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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
NORVIR (NDA-020659)
(RITONAVIR)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
10/21/2020 (SUPPL-72)
6 Adverse Reactions
6.2 Postmarketing Experience(Additions underlined)
…
Renal and Urinary Disorders:
Nephrolithiasis
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION(Additions underlined)
…
What are the possible side effects of NORVIR?
NORVIR can cause serious side effects including:
…
Kidney stones
…
12/19/2019 (SUPPL-71)
4 Contraindications
(Additions underlined)
NORVIR is contraindicated with drugs that are potent CYP3A inducers where significantly reduced ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].
Anticancer Agents: apalutamide
7 Drug Interactions
Potential for NORVIR to Affect Other Drugs(Newly added information)
These examples are a guide and not considered a comprehensive list of all possible drugs that may interact with ritonavir. The healthcare provider should consult appropriate references for comprehensive information.
(Table 4 updated to add several drug interactions; see label for complete information)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Patient Information(Additions underlined)
Do not take NORVIR if you or your child:
- If you take any of the following medicines:
Apalutamide
08/21/2019 (SUPPL-70)
4 Contraindications
Section has been revised from a chart format to a bulleted line listing.
Addition of the lipid modifying agent lomitapide
7 Drug Interactions
7.2 Established and Other Potentially Significant InteractionsAddition of the following drug-drug interaction information to Table 4 Established and Other Potentially Significant Drug Interactions:
anticancer agents: neratinib and abemaciclib
lipid modifying agent: Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide
hepatitis C direct acting antivirals: glecaprevir/pibrentasvir
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATIONDo not take NORVIR if you or your child:
If you take any of the following medicines:
Addition of ‘lomitapide’
11/15/2018 (SUPPL-69)
7 Drug Interactions
7.2 Established and Other Potentially Significant Drug Interactions(added ibrutinib to the list of Anticancer Agents under Table 5, please refer to label to view Table 5)
09/29/2017 (SUPPL-68)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Patient Information(Additions and/or revisions are underlined)
How should I take NORVIR?
Contact your doctor if you are planning to take Norvir Oral Solution through a feeding tube because some feeding tubes are not recommended for use with ethanol and/or propylene glycol-containing products like NORVIR.
06/29/2017 (SUPPL-66)
4 Contraindications
(additions to Table 2; please refer to label)
7 Drug Interactions
7.2 Established and Other Potentially Significant Drug Interactions(additions to Table 5, please refer to label)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Patient Information(additions and revisions; please refer to label)
06/07/2017 (SUPPL-67)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use)
General Information Dosing and Preparation Information
Advise patients and caregivers to pay special attention to accurate preparation and administration of their dose to minimize the risk of accidental overdose or underdose of NORVIR.
For Norvir oral powder, advise patients or caregivers to read and follow the Instructions for Use for preparing the correct dose.
Advise caregivers to inform their healthcare provider if their children’s weight changes in order to make sure that the child’s NORVIR dose is adjusted as needed.
Advise patients to take NORVIR with meals.
Advise patients to remain under the care of a physician while using NORVIR and to take NORVIR and other concomitant antiretroviral therapy every day as prescribed. NORVIR must always be used in combination with other antiretroviral drugs. Advise patients not to alter the dose or discontinue therapy without consulting with their healthcare provider….
Hepatotoxicity
Pre-existing liver disease including Hepatitis B or C can worsen with use of NORVIR. This can be seen as worsening of transaminase elevations or hepatic decompensation. Advise patients that their liver function tests…
Pancreatitis
Pancreatitis, including some fatalities, has been observed in patients receiving NORVIR therapy. Advise patients to notify their healthcare provider of signs and symptoms…
Allergic Reactions/Hypersensitivity
Skin rashes ranging in severity from mild to Stevens-Johnson syndrome have been reported in patients receiving NORVIR. Advise patients to contact their…
PR Interval Prolongation
NORVIR may produce changes in the electrocardiogram (e.g., PR prolongation). Advise patients to consult their healthcare provider if they experience…
Lipid Disorders
Advise patients that treatment with NORVIR therapy can result in substantial increases in the concentration of total cholesterol and triglycerides.
