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Jazz Pharmaceuticals 7/6/10

  

Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
 Silver Spring, MD 20993

 


TRANSMITTED BY FACSIMILE


Bruce C. Cozadd
Chairman and Chief Executive Officer
Jazz Pharmaceuticals
3180 Porter Drive
Palo Alto, CA 94304


RE: NDA #022033
Luvox CR® (fluvoxamine maleate) Extended-Release Capsules
MACMIS #18319


WARNING LETTER


Dear Mr. Cozadd:


The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed a patient brochure (LCR-PEB-02) for Luvox CR® (fluvoxamine maleate) Extended-Release Capsules (Luvox CR) submitted by Jazz Pharmaceuticals (Jazz) under cover of Form FDA- 2253. The patient brochure is false or misleading because it omits and minimizes important risk information associated with Luvox CR and overstates the efficacy of Luvox CR. Thus the patient brochure misbrands the drug in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a) & 321(n). Cf. 21 CFR 202.1(e)(3)(i); (e)(5) & (e)(6)(i). These violations are concerning from a public health perspective because they suggest that Luvox CR is safer and more effective than has been demonstrated.


Background


The INDICATION AND USAGE section of the FDA-approved product labeling (PI) for Luvox CR states, in pertinent part (emphasis in original):


Social Anxiety Disorder: LUVOX CR Capsules are indicated for the treatment of social anxiety disorder, also known as social phobia, as defined in DSM-IV (300.23). Social anxiety disorder is characterized by a marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person’s normal routine, occupational or academic functioning, or social activities or relationships, or there is marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment. . . .
 

Obsessive Compulsive Disorder: LUVOX CR Capsules are indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD), as defined in the DSM-IV. The obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning. . . .


Luvox CR is associated with numerous risks. The PI contains a Boxed Warning regarding suicidality and antidepressant drugs, as well as Contraindications including co-administration with alosetron, tizanidine, thioridazine, or pimozide, use in combination with monoamine oxidase inhibitors (MAOIs), or within 14 days of discontinuing treatment with an MAOI, or in patients with a history of hypersensitivity to fluvoxamine maleate or any of its excipients. The PI also contains numerous Warnings and Precautions, including clinical worsening and suicide risk, serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions, potentially important drug interactions, such as those with warfarin, adverse events upon discontinuation of treatment with Luvox CR capsules, abnormal bleeding, activation of mania/hypomania, seizures, hyponatremia, interference with cognitive or motor performance, and use in patients who are pregnant or nursing.


The most common adverse reactions associated with the use of Luvox CR (incidence of at least 5% and at least twice the incidence in placebo patients) include abnormal ejaculation, anorexia, anorgasmia, asthenia, diarrhea, nausea, somnolence, sweating and tremor. In
addition, patients with social anxiety disorder experienced dyspepsia, dizziness, insomnia, and yawning, and patients with OCD experienced accidental injury, anxiety, decreased libido, myalgia, pharyngitis, and vomiting.


Omission and Minimization of Risk Information


Promotional materials are misleading if they fail to reveal facts that are material in light of representations made or with respect to consequences that may result from the use of the drug as recommended or suggested in the materials.


The patient brochure presents numerous effectiveness claims for Luvox CR, but omits material risks associated with the drug. For example, the brochure entirely omits the Warnings regarding potentially fatal serotonin syndrome and NMS-like reactions, and also omits information about serious drug interactions, such as warfarin. The brochure also omits Precautions related to the discontinuation of treatment with Luvox CR, abnormal bleeding risk, activation of mania/hypomania, seizures, hyponatremia, interference with cognitive or motor performance, pregnancy, and breast feeding. Because the patient brochure omits important risk information, it misleadingly suggests that Luvox CR is safer than has been demonstrated by substantial evidence or substantial clinical experience.

The patient brochure also minimizes the risk information that it does disclose. For example, pages 7 and 14 of the patient brochure include the claim, “. . . Luvox CR was shown to have a low incidence of sexual side effects.” However, according to the ADVERSE REACTIONS section of the PI, Luvox CR was associated with an appreciable incidence of sexual side effects, including the following adverse events that were reported in Luvox CR patients vs. placebo: abnormal ejaculation (SAD: 11% vs. 2%; OCD: 10% vs. 0%), anorgasmia (SAD: 5% vs. 1%; OCD: 5% vs. 0%), and decreased libido (SAD: 6% vs. 4%; OCD: 6% vs. 2%). In addition, the ADVERSE REACTIONS section of the PI lists abnormal ejaculation and anorgasmia as among “[t]he most commonly observed adverse events associated with the use of LUVOX CR Capsules. . .”, and lists decreased libido as an additional commonly observed adverse event in patients with OCD. Thus, the claims of a “low incidence of sexual side effects” misleadingly minimize the risk of sexual adverse reactions with Luvox CR treatment.


