FDA Notifications

Darunavir package updated

Updates to the darunavir (Prezista®) package insert, specifically sections: 6 Adverse Reactions, 12.4 Microbiology, 14 Clinical Studies and were approved on Oct. 19, 2011, to include results from the 192-week safety, resistance and efficacy data from study TMC114-C211, "A randomized, controlled, open-label Phase 3 trial comparing darunavir/ritonavir 800/100 mg once daily versus lopinavir/ritonavir 800/200 mg per day (given as a twice daily or as a once daily regimen) in antiretroviral treatment-naïve HIV-1-infected adult subjects."

In addition section 5.3 Severe Skin Reactions now includes the following text about darunavir/ritonavir + raltegravir containing regimens. Rash occurred more commonly in treatment-experienced subjects receiving regimens containing darunavir/ritonavir + raltegravir compared to subjects receiving darunavir/ritonavir without raltegravir or raltegravir without darunavir/ritonavir. However, rash that was considered drug related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.

The complete revised label will be posted soon at Drugs@FDA.

Pegasys antiviral approved

On Sept. 29, 2011, the Food and Drug Administration approved a135 mcg/0.5ml and 180 mcg/0.5 ml disposable autoinjector (DAI) to administer peginterferon alfa-2a (Pegasys®), an antiviral indicated for treatment of Chronic Hepatitis C (CHC) by subcutaneous injection.

Pegasys continues to be available in a vial or prefilled syringe, and now also in a 135 mcg/0.5ml and 180 mcg/0.5 ml PEGASYS disposable autoinjector. The package insert and the Medication Guide have been updated to provide new information and instructions for use related to the disposable autoinjector.

Because the autoinjectors are designed to deliver the full content, autoinjectors should only be used for patients who need the full dose (180 or 135 mcg). If the required dose is not available in an autoinjector, prefilled syringes, or vials should be used to administer the required dose. The autoinjector is for subcutaneous administration only.

The updated label and Medication Guide can be found on the FDA web site at http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/103964s5204lbl.pdf

Pegasys is a product of Hoffmann-La Roche, of Nutley, NJ.

ART guidelines updated

On Oct. 14, 2011, updated Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents were made available through the AIDSinfo web site.

Guidelines for treating HIV-infected adults and adolescents, including utilization of resistance testing, initiation of treatment, preferred first-line regimens, adverse events to antiretroviral medications, managing treatment-experienced patients, and considerations for special populations.

This revision to the guidelines is focused on What to Start: Initial Combination Regimens for the Antiretroviral-Naive Patient. Additions and key changes to the section are outlined below. More detailed discussion of the rationale for changes to the What to Start recommendations can be found in the updated section. Tables in the guidelines corresponding to the What to Start section have also been updated to reflect changes.

• Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)-Based Regimens

Rilpivirine added as an alternative NNRTI option for initial therapy in treatment-naive patients.

All nevirapine-based regimens reclassified as acceptable options for treatment-naive patients (females with pretreatment CD4 count <250 cells/mm3 or males with pretreatment CD4 count <400 cells/mm3). Previously, "nevirapine + zidovudine/lamivudine" was classified as an alternative regimen and "nevirapine + abacavir/lamivudine" and "nevirapine + tenofovir/emtricitabine" were recommended as regimens that may be acceptable but should be used with caution.

• Protease Inhibitor (PI)-Based Regimens

"Ritonavir-boosted darunavir + abacavir/lamivudine" reclassified as an alternative regimen (BIII); previously the regimen was recommended as a regimen that may be acceptable but more definitive data are needed (CIII).

Regimens with unboosted fosamprenavir removed as PI options for treatment-naive patients. The Panel removed the regimens because they have inferior potency compared with other PI-based regimens and because of the potential for selection of mutations that confer resistance to darunavir in patients who experience virologic failure while on these regimens.

• Raltegravir-Based Regimens

"Raltegravir + abacavir/lamivudine" reclassified as an alternative regimen (BIII); previously, the regimen was classified as a regimen that may be acceptable but more definitive data are needed (CIII).

Dual-Nucleoside Reverse Transcriptase Inhibitor (NRTI) Options

"Zidovudine + lamivudine" reclassified from an alternative dual-NRTI option to an acceptable option because the combination has greater toxicities compared with tenofovir/emtricitabine and abacavir/lamivudine and requires twice daily dosing. However, zidovudine + lamivudine remains as the preferred dual-NRTI for pregnant women receiving antiretroviral therapy (ART) for prevention of perinatal transmission of HIV.

"Didanosine + lamivudine" removed as a dual-NRTI option for initial therapy because the combination has the least clinical trial experience and greater toxicity compared with other available dual-NRTI options.

Discussion on the association between abacavir use and the risk of a cardiovascular event updated.

In addition to the changes highlighted above, the following tables are updated with information relevant to rilpivirine:

  1. Tables 14, 15b, and 16b – Drug interaction tables
  2. Appendix B, Table 2 – Drug characteristic table
  3. Appendix B, Table 7 – Dosing recommendation for patients with renal or hepatic insufficiency

Raltegravir package insert updated

The FDA approved updates to the raltegravir (Isentress®) package insert on Nov. 2, 2011, to include a new subsection in the Warnings and Precautions section and update the postmaketing experience section. Specifically, the following subsection was added to section 5 Warnings and Precautions:

5.1 Severe Skin and Hypersensitivity Reactions

"Severe, potentially life-threatening, and fatal skin reactions have been reported. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure. Discontinue ISENTRESS and other suspect agents immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping ISENTRESS treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction."

In Section 6 Adverse Reactions, subsection 6.2 Postmarketing Experience, cerebellar ataxia and drug rash with eosinophilia and systemic symptoms was added.

The Patient Counseling Information section and the patient labeling was also revised to incorporate the following paragraph, which was added at the beginning of the Patient Counseling Information section:

"Patients should be informed that severe and potentially life-threatening rash has been reported. Patients should be advised to immediately contact their healthcare provider if they develop rash. Instruct patients to immediately stop taking ISENTRESS and other suspect agents, and seek medical attention if they develop a rash associated with any of the following symptoms as it may be a sign of a more serious reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis or severe hypersensitivity: fever, generally ill feeling, extreme tiredness, muscle or joint aches, blisters, oral lesions, eye inflammation, facial swelling, swelling of the eyes, lips, mouth, breathing difficulty, and/or signs and symptoms of liver problems (e.g., yellowing of the skin or whites of the eyes, dark or tea colored urine, pale colored stools/bowel movements, nausea, vomiting, loss of appetite, or pain, aching or sensitivity on the right side below the ribs). Patients should understand that if severe rash occurs, they will be closely monitored, laboratory tests will be ordered and appropriate therapy will be initiated."