Diabetes Mellitus/Hyperglycemia
Advise patients that new onset of diabetes or exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported...
Immune Reconstitution Syndrome
Advise patients that immune reconstitution syndrome syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including NORVIR.
Fat Redistribution
Advise patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long term health effects of these conditions are not known at this time.
Patients with Hemophilia
Advise patients with hemophilia that they may experience increased bleeding when treated with protease inhibitors such as NORVIR.
NORVIR Oral Solution Not Recommended During Pregnancy
Advise pregnant women that use of NORVIR oral solution during pregnancy is not recommended due to its alcohol content.
Pregnancy Exposure Registry
Inform patients that there is an antiretroviral pregnancy registry that monitors fetal outcomes of pregnant women exposed to NORVIR.
Lactation
Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk.
12/22/2016 (SUPPL-64)
8 Use in Specific Populations
8.1 Pregnancy(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to NORVIR during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1–800–258–4263.
Risk Summary
Prospective pregnancy data from the Antiretroviral Pregnancy Registry (APR) are not sufficient to adequately assess the risk of birth defects or miscarriage. Available data from the APR show no difference in the rate of overall birth defects for ritonavir compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP)
In animal reproduction studies, no evidence of adverse developmental outcomes was observed with oral administration of ritonavir to pregnant rats and rabbits. During organogenesis in the rat and rabbit, systemic exposure (AUC) was approximately 1/3 lower than human exposure at the recommended daily dose. In the rat pre- and post-natal developmental study, maternal systemic exposure to ritonavir was approximately 1/2 of the exposure in humans at the recommended daily dose, based on a body surface area conversion factor.
NORVIR oral solution is not recommended during pregnancy because there is no known safe level of alcohol exposure during pregnancy.
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations
Dose Adjustments During Pregnancy and the Postpartum Period
NORVIR oral solution contains 43.2% alcohol and 26.57% propylene glycol and is not recommended during pregnancy because there is no known safe level of alcohol exposure during pregnancy.
Data
Human Data
Based on prospective reports to the APR of approximately 6100 live births following exposure to ritonavir-containing regimens (including over 2800 live births exposed in the first trimester and over 3200 live births exposed in the second and third trimesters), there was no difference in the rate of overall birth defects for ritonavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.7%-2.9%) following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.3%-3.5%) following second and third trimester exposure to ritonavir-containing regimens.
While placental transfer of ritonavir and fetal ritonavir concentrations are generally low, detectable levels have been observed in cord blood samples and neonate hair.
Animal Data
Ritonavir was administered orally to pregnant rats (at 0, 15, 35, and 75 mg/kg/day) and rabbits (at 0, 25, 50, and 110 mg/kg/day) during organogenesis (on gestation days 6 through 17 and 6 through 19, respectively). No evidence of teratogenicity due to ritonavir was observed in rats and rabbits at doses producing systemic exposures (AUC) equivalent to approximately 1/3 lower than human exposure at the recommended daily dose. Developmental toxicity observed in rats (early resorptions, decreased fetal body weight and ossification delays and developmental variations) occurred at a maternally toxic dose, at an exposure equivalent to approximately 1/3 lower than human exposure at the recommended daily dose. A slight increase in the incidence of cryptorchidism was also noted in rats (at a maternally toxic dose) at an exposure approximately 1/5 lower than human exposure at the recommended daily dose. Developmental toxicity was observed in rabbits (resorptions, decreased litter size and decreased fetal weights) at maternally toxic doses approximately 1.8 times higher than the recommended daily dose, based on a body surface area conversion factor. In pre-and postnatal development study in rats, ritonavir was administered at doses of 0, 15, 35, and 60 mg/kg/day from gestation day 6 through postnatal day 20. At doses of 60 mg/kg/day, no developmental toxicity was noted with ritonavir dosage equivalent to 12 of the recommended daily dose, based on a body surface area conversion factor.
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)
Risk Summary
Limited published data reports that ritonavir is present in human milk.
There is no information on the effects of ritonavir on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants) and (3) serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving NORVIR.
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)
Contraception
Use of NORVIR may reduce the efficacy of combined hormonal contraceptives. Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
General Information
- Advise pregnant women that use of NORVIR oral solution during pregnancy is not recommended due to its alcohol content.