Pages 7 and 14 also include a claim that “. . . nausea was the most common side effect, but was typically mild to moderate” (emphasis added). However, according to the ADVERSE REACTIONS section of the PI, 8% of SAD patients vs. <1% of placebo patients and 6% of OCD patients vs. 0% of placebo patients experienced nausea troubling enough to discontinue treatment. This important contextual information is not disclosed in the brochure, and the claims on these pages therefore significantly minimize the effects of this adverse reaction.


The patient brochure also fails to include risk information in each specific part as necessary to qualify the safety and effectiveness claims for Luvox CR. Specifically, the patient brochure includes a 7-page patient profile of a SAD patient (Ana, a 19-year-old student) followed by a 6-page patient profile of an OCD patient (Robert, a 27-year-old engineer); both profiles include numerous claims about how Luvox CR treatment helped each patient. However, aside from the misleading safety claims discussed above, the only risk information included in the 17-page brochure is located at the end of each patient profile (on pages 9 and 17 of the brochure). The patient profiles themselves entirely omit material risk information, including information from the Boxed Warning and WARNINGS section of Luvox CR’s PI regarding increased suicidality in children, adolescents, and young adults (ages 18-24). Furthermore, while the rest of the information in the patient brochure is presented in consumer-friendly language, the risk information on pages 9 and 17 is presented in medical terminology that is not likely to be understood by consumer audiences.


We note the statement, “Please see accompanying full prescribing information, including boxed warning,” appears at the bottom of selected pages of the patient brochure in small type print. However, this statement does not mitigate the misleading omission and minimization of risk information.


Overstatement of Efficacy


Promotional materials are misleading if they contain representations or suggestions that a drug is better or more effective than has been demonstrated by substantial evidence or substantial clinical experience. The patient profile for Ana, a 19-year-old student, includes the following statements:


The knots would form in my stomach weeks ahead of anything social. . . . So I made excuses as to why I couldn’t go out. I’d sit alone in my dorm room feeling nervous and sick to my stomach. I stopped going to class. My grades were suffering. If it kept up, I would flunk out of school. I knew other people who were anxious. They went to see a psychiatrist and took medication.
 

 

Following Ana’s treatment with Luvox CR, she claims:



Recently, I got a B on my bio midterm and I’ve been playing flute in a jazz quartet after classes. Small steps, but everything is starting to go well. My psychiatrist is really pleased and thinks I’m doing better.


The overall impression created by these presentations is that treatment with Luvox CR will markedly improve a patient’s social functioning and academic performance (i.e., patients will go from sitting “alone in [their] dorm room feeling nervous and sick to [their] stomach[s]” and being in danger of flunking out of school to “playing flute in a jazz quartet after classes” and getting good grades in school). We are not aware of substantial evidence or substantial clinical experience to support the implication that patients treated with Luvox XR will experience such improvements in social functioning or academic performance.


We acknowledge that the diagnostic criteria for social anxiety disorder encompasses a range of symptoms (see Background). However, according to the CLINICAL TRIALS section of Luvox CR’s PI, the effectiveness of Luvox CR in the treatment of social anxiety disorder was demonstrated in two 12-week, multicenter, placebo-controlled studies of adult outpatients with social anxiety disorder (DSM-IV), evaluated on the basis of change from baseline in the Liebowitz Social Anxiety Scale (LSAS). While Luvox CR has been shown to improve total scores in the LSAS, this scale does not measure the impact of treatment on the six individual subscales of the LSAS (total fear, fear of social interaction, fear of performance, total avoidance, avoidance of social interaction, and avoidance of performance) or the 24 individual items of the LSAS. In addition, the Medical Officer(s) Review of the clinical trial dataindicates the LS [Least Squares] Mean treatment effects of Luvox CR in patients with social anxiety disorder were improvements of 13.4 (Study 3107) and 8.4 (Study 3108) in total LSAS scores. Considering that the scoring scale of the LSAS may categorize the level of severity of social anxiety (moderate [score of 55-65], marked [score of 65-80], severe [score of 80-95], very severe [score greater than 95]) in 15-point increments, improvements of the magnitude demonstrated by the results of in the clinical trials do not correlate with the drastic improvements in social functioning suggested by the patient brochure. Moreover, the LSAS does not measure academic performance. Academic performance is a general concept that includes cognitive performance, attention, physical performance, and behavior (e.g., ability to maintain an acceptable level of performance over the course of a day for five days a week, the ability to memorize, retain, and apply learned information).


