The Dangers of Meperidine [Demerol]: Contraindications, Warnings, Precautions

June 30, 2009

June 30, 2009 –  Meperidine [Demerol] is a narcotic analgesic with multiple actions qualitatively similar to those of morphine; the most prominent of these involve the central nervous system and organs composed of smooth muscle. The principal actions of therapeutic value are analgesia and sedation. Its indication is for the relief of moderate to severe pain, for preoperative medication, for support of anesthesia, and for obstetrical analgesia. Meperidine [Demerol] may be habit forming.

Meperidine [Demerol] has just come to enormeous international public attention, because media reports link it to the unfortunate early death of the king of pop, Michael Jackson on June 25, 2009. According to several news reports, Michael Jackson has supposedly received an injection of the painkiller just one hour before his death. The death of Michael Jackson is tragic. The exact reason(s) for his death need(s) yet to be determined and confirmed, and the authoroties are in the process of performing an autopsy and further test, whose results will only be available to the public sometime in the future.

This contribution to the Theragenomics Blog does not in any way prematurely propagate Meperidine [Demerol] as the drug cause of Michael Jacksons death. However, the contribution would like to rise, among our readers, the awareness for the dangers of drugs like Meperidine [Demerol] to patients taking them, by recapitulating here excerpts of the “Contraindication”, “Precautions”, and “Warnings” sections of the drug label document of Meperidine [Demerol] by the American Food and Drug Administration (FDA).

Contraindications

Meperidine [Demerol] should not be taken, if the patient has a hypersensitivity to the active ingredient meperidine. Meperidine is contraindicated in patients who are receiving monoamine oxidase (MAO) inhibitors or those who have recently received such agents. Therapeutic doses of meperidine have occasionally precipitated unpredictable, severe, and occasionally fatal reactions in patients who have received such agents within 14 days. The mechanism of these reactions is unclear, but may be related to a preexisting hyperphenylalaninemia. Some have been characterized by coma, severe respiratory depression, cyanosis, and hypotension, and have resembled the syndrome of acute narcotic overdose. In other reactions the predominant manifestations have been hyperexcitability, convulsions, tachycardia, hyperpyrexia, and hypertension. Although it is not known that other narcotics are free of the risk of such reactions, virtually all of the reported reactions have occurred with meperidine. If a narcotic is needed in such patients, a sensitivity test should be performed in which repeated, small, incremental doses of morphine are administered over the course of several hours while the patient’s condition and vital signs are under careful observation. (Intravenous hydrocortisone or prednisolone have been used to treat severe reactions, with the addition of intravenous chlorpromazine in those cases exhibiting hypertension and hyperpyrexia. The usefulness and safety of narcotic antagonists in the treatment of these reactions is unknown.) Solutions of Demerol and barbiturates are chemically incompatible.

Warnings

Drug Dependence. Meperidine can produce drug dependence of the morphine type and therefore has the potential for being abused. Psychic dependence, physical dependence, and tolerance may develop upon repeated administration of meperidine, and it should be prescribed and administered with the same degree of caution appropriate to the use of morphine. Like other narcotics, meperidine is subject to the provisions of the Federal narcotic laws.

Interaction with Other Central Nervous System Depressants. Meperidine should be used with great caution and in reduced dosages in patients who are concurrently receiving other narcotic analgesics, general anesthetics, phenotiazines, other tranquilizers, sedative hypnotics (including barbiturates), tricyclic antidepressants and other CNS depressants (including alcohol). Respiratory depression, hypotension, and profound sedation or coma may result.

Head Injury and Increased Intracranial Pressure. The respiratory depressant effects of meperidine and its capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or a preexisting increase in intracranial pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries. In such patients, meperidine must be used with extreme caution and only if its use is deemed essential.

Intravenous Use. If necessary, meperidine may be given intravenously, but the injection should be given very slowly, preferably in the form of a diluted solution. Rapid intravenous injection of narcotic analgesics, including meperidine, increases the incidence of adverse reactions; severe respiratory depression, apnea, hypotension, peripheral circulatory collapse, and cardiac arrest have occurred. Meperidine should not be administered intravenously unless a narcotic antagonist and the facilities for assisted or controlled respiration are immediately available. When meperidine is given parenterally, especially intravenously, the patient should be lying down.

