Released by FDA:  6/10/04.  Posted by FDA:  6/10/04

Miles D. White, MBA
Chairman and Chief Executive Officer
Abbott Laboratories
200 Abbott Park Road
D-491, AP30-IE
Abbott Park, Illinois 60064-6157

Re:   NDA 20-659
         Norvir (ritonavir capsules) Soft Gelatin
         MACMIS # 12335

Dear Mr. White:

The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed a promotional cost comparison chart¹ (cost chart) (04A-017-13002-1), two brochures (03A-036-6655-2 and 04A-017-13770-2), a pill wall chart (01K-036-1054-1), and updates² to a promotional web site (www.norvir.com) for Norvir® (ritonavir capsules) Soft Gelatin disseminated by Abbott Laboratories, Inc. (Abbott). The cost chart is false or misleading in violation of section 502(a) of the Federal Food, Drug, and Cosmetic Act (Act) (21 U.S.C. 352(a)) because it claims that Norvir has the lowest daily cost of all antiretroviral drugs and minimizes the risks of Norvir. In addition, these materials were not submitted to FDA under cover of Form 2253, as required by 21 CFR 314.81(b)(3)(i).  Your cost chart raises significant public health and safety concerns because of the violations outlined above and the potential adverse impact these false and misleading messages may have on the HIV community by promoting a subtherapeutic dose and regimen of Norvir.

Background
The Indications and Usage section of the approved product labeling (PI) for Norvir states:

NORVIR is indicated in combination with other antiretroviral agents for the treatment of HIV-infection. This indication is based on the results from a study in patients with advanced HIV disease that showed a reduction in both mortality and AIDS-defining clinical events for patients who received NORVIR either alone or in combination with nucleoside analogues.  Median duration of follow-up in this study was 13.5 months.

The Dosage and Administration section of the PI states (in pertinent part):

The recommended dosage of ritonavir is 600 mg twice daily by mouth.  Use of a dose titration schedule may help to reduce treatment-emergent adverse events while maintaining appropriate ritonavir plasma levels.  Ritonavir should be started at no less than 300 mg twice daily and increased at 2 to 3 day intervals by 100 mg twice daily.

There are serious, potentially fatal risks associated with the use of Norvir.  The PI includes a Boxed Warning that states (in pertinent part):

CO-ADMINISTRATION OF NORVIR WITH CERTAIN NONSEDATING ANTIHISTAMINES, SEDATIVE HYPNOTICS, ANTIARRHYTHMICS, OR ERGOT ALKALOID PREPARATIONS MAY RESULT IN POTENTIALLY SERIOUS AND/OR LIFE-THREATENING ADVERSE EVENTS DUE TO POSSIBLE EFFECTS OF NORVIR ON THE HEPATIC METABOLISM OF CERTAIN DRUGS.

As communicated in the Contraindications, Warnings, and Precautions sections of the PI, Norvir has been linked to a number of risks.  For example, co-administration of Norvir is contraindicated with amiodarone, bepridil, flecainide, propafenone, quinidine, astemizole, terfenadine, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, pimozide, midazolam, and triazolam. (see Table 4 of the PI).  Concomitant therapy with these drugs and Norvir could result in serious and/or life-threatening reactions such as cardiac arrhythmias, prolonged or increased sedation, and respiratory depression.

Likewise, the PI cautions that "Particular caution should be used when prescribing sildenafil in patients receiving NORVIR.  Co-administration of NORVIR with sildenafil is expected to substantially increase sildenafil concentrations (11-fold increase in AUC) and may result in an increase in sildenafilassociated adverse events, including hypotension, syncope, visual changes, and prolonged erection."

The PI also states:

Resistance/Cross-resistance.  Varying degrees of cross-resistance among protease inhibitors have been observed.  Continued administration of ritonavir therapy following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors.

Lipid Disorders.  Treatment with NORVIR therapy alone or in combination with saquinavir has resulted in substantial increases in the concentration of total triglycerides and cholesterol.  Triglyceride and cholesterol testing should be performed prior to initiating NORVIR therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate.

Finally, under the heading "Information for Patients," the PI states (in relevant part)

"Patients should be informed that NORVIR is not a cure for HIV infection and that they may continue to acquire illnesses associated with advanced HIV infection, including opportunistic infections.  Patients should be told that the long-term effects of NORVIR are unknown at this time.  They should be informed that NORVIR therapy has not been shown to reduce the risk of transmitting HIV to others through sexual contact or blood contamination."

Misleading Comparative Claim
The cost chart is misleading for two reasons.  First, it compares a subtherapeutic dose of Norvir (100 mg once daily) to the labeled dosing regimens of other antiretroviral agents.  Second, the chart implies that Norvir may be used other than in combination therapy, when it is not labeled for such use.  Given by itself as a subtherapeutic dose, Norvir would likely have no antiviral activity and would place patients at risk for developing protease inhibitor resistance mutations.