- Do not breastfeed. Instruct women with HIV-1 infection not breastfeed because HIV-1 can be passed to the infant in the breast milk.
Drug Interactions
- Instruct patients receiving combined hormonal contraception to use an effective alternative contraceptive method or an additional barrier method during therapy with NORVIR because hormonal levels may decrease.
Potential Adverse Effects
- Pregnancy Exposure Registry
11/22/2016 (SUPPL-63)
4 Contraindications
(addition underlined)
• When co-administering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including contraindication information.
• NORVIR is contraindicated in patients with known hypersensitivity (e.g., toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome) to ritonavir or any of its ingredients.
• NORVIR is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life- threatening reactions.
NORVIR is contraindicated with drugs that are potent CYP3A inducers where significantly reduced lopinavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance.
Table 2. Drugs that are Contraindicated with NORVIR (updater; please refer to label)
5 Warnings and Precautions
5.1 Risk of Serious Adverse Reactions Due to Drug Interactions (addition underlined)Initiation of NORVIR, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving NORVIR, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of NORVIR, respectively. These interactions may lead to:
• Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.
• Clinically significant adverse reactions from greater exposures of NORVIR.
• Loss of therapeutic effect of NORVIR and possible development of resistance.
When co-administering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including important Warnings and Precautions.
See Table 5 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during NORVIR therapy; review concomitant medications during NORVIR therapy, and monitor for the adverse reactions associated with the concomitant medications
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia
have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin
or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis
has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia
persisted in some cases. Because these events have been reported voluntarily during clinical
practice, estimates of frequency cannot be made and a causal relationship between protease
inhibitor therapy and these events has not been established. Consider monitoring
for hyperglycemia, new onset diabetes mellitus, or an exacerbation of diabetes mellitus in
patients treated with NORVIR.
7 Drug Interactions
Subsection updated with colchicine and strong CY3A inhibitorinformation for patients with renal and/or hepatic impairment .
Table 5. Established and Other Potentially Significant Drug Interactions (table updated; please refer to label)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Patient Information (addition underlined)Who should not take NORVIR?
Do not take NORVIR if you are allergic to ritonavir or any of the ingredients in NORVIR. See the end of this leaflet for a complete list of ingredients in NORVIR.
Do not take NORVIR with any of the following medicines:
• alfuzosin (Uroxatral)
• amiodarone (Cordarone, Nexterone, Pacerone), dronedarone (Multaq), flecainide (Tambocor), propafenone (Rythmol) or quinidine (Nuedext, Quinaglute, Cardioquin, Quinidex, and others)
• colchicine (Colcrys, Col-Probenecid, Probenecid and Colchine), if you have kidney and/or liver problems
• voriconazole (VFend) if NORVIR dose is 400 mg every 12 hours or greater
• dihydroergotamine (D.H.E. 45, Embolex, Migranal), ergotamine (Cafergot, Ergomar)
methylergonovine (Methergine)
• cisapride (Propulsid)
• St. John’s Wort (Hypericum perforatum)
• the cholesterol lowering medicines lovastatin (Mevacor, Altoprev, Advicor) or simvastatin
(Zocor, Simcor, Vytorin)
• lurasidone (Latuda), pimozide (Orap)
• sildenafil (Revatio) only when used for the treatment of pulmonary arterial hypertension
• oral midazolam or triazolam (Halcion)
Serious problems can happen if you or your child takes any of these medicines with NORVIR.
09/15/2016 (SUPPL-65)
4 Contraindications
Table 1. Drugs that are Contraindicated with NORVIR (updated)
Drug Class : Antipsychotics (added)
Drugs Within Class That Are Contraindicated With NORVIR
Lurasidone
Clinical Comments: Potential for serious and/or life –threatening reactions.
Pimozide
Clinical Comments: Potential for cardiac arrhythmias.
7 Drug Interactions
7.2 Established and Other Potentially Significant Drug Interactions
Table 4. Established and Other Potentially Significant Drug Interactions (updated)
Drug Class : Antipsychotics
Perphenazine, risperidone and thioridazine (added) increase.
Effect on Concentration of Ritonavir or Concomitant Drug: Levels of antipsychotic will increase.