Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)
WARNINGS AND PRECAUTIONS
Importance of Co-administration with Ritonavir (updated subheading – replaces General subheading)
Not Recommended in Pediatric Patients Below 3 Years of Age (updated subheading - replaces Pediatric Patients subheading)
The following adverse reactions are discussed in other sections of labeling:
- Severe Skin Reactions
- Diabetes Mellitus/Hyperglycemia
- Fat Redistribution
- Immune Reconstitution Syndrome
HIV-1-Antiviral Agents: HIV-Protease Inhibitors (PIs)
- Other HIV protease inhibitors, except atazanavir (added under Drug name column)
- As coadministration with PREZISTA/ritonavir has not been studied, coadministration is not recommended.(added in same row, under clinical comment)
- Oral contraceptives/estrogen - Update the clinical comment for this group of drugs: Effective alternative contraceptive method or barrier method of contraception is recommended.
Drugs without Clinically Significant Interactions with PREZISTA (added subheading)
- No dosage adjustments are recommended when PREZISTA/ritonavir is co-administered with the following medications: atazanavir, dolutegravir, efavirenz, etravirine, nevirapine, nucleoside reverse transcriptase inhibitors (abacavir, emtricitabine, lamivudine, stavudine, tenofovir disoproxil fumarate, zidovudine), pitavastatin, raltegravir, ranitidine, and rilpivirine.
USE IN SPECIFIC POPULATIONS
Pregnancy related sections updated to reflect PLLR conversion. Refer to label.
- PREZISTA/ritonavir is not recommended in pediatric patients… replaces Do not administer Prezista/ritonavir in pediatric patients …
Juvenile Animal Data (addition)
- In a juvenile toxicity study where rats were directly dosed with darunavir (up to 1000 mg/kg), deaths occurred from post-natal day 5 at plasma exposure levels ranging from 0.1 to 1.0 of the human exposure levels. In a 4-week rat toxicology study, when dosing was initiated on post-natal day 23 (the human equivalent of 2 to 3 years of age), no deaths were observed with a plasma exposure (in combination with ritonavir) 2 times the human plasma exposure levels.
PATIENT COUNSELING INFORMATION and PATIENT INFORMATION have both been extensively updated – please refer to label.
- Added medications to Table 6: dronedarone, colchicine, and ranolazine. Modified the information for pimozide.
Potential for PREZISTA/ritonavir to Affect Other Drugs
- P-gp information added...PREZISTA co-administered with ritonavir is an inhibitor of CYP3A, CYP2D6, and P-gp. Co-administration of PREZISTA and ritonavir with drugs that are primarily metabolized by CYP3A and CYP2D6, or are transported by P-gp may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events (see Table 11).
Potential for Other Drugs to Affect Darunavir
- P-gp information added...Darunavir and ritonavir are metabolized by CYP3A. In vitro data indicate that darunavir may be a P-gp substrate. Drugs that induce CYP3A activity would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma concentrations of darunavir and ritonavir. Co-administration of darunavir and ritonavir and other drugs that inhibit CYP3A, or P-gp may decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and ritonavir (see Table 11).
Established and Other Potentially Significant Drug Interactions
Update to Table 11 for the following drug classes:
- Antiarrhythmics, Antibacterial, Anticoagulant, Antidepressant, Antifungals, Antigout, Antimycobacterial, Antineoplastics, Antipsychotics/Neuroleptics, ß-Blockers, Calcium Channel Blockers, Corticosteroid, Hepatitis C Virus (HCV) Direct-Acting Agents: NS3-4A protease inhibitors, HMG-CoA Reductase Inhibitors, Immunosupressants, Narcotic Analgesic/Treatment of Opiod Dependance, PDE-5 inhibitors, Sedative/Hypnotics
- added..Pitavastatin had no clinically significant effect on the pharmacokinetics of darunavir/ritonavir.
- added..Acid modifying medications are not predicted to alter darunavir exposure.
Integrase strand transfer inhibitors
- section edited...No dose adjustments are needed for either raltegravir or darunavir based on pharmacokinetic data from literature references. Please refer to the elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate U.S. prescribing information for information regarding concomitant use with other antiretroviral medications.
5 WARNINGS AND PRECAUTIONS
5.3 Severe Skin Reactions
- During the clinical development program (n=3063), severe skin reactions, accompanied by fever and/or elevations of transaminases in some cases, have been reported in 0.4% of subjects. Stevens-Johnson Syndrome was rarely (less than 0.1%) reported during the clinical development program. During post-marketing experience toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and .....
7 DRUG INTERACTIONS
- added ....information for dolutegravir and in vitro antiviral activity data for rilpivirine
NOTE: information related to the 400 mg tablet strength of darunavir and ergonovine were removed because they are no longer marketed and distributed in the United States.
ADVERSE DRUG REACTIONS
Was update to reflect clinical trial experience in pediatric patients from Study TMC1140C228 as follows:
- ADRs to Prezista/ritonavir (all grades, greater than or equal to 3%), excluding laboratory abnormalities, were diarrhea (19%), vomiting (14%) and rash (10%).
- There were no Grade 3 or 4 laboratory abnormalities considered as ADRs in this study.