Asthma and Other Respiratory Conditions. Meperidine should be used with extreme caution in patients having an acute asthmatic attack, patients with chronic obstructive pulmonary disease or cor pulmonale, patients having a substantially decreased respiratory reserve, and patients with preexisting respiratory depression, hypoxia, or hypercapnia. In such patients, even usual therapeutic doses of narcotics may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea.

Hypotensive Effect. The administration of meperidine may result in severe hypotension in the postoperative patient or any individual whose ability to maintain blood pressure has been compromised by a depleted blood volume or the administration of drugs such as the phenothiazines or certain anesthetics.

Usage in Ambulatory Patients. Meperidine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. The patient should be cautioned accordingly. Meperidine, like other narcotics, may produce orthostatic hypotension in ambulatory patients.

Usage in Pregnancy and Lactation. Meperidine should not be used in pregnant women prior to the labor period, unless in the judgment of the physician the potential benefits outweigh the possible hazards, because safe use in pregnancy prior to labor has not been established relative to possible adverse effects on fetal development. When used as an obstetrical analgesic, meperidine crosses the placental barrier and can produce depression of respiration and psychophysiologic functions in the newborn. Resuscitation may be required. Meperidine appears in the milk of nursing mothers receiving the drug.

Precautions

As with all intramuscular preparations, Demerol intramuscular injection should be injected well within the body of a large muscle.

Supraventricular Tachycardias. Meperidine should be used with caution in patients with atrial flutter and other supraventricular tachycardias because of a possible vagolytic action which may produce a significant increase in the ventricular response rate.

Convulsions. Meperidine may aggravate preexisting convulsions in patients with convulsive disorders. If dosage is escalated substantially above recommended levels because of tolerance development, convulsions may occur in individuals without a history of convulsive disorders.

Acute Abdominal Conditions. The administration of meperidine or other narcotics may obscure the diagnosis or clinical course in patients with acute abdominal conditions.

Special Risk Patients. Meperidine should be given with caution and the initial dose should be reduced in certain patients such as the debilitated, and those with severe impairment of hepatic or renal function, hypothyroidism, Addison’s disease, and prostatic hypertrophy or urethral stricture.


Stimulant Medications used in Children with Attention-Deficit/Hyperactivity Disorder – Communication about an Ongoing Safety Review

June 16, 2009

June 16, 2008 – Yesterday, we learned about an ongoing safety review by the American Food and Drug Administration (FDA) concerning Stimulant Medications used in Children with Attention-Deficit/Hyperactivity Disorder.

These medications include the following products: Focalin, Focalin XR (dexmethylphenidate HCl); Dexedrine, Dexedrine Spansules, Dextroamphetamine ER, Dextrostat (dextroamphetamine sulfate); Vyvanse (lisdexamfetamine dimesylate); Desoxyn (methamphetamine); Concerta, Daytrana, Metadate CD, Metadate ER, Methylin, Methylin ER, Ritalin, Ritalin-LA, Ritalin-SR (methylphenidate); Adderall, Adderall XR (mixed salts amphetamine); Cylert (pemoline) and generics.

Here the FDA’s notification: FDA notified healthcare professionals that it is providing its perspective on study data published in the American Journal ofPsychiatry on the potential risks of stimulant medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in children. This study, funded by the FDA and the National Institute of Mental Health (NIMH), compared the use of stimulant medications in 564 healthy children from across the United States who died suddenly to the use of stimulant medications in 564 children who died as passengers in a motor vehicle accident.The study authors concluded that there may be an association between the use of stimulant medications and sudden death in healthy children. Given the limitations of this study’s methodology, the FDA is unable to conclude that these data affect the overall risk and benefit profile of stimulant medications used to treat ADHD in children. FDA believes that this study should not serve as a basis for parents to stop a child’s stimulant medication. Parents should discuss concerns about the use of these medicines with the prescribing healthcare professional. Any child who develops cardiovascular symptoms (such as chest pain, shortness of breath or fainting) during stimulant medication treatment should immediately be seen by a doctor.

FDA is continuing its review of the strengths and limitations of this and other epidemiological studies that evaluate the risks of stimulant medications used to treat ADHD in children. FDA and the Agency for Healthcare Research and Quality are sponsoring a large epidemiological study that will provide further information about the potential risks associated with stimulant medication use in children. The data collection for this study will be complete later in 2009.

