used alone or in combination with other medications such as anti-depressants or anti-manic agents.

The medication Invega is a metabolite of Risperdal. Risperdal is broken down by the liver into its metabolites, one of which is the same chemical (paliperidone) which is sold as Invega.  Invega has the same effects as Risperdal as it is actually the most important metabolite of Risperdal.

Risperdal is sold as a tablet or liquid for oral use. An injectable form has also been developed, known as Risperdal Consta which is given once a month.  Risperdal tablets are now available generically but J&J is still making a great deal of profit from the Risperdal line.  Invega, made by the same manufacturer is available as an extended release tablet and as Invega Sustenna which is a once monthly injection.  A 3-month injection formulation is in development.

Side Effects and Drug Interactions of Risperdal

Because of its mechanism of action, working on a number of different neurotransmitter receptors, Risperdal carries a number of side effects and interactions.  Though some of these effects may be minor, some are severely damaging and may be permanent or even life-threatening.

The most common side effects of Risperdal include:

  • Fatigue
  • Sedation
  • Restlessness (akathesia)
  • Drooling
  • Prolonged erection of the penis (priapism)
  • Nausea
  • Vomiting
  • Tremor
  • Dizziness
  • Anxiety

Risperdal can also have drug interactions with other medications including:

  • Anti-nauseants such as Anzemet or Zofran (irregular heart rhythm)
  • Beta-blockers used for hypertension or arrhythmia (irregular heart rhythm)
  • Antiepileptics such as Geodon and Topamax (irregular heart rhythm)
  • Quinolone antibiotics such as Avelox or Cipro (irregular heart rhythm)
  • Antiarrhythmics such as amiodarone, procainamide and disopyramide (irregular heart rhythm)
  • Immunomodulators such as Gilenya or Xalkori (irregular heart rhythm)
  • Imaging agents used in X-ray procedures (increase risk of seizures)
  • Platelet inhibitors such as Plavix (irregular heart rhythm)
  • Antidepressants (increases toxicity)
  • Pain medications (increases sedation)
  • Anxiety agents (increases sedation and may cause agitation)
  • Other antipsychotics (increases sedation and toxicity)

Serious Adverse Events of Risperdal

Breast Development in Boys

Gynecomastia is enlargement or development of breast tissue in males.  It is more common and particularly disturbing in children and adolescents.  The development of gynecomastia is usually a permanent change that will require surgical removal by a reconstructive surgeon.  Gynecomastia has been attributed to Risperdal’s stimulation of prolactin, a hormone common in women who are pregnant or nursing.  Adolescents or boys who develop breast tissue suffer not only physical changes but also severe emotional trauma.

Lactation in Girls

Lactation in girls who are not of child-bearing age and of women who are not pregnant or nursing has been seen with Risperdal use.  Girls may develop breast tissue prematurely and the development will be permanent.  No long term damage is seen other than premature development and resulting emotional trauma.

Movement Disorders

Risperdal was thought to have a lower risk of movement disorders known as extrapyramidal symptoms or side effects than older antipsychotics.  For this reason, the company downplayed the risks but adequate testing of children and widespread use for a number of psychiatric conditions has made this side effect much more prevalent.  Extrapyramidal symptoms include

  • Akathesia (restlessness)
  • Akinesia (inability to move or hesitational movement)
  • Tardive Dyskinesia (abnormal movement of face, shoulders, arms and legs)
  • Parkinson’s like tremor
  • Torticolis (stiffening of the tongue, which may cause difficulty breathing)

All of the movement disorders may be permanent even after the medication has been discontinued.  Many patients also require additional medication to control the symptoms.

Diabetes

Risperdal has been associated with an increased risk of development or worsening of diabetes.  The exact relationship is unknown.

Death in the Elderly

Risperdal has been associated with mortality in elderly dementia patients.  The FDA required a Black Box warning regarding use in the elderly.  Patients who have died from Risperdal use had an actual cause of death of adverse events such as cardiac failure, pneumonia and cerebrovascular events (stroke).  The exact relationship is unknown and the dose of medication did not matter.