Subtherapeutic Dose

The cost chart compares the daily costs (based on wholesale acquisition costs) of common antiretroviral drugs.  According to footnote 1, the dosages selected for the compared drugs "reflect commonly prescribed milligrams per day."  Norvir appears in the cost chart with a daily cost of $8.57 per day for a dosage of 100 milligrams/day.  All the other compared drugs have higher daily costs, ranging from $9.84 to $32.00.  The cost chart thus suggests that Norvir, at a dosage of 100 milligrams/day, has the lowest daily cost of all the antiretroviral drugs listed.  However, FDA has found Norvir to be safe and effective only at the dosages set forth in the PI (300-600 mg twice daily).

Monotherapy/Combination Therapy

Norvir has been determined to be safe and effective only when used in combination with other antiretroviral agents.  However, the cost chart compares the cost of Norvir to other antiretrovirals as monotherapy, and includes a comparison to an antiretroviral that is approved as monotherapy, suggesting that all antiretrovirals can be taken effectively as monotherapy.  With the exception of Trizivir®, this has not been demonstrated by substantial evidence or substantial clinical experience.  The footnote "Please reference the Prescribing Information for these products for complete dosing instructions" in smaller print at the bottom of the cost chart is not sufficient to correct the overall misleading implication.

Additionally, the claim is accompanied by a citation to the PI for ReyatazTM (atazanavir sulfate), which is another of the antiretroviral drugs listed in the cost chart.  According to the PI for Reyataz, that drug can be coadministered with Norvir at a 100mg dose as part of a combination regimen.  Therefore, FDA is not aware of substantial evidence or substantial clinical experience demonstrating that Norvir is safe and effective as monotherapy at 100 milligrams/day.  Accordingly, the cost chart is false or misleading.

Misleading Presentation of Risk Information
The contraindicated list of drugs provided with the cost chart is incomplete because you excluded ergonovine and methylergonovine.  Both drugs are contraindicated with Norvir due to a potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. In addition, the cost chart fails to disclose that adverse events may occur when Norvir is taken concomitantly with sildenafil and the possibility exists of cross resistance among protease inhibitors and of lipid disorders.

Finally, the cost chart fails to state, as the PI notes, that Norvir is not a cure for HIV infection and that patients taking the drug may continue to acquire illnesses associated with advanced HIV infection.  Neither does the cost chart state that the long term effects of Norvir are unknown, and that Norvir has not been shown to reduce the risk of transmitting HIV to others through sexual contact or blood contamination. FDA previously brought similar deficiencies to Abbott's attention in a letter dated April 27, 2001. In a response dated May 18, 2001, Abbott agreed to "revise or destroy" three promotional materials that "d[id] not comply with DDMAC's request" i.e., promotional materials directed to consumers should prominently convey that the drug does not cure HIV infection, does not reduce the transmission of HIV infection, must be taken in combination regimens (if applicable), and refrain from using images not generally representative of patients with HIV infection.

Failure to Submit Under Form 2253
FDA regulations require you to submit specimens of mailing pieces and any other labeling or advertising devised for promotion of the drug product at the time of initial dissemination of the labeling and at the time of initial publication of the advertisement for a prescription drug product.  Each submission is required to be accompanied by a completed transmittal Form FDA-2253 (Transmittal of Advertisements and Promotional Labeling for Drugs for Human Use) and is required to include a copy of the product's current professional labeling.

You did not submit any of the promotional materials referred to in this letter to FDA under cover of Form 2253 as required by 21 CFR 314.81(b)(3)(i).

Conclusions and Requested Actions
The cost chart misleadingly claims that Norvir has the lowest daily cost of all antiretroviral drugs and minimizes the risks of Norvir, and thus misbrands Norvir under 21 U.S.C. 352(a).  In addition, the promotional materials identified above were not submitted to FDA under cover of Form 2253, as required by 21 CFR 314.81(b)(3)(i).

DDMAC requests that Abbott immediately cease the dissemination of violative promotional materials for Norvir such as those described above.  Please submit a written response to this letter on or before June 25, 2004, stating whether you intend to comply with this request, listing all violative promotional materials for Norvir such as those described above, and explaining your plan for discontinuing use of such materials. Because the violations described above are serious, we request, further, that your submission include a plan of action to disseminate truthful, non-misleading, and complete information to the audience(s) that received the violative promotional materials. Please direct your response to me at the Food and Drug Administration, Division of Drug Marketing, Advertising, and Communications, HFD-42, Rm. 8B-45, 5600 Fishers Lane, Rockville, MD 20857, facsimile at 301-594-6771.  In all future correspondence regarding this particular matter please refer to the MACMIS ID # 12335 in addition to the NDA number(s).  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 Norvir comply with each applicable requirement of the Act and FDA implementing regulations.

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

Sincerely,

Thomas W. Abrams, RPh, MBA
Director
Division of Drug Marketing,
    Advertising, and Communications

_____________________________________________

¹  The cost chart, initially brought to DDMAC's attention in hard copy, was also placed on the web at www.norvir.com.

²  A code imbedded in www.norvir.com indicates that you updated the site in March 2001, June 2002, and February 2004 (the February 2004 version of this website is what is discussed in this letter).