Please read here therelated  News Release by the FDA, the complete Communication About An Ongoing Safety Review by the FDA, and FDA’s request  for Stimulant Medications Prescribing Information, Medication Guides.

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Neuropsychiatric Events Associated with Leukotriene Inhibitors: Montelukast [Singulair], Zafirlukast [Accolate], and Zileuton [Zyflo and Zyflo CR]

June 13, 2009

June 12, 2009 – From a MedWatch Safety Alert RSS Feed we learn that today, the American Food and Drug Administration (FDA) provided healthcare professionals with updated information on the original March 2008 early communication and January 2009 follow-up communication about the ongoing safety review for the leukotriene inhibitors Montelukast [Singulair], Zafirlukast [Accolate], and Zileuton [Zyflo and Zyflo CR].

Neuropsychiatric events have been reported in some patients taking Montelukast [Singulair], Zafirlukast [Accolate], and Zileuton [Zyflo and Zyflo CR]. FDA has requested that manufacturers include a precaution in the drug prescribing information (drug labeling). The reported neuropsychiatric events include postmarket cases of agitation, aggression, anxiousness, dream abnormalities and hallucinations, depression, insomnia, irritability, restlessness, suicidal thinking and behavior (including suicide), and tremor. FDA recommends that:

  • Patients and healthcare professionals should be aware of the potential for neuropsychiatric events with these medications.
  • Patients should talk with their healthcare providers if these events occur.
  • Healthcare professionals should consider discontinuing these medications if patients develop neuropsychiatric symptoms.

See the complete FDA Healthcare Professional Information here. Adverse reactions or quality problems experienced with the use of any of these products may be reported to the FDA’s MedWatch Adverse Event Reporting program either online, by regular mail or by fax, using the contact information to be found here.


Clinical Trial Data that Suggest Increased Mortality in Stable Liver Transplant Patients Receiving Sirolimus [Rapamune]

June 11, 2009

June 11, 2009 – From a today’s  MedWatch Safety Alert we learn that the American Food and Drug Administration (FDA) notified healthcare professionals of clinical trial data that suggest increased mortality in stable liver transplant 2009 06 11 Sirolimus [Rapamune] Illustration enpatients after conversion from a calcineurin inhibitor (CNI)-based immunosuppressive regimen to Sirolimus [Rapamune], which is available on all major markets worldwide (see graphic).  The trial was conducted by Sirolimus’ [Rapamune]  manufacturer, Wyeth. The Agency will continue to examine the data on mortality and other adverse events in this study, and will make further recommendations, as appropriate. The FDA is determining whether a labeling change for Sirolimus [Rapamune] is needed. In the interim, physicians should continue to use the drug’s professional labeling as a guide to therapy.

This information reflects FDA’s current analysis of data available to FDA concerning Sirolimus [Rapamune].  Posting this information does not mean that FDA has concluded there is a causal relationship between the drug product and the emerging safety issue.  Nor does it mean that FDA is advising health care professionals to discontinue prescribing this product. FDA intends to update this document when additional information or analyses become available.

Background Information: On March 25, 2009, Wyeth submitted to FDA results of a clinical trial, titled “A Randomized, Open-Label, Comparative Evaluation Of Conversion From Calcineurin Inhibitor Treatment to Sirolimus Treatment Versus Continuation Of Calcineurin Inhibitor Treatment In Liver Allograft Recipients Undergoing Maintenance Therapy”. The trial compared stable liver transplant patients who were converted from a CNI to Sirolimus [Rapamune] to patients who remained on CNI-based therapy. The trial data suggested that there may be increased mortality in patients converted from calcineurin inhibitor (CNI) therapy to Sirolimus [Rapamune]. The trial also provided additional safety and efficacy information on sirolimus:

  • The overall treatment failure rates at one year, defined as the occurrence of acute rejection or premature discontinuation for any reason, for the Intent-to-Treat population were significantly higher for the cohort of stable liver transplant patients converted to sirolimus compared to the cohort that continued on CNIs.
  • Drug discontinuation due to an adverse event was also more frequent in the Sirolimus [Rapamune] cohort compared to those patients continued on CNI.
  • Peripheral edema, stomatitis, rash, and mouth ulceration were the most frequent adverse events resulting in discontinuation in the trial.
  • Mean fasting lipid concentrations increased significantly after the Sirolimus [Rapamune] conversion, and remained elevated throughout the one year follow-up evaluation period.