Risperdal events, FDA actions and lawsuits

Risperdal has one of the longest histories of difficulties and disputes.  Problems with Risperdal use were noted as early as 2001 and litigation is still ongoing.  The company has paid well over $5 billion in fines and settlements to date.

  • 1994 – Risperdal receives FDA approval for the treatment of schizophrenia. It is the first of a new category of “atypical antipsychotics” and rapidly becomes one of the most popular and profitable medications in America
  • 1996 Total Risperdal prescriptions exceed one million
  • 2001 The Miami Herald reports that Risperdal has caused severe side effects in the Florida foster care system when used as a chemical restraint on disruptive juveniles.
  • 2002 Janssen (a Johnson & Johnson subsidiary) issues warning letter to Canadian practitioners regarding potential risks associated Risperdal use in elderly patients with senile dementia. Risperdal is reportedly responsible for 37 cases of stroke-like events and blood clots and 16 deaths
  • 2003 Risperdal approved by the FDA for the short-term treatment of manic and mixed-manic Bipolar disorder
  • 2003 Janssen issues warning letter to US practitioners
  • 2005 – Black Box warning was required by the FDA regarding the increased risk of death when Risperdal is used in the elderly
  • 2006 Risperdal approved by the FDA for the treatment of irritability in children and adolescents with Autism
  • 2006 – Clinical study at Duke University shows that Risperdal may cause breast growth in males (gynecomastia).  Study also reveals that female patients, including children may begin lactating while on the medication
  • 2007 – Risperdal approved by the FDA for the treatment of schizophrenia in children ages 13 to 17 and for the treatment of bipolar disorder in children ages 10 to 17.
  • 2008 – first generic version of risperidone becomes available
  • 2008 – Wall Street Journal reports that Risperdal stimulates the production of prolactin (a nursing hormone) in boys.  One co-author of the 2006 Duke study also stated that the side effects were serious.  70% of childhood gynecomastia events were found to be related to Risperdal
  • 2008 – FDA hosts meeting to discuss Risperdal side effects in children, however the FDA concludes they will not strengthen warnings
  • 2010 – First lawsuit is filed by 21 year old man who took Risperdal between 1999 and 2004 (while a juvenile) and suffered emotional trauma from breast growth.  The patient, a juvenile at the time received Risperdal for off-label use.
  • 2011 – Lots of Risperdal are recalled due to a possible contamination from chemicals used to treat shipping pallets.  Some patients claim gastrointestinal disturbance
  • 2012 Johnson & Johnson agree to settle for $181 million in suit by 36 states and District of Columbia regarding improper marketing of off-label uses for Risperdal, specifically the treatment of children.  The lawsuit also claimed that the company minimized side effects
  • 2012 Janssen and Johnson & Johnson are fined $1.2 billion by Judge Timothy D. Fox of the Sixth Division of The Sixth Judicial Circuit of the State of Arkansas.  Jury found that company had downplayed risk and held that 240,000 violations of Medicaid fraud law were committed.  Company also fined for 4,500 violations of deceptive practices law
  • 2012 September – Bloomberg News reports of 420 Risperdal lawsuits in courts throughout the US, 130 of which were gynecomastia complaints.  Lawsuits claim that the company did not properly advise of the risk of breast growth in children.
  • 2012 – Johnson & Johnson settles six gynecomastia lawsuits for undisclosed amounts.  Settlements are reached before the former FDA Commissioner is called as a witness.
  • 2013 – Department of Justice begins probe into J&J practices regarding labeling and handling of risk concerns with improper marketing to promote deliberate overmedication of children, elderly and mentally disabled.
  • 2013 – J&J stops DOJ investigation by payment of $2.2 billion with provision that company does not admit to improper conduct.
  • DOJ continues to inspect J&J practices regarding labeling and handling of risk concerns

Lawyers for plaintiffs have argued that Johnson & Johnson and its subsidiary, Janssen were not truthful and minimized concerns of gynecomastia, movement disorders and the threat of death along with the improper use of illegal marketing promoting of off-label uses for Risperdal.

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