Therefore, the implication that Luvox CR will markedly improve a patient’s social functioning and academic performance is not supported by the data in the PI. If you have data to support such claims, please submit them to FDA for review.


Similarly, the patient brochure section on OCD includes a patient profile for Robert, a 27-year-old engineer, who states:


The rituals spiraled out of control. They got longer and more involved. . . . It began to eat into entire chunks of my day. The doorknob to my office had to be turned 16 times before I entered. All my pens and markers had to be lined up in size order. I couldn’t stop. And when I tried explaining it to my fiancée, she didn’t understand. All she saw was the obsessions getting worse, and the compulsions occupying more and more of my life. It wasn’t long before the engagement was off.


Following Robert’s treatment with Luvox CR, he claims:


For me, CBT [cognitive behavioral therapy] was the start, but my treatment really turned around when they started me on combination therapy and put me on medicine specifically suited for OCD, Luvox CR. . . . Getting help has improved my life in significant ways. I’m back on track at work, and my wedding is back on. All because I sought help to manage my OCD. . . . You can get your life back on track. I know, because I did.


The overall impression created by these claims is that treatment with Luvox CR will markedly improve a patient’s work productivity and social functioning (i.e., get them “back on track at work” and revive failed romantic relationships (“my wedding is back on”)). We are not aware of substantial evidence or substantial clinical experience to support the implication that patients on treatment with Luvox XR will experience this magnitude of improvement in work productivity or social functioning.

We acknowledge that the diagnostic criteria for OCD encompasses a range of symptoms (see Background). However, according to the CLINICAL TRIALS section of the PI, the effectiveness of Luvox CR for the treatment of OCD was demonstrated in a 12-week, multicenter, placebo-controlled study of adult outpatients with moderate to severe OCD (DSM-IV), demonstrating mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) total scores of 26.6 and 26.3 for fluvoxamine and placebo-treatment groups, respectively. While Luvox CR has been shown to improve the total Y-BOCS score, this scale does not measure the impact of treatment specifically on work productivity or social functioning. The Y-BOCS is a 10-item scale that was designed to measure the severity of symptoms of OCD based on a clinician’s assessment, with each item rated from 0 (no symptoms) to 4 (extreme symptoms), for a maximum possible score of 40. The scale measures obsessions separately from compulsions, without influence from the type of obsessions or compulsions present. In addition, the Medical Officer(s) Review of the clinical trial data2 indicates that the LS Mean treatment effect for patients with OCD was an improvement of 2.8 (Study 3103) in total Y-BOCS score. Consequently, this improvement in the Y-BOCS score does not necessarily correlate with the markedly positive effects on work productivity or social functioning suggested by the patient brochure. If you have data to support such claims, please submit them to FDA for review.


Conclusion and Requested Action


For the reasons discussed above, the patient brochure misbrands Luvox CR in violation of the Act, 21 U.S.C. 352(a) & 321(n). Cf. 21 CFR 202.1(e)(3)(i); (e)(5) & (e)(6)(i).


DDMAC requests that Jazz immediately cease the dissemination of violative promotional materials for Luvox CR such as those described above. Please submit a written response to this letter on or before July 20, 2010, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Luvox CR that contain violations such as those described above, and explaining your plan for discontinuing use of such violative materials. Because the violation/violations described above are serious, we request, further, that your submission include a comprehensive plan of action to disseminate truthful, non-misleading, and complete corrective messages about the issues discussed in this letter to the audience(s) that received the violative promotional materials. Please direct your response to me at the Food and Drug Administration, Center for Drug Evaluation and Research, Division of Drug Marketing, Advertising, and Communications, 5901-B Ammendale Road, Beltsville, MD 20705-1266, or facsimile at 301-847-8444. In all future correspondence regarding this matter, please refer to MACMIS #18319 in addition to the NDA number. We remind you that only written communications are considered official.


The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that your promotional materials for Luvox CR comply with each applicable requirement of the Act and FDA implementing regulations.


Failure to correct the violations discussed above may result in FDA regulatory action, including seizure or injunction, without further notice.

Sincerely,
{See appended electronic signature page}
Thomas W. Abrams, RPh, MBA
Director
Division of Drug Marketing,
Advertising, and Communications

1Accessed at http://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022033s000_MedR_P1.pdf, pages 32-33 (Feb, 26, 2007).
 

2Accessed at http://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022033s000_MedR_P1.pdf, page 33 (Feb. 26, 2007).

Application Type/NumberSubmission Type/NumberSubmitter NameProduct Name
NDA-22033ORIG-1Jazz Pharmaceutica LSLuvox CR (FLUVOXAMINE MALEATE)


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This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.
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/s/
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THOMAS W ABRAMS
07/06/2010