At this time, FDA has not made any changes to the professional label for Sirolimus [Rapamune].  Sirolimus [Rapamune] is indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving kidney transplants. The safety and the efficacy of Sirolimus [Rapamune] as an immunosuppressant have not been established in liver or lung transplant patients. This information is in the Boxed Warning of the Sirolimus [Rapamune] label.

  • The current Boxed Warning of Sirolimus [Rapamune] indicates that the use of Sirolimus [Rapamune] in combination with Tacrolimus [Prograf] was associated with excess mortality and graft loss in a study in de novo liver transplant patients.  Many of these patients had evidence of infection at or near the time of death.
  • Therapeutic drug monitoring is recommended for all patients receiving sirolimus.
  • Therapeutic drug monitoring should not be the sole basis for adjusting Sirolimus [Rapamune] therapy. Careful attention should be paid to clinical signs and symptoms, tissue biopsy findings, and laboratory parameters.
  • Patients unable to take the tablets should be prescribed the Sirolimus [Rapamune] oral solution and instructed in its use.
  • Patients should be counseled that Sirolimus [Rapamune] is to be taken by mouth, once a day, consistently and with or without food.
  • Sirolimus [Rapamune] tablets should not be crushed, chewed or split.

See the FDA Healthcare Professional Information sheet for current FDA recommendations. Adverse reactions or quality problems experienced with the use of this Product may be reported to the FDA’s MedWatch Adverse Event Reporting program either online, by regular mail or by fax, using the contact information to be found here.


FDA Requires Boxed Warning for All Botulinum Toxin Products

June 10, 2009

June 10, 2009 – From a todays’ press release by the FDA, we learn the following concerning botulinum toxin products:

Prompted by reports of serious adverse events, the American Food and Drug Administration (FDA) today announced that safety label changes, including a boxed warning, and a Risk Evaluation and Mitigation Strategy (REMS), are necessary for all botulinum toxin products.

The agency said it took the action because of reports that the effects of the botulinum toxin may spread from the area of injection to other areas of the body, causing symptoms similar to those of botulism, including unexpected loss of strength or muscle weakness, hoarseness or trouble talking, trouble saying words clearly, loss of bladder control, trouble breathing, trouble swallowing, double vision, blurred vision and drooping eyelids. These symptoms have mostly been reported in children with cerebral palsy being treated with the products for muscle spasticity, an unapproved use of the drugs. Symptoms have also been reported in adults treated both for approved and unapproved uses.

The agency also took the action because of the potential for serious risks associated with the lack of interchangeability among the three licensed botulinum toxin products.

“Updated labels for this class of products will help health care professionals and patients better understand the risks and benefits,” said Russell Katz, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “Botulinum toxin products have benefits but can cause serious health problems and it is important that anyone who administers or uses these products understands these risks.”

Product Names

The products required to add the new label and a REMS are Botox and Botox Cosmetic (botulinum toxin type A), marketed by Allergan; Myobloc (botulinum toxin type B), marketed by Solstice Neurosciences; and a new FDA-approved product, Dysport (abobotulinumtoxin A), marketed by Ipsen Biopharm Ltd.

Botox, Myobloc, and Dysport are approved by the FDA for the treatment of a condition marked by repetitive contraction of the neck muscles (cervical dystonia). Botox Cosmetic and Dysport are approved by the FDA for dermatologic use in the temporary improvement in the appearance of frown lines between the eyebrows called glabellar lines. In addition, Botox is approved for the treatment of severe underarm sweating (primary axillary hyperhidrosis), crossed eyes (strabismus), and abnormal tics and twitches of the eyelids (blepharospasm).

Recommendations for Health Care Professionals

The FDA has notified the manufacturers of Botox and Myobloc that label changes and a REMS are necessary to ensure that the benefits of the product outweigh the risks. The FDA approved a REMS for Dysport as part of the product approval. The REMS for each of these products will include a Medication Guide and a Communication Plan. Medication Guides are FDA-approved handouts given to patients, or their families and caregivers, when a medicine is dispensed. The Medication Guides will contain information about the risks associated with botulinum toxin products. The FDA is also requiring the manufacturers to collect safety data in children and adults with muscle spasticity to assess the signal of risk regarding distant spread of toxin effects.

Treatment of muscle spasticity is not an FDA-approved use of botulism toxin products. The doses used in treatment of muscle spasticity are often much higher than the doses for uses described in FDA-approved product label. Symptoms consistent with spread of toxin effects have been reported at doses comparable to or lower than doses used to treat cervical dystonia. For the FDA-approved dermatologic use of temporary improvement in the appearance of glabellar lines, the agency has not identified any definitive serious adverse event reports of a distant spread of toxin effect producing symptoms consistent with botulism when the botulinum toxin products are used in accordance with the approved label.

The companies that make Botox and Myobloc are required to submit the requested safety label changes, including the boxed warning and the Medication Guide, to the FDA within 30 days, or to provide a reason why they do not believe such changes are necessary. If they do not submit new language, or the FDA disagrees with the language the companies propose, the Food, Drug, and Cosmetic Act provides strict timelines for discussions regarding the changes. At the end of these discussions the agency is allowed to issue an order directing the label change as deemed appropriate to address the new safety information.

Health care professionals who use botulinum toxins should do the following:

  • Understand that dosage strength (potency) expressed in “Units” is different among the botulinum toxin products; clinical doses expressed in units are not interchangeable from one product to another.
  • Be alert to and educate patients and caregivers about the potential for effects following administration of botulinum toxins such as: unexpected loss of strength or muscle weakness, hoarseness or trouble talking, trouble saying words clearly, loss of bladder control, trouble breathing, trouble swallowing, double vision, blurred vision and drooping eyelids.
  • Understand that these effects have been reported as early as several hours and as late as several weeks after treatment.
  • Advise patients to seek immediate medical attention if they develop any of these symptoms.

Health care professionals and consumers may report serious adverse events (side effects) or product quality problems with the use of this product to the FDA’s MedWatch Adverse Event Reporting program either online, by regular mail, fax or phone.
Online
Regular Mail: use postage-paid FDA form 3500 and mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787
Fax: 800-FDA-0178
Phone: 800-FDA-1088

Today’s action updates a February 2008 announcement that the FDA was conducting an ongoing safety review of botulinum toxin products.

The FDA also issued a response to a citizen petition related to the risk of spread of botulinum toxin effects from the site of injection. This response provides additional detail regarding the FDA’s analysis of this safety issue. The FDA’s response to the Citizen Petition can be found at http://www.fda.gov/cder/drug/early_comm/botulinum_CP_response.pdf

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Health Canada: Important Safety Information on CellCept [Mycophenolate Mofetil] and its Associated Risk for Pure Red Cell Aplasia (PRCA)

June 6, 2009

June 6, 2009 – From a new posting on Health Canada’s website, we learn that on June 03, 2009, in consultation with Health Canada, Hoffmann-La Roche Limited (Roche), has informed Canadian healthcare professionals of important new safety information regarding reports of a type of anemia called pure red cell aplasia (PRCA) in patients treated with Mycophenolate Mofetil [CellCept]. This information is summarized as follows:

  • Cases of PRCA have been reported in patients treated with Mycophenolate Mofetil [CellCept] in combination with other anti-rejection drugs.
  • In some cases, PRCA was found to be reversible when the dosage of Mycophenolate Mofetil [CellCept] was reduced or Mycophenolate Mofetil [CellCept] therapy was discontinued. There may be a risk to the transplanted organ if anti-rejection medications, such as Mycophenolate Mofetil [CellCept] are reduced in dosage or discontinued.
  • Patients taking Mycophenolate Mofetil [CellCept] and any other prescribed anti-rejection medications should not discontinue or change their medication without discussion with their transplant physician.

Mycophenolate Mofetil [CellCept] is authorized for the prevention of organ rejection in adults receiving kidney, heart or liver transplants, and in children and adolescents (2-18 years) receiving kidney transplants. Mycophenolate Mofetil [CellCept] should be used in combination with other anti-rejection drugs such as cyclosporine and corticosteroids.

As of 24 February 2008, 41 cases of PRCA have been reported in patients receiving Mycophenolate Mofetil [CellCept] in combination with other immunosuppressive agents (tacrolimus, cyclosporine, corticosteroids, azathioprine, sirolimus and alemtuzumab), and the data related to these case reports have been reviewed by Health Canada. Based on the preclinical in vivo evidence and post-marketing database, a causal contribution of Mycophenolate Mofetil [CellCept] on PRCA is considered possible in a few cases received. The mechanism for the PRCA is not well understood but may be related to immunosuppression. In some cases, the PRCA was found to be reversible with dose reduction or discontinuation of Mycophenolate Mofetil [CellCept]. When PRCA occurs in a patient on multiple immunosuppressants the relative contribution of the drugs to PRCA and the prophylaxis of rejection must be considered before a decision is made to discontinue a drug.

PRCA is a condition in which a patient develops severe anaemia due to failure of the bone marrow to produce red blood cells. PRCA is a type of anaemia that develops secondary to failure of erythropoiesis. Erythropoiesis is a process by which red blood cells (RBCs) are produced from immature precursors in the bone marrow. PRCA describes a condition in which RBC precursors in bone marrow are nearly absent, while megakaryocytes and white blood cell precursors are usually present at normal levels. PRCA may be idiopathic or occur as a manifestation of an underlying condition. Approximately 5% of all cases of PRCA are drug induced. Patients with PRCA may present with fatigue, lethargy, and/or abnormal paleness of the skin (pallor). Anaemia is the primary clinical concern in PRCA. The degree of anaemia can range from subclinical to severe. Anaemia in acute self-limited PRCA is barely noticeable; however, profound anaemia can occur in chronic acquired PRCA and in congenital PRCA. Patients with severe anaemia have symptoms and signs of uncompensated anaemia and present with weakness, tachycardia, and dyspnoea.  As a patient, you should consult your transplant physician immediately if you are feeling unusually tired or short of breath.

Please read the full advisory by Health Canada here. Any occurrence of serious and/or unexpected adverse reactions in patients receiving Mofetil [CellCept] should be reported to Hoffmann-La Roche Limited (email to: mississauga.drug_safety@roche.com) or Health Canada (email  to: CanadaVigilance@hc-sc.gc.ca). Moreover, the Adverse Reaction Reporting Form and the Adverse Reaction Guidelines can be found on the Health Canada Web site or in The Canadian Compendium of Pharmaceuticals and Specialties.


Propylthiouracil Associated with Risk of Serious Liver Injury, Including Liver Failure and Death

June 4, 2009

June 4, 2009 – Yesterday, The American Food and Drug Administration (FDA) has published the following safety alert (adapted) on propylthiouracil.

FDA is notifying healthcare professionals of the risk of serious liver injury, including liver failure and death, with the use of propylthiouracil (PTU) in adult and pediatric patients.

2009 0604 PropylthiouracilReports to FDA’s Adverse Event Reporting System (AERS) suggest there is an increased risk of hepatotoxicity with PTU when compared to methimazole (MMI). Although both PTU and MMI are indicated for the treatment of hyperthyroidism due to Graves’ disease, healthcare professionals should carefully consider which drug to initiate in a patient recently diagnosed with Graves’ disease. Physicians should closely monitor patients on PTU therapy for symptoms and signs of liver injury, especially during the first six months after initiation of therapy.

FDA has identified 32 AERS cases (22 adult and 10 pediatric) of serious liver injury associated with PTU use. Of the adult cases, 12 deaths and 5 liver transplants occurred. Among the pediatric patients, 1 case resulted in death and 6 in liver transplants. In contrast, for MMI 5 AERS cases of serious liver injury were identified. All five cases were in adult patients and 3 resulted in death.

PTU and MMI were approved in 1947 and 1950, respectively. In general, PTU is considered second-line drug therapy except in patients who are allergic to or intolerant of methimazole. Rare cases of embryopathy, including aplasia cutis, have been reported with use of MMI during pregnancy, while no such cases have been reported with PTU use. Thus, PTU may be more appropriate for patients with Graves’ disease who are in their first trimester of pregnancy.

On April 18, 2009, FDA held a public workshop with the American Thyroid Association (ATA) to discuss PTU-related hepatotoxicity. FDA is continuing to monitor these serious reported adverse events and working to make changes to the PTU prescribing information, particularly for use in pediatric patients. Also, the ATA plans to update its treatment guidelines for Graves’ disease in the upcoming months.

You are encouraged to report all serious adverse events and product quality problems to FDA MedWatch at www.fda.gov/medwatch/report.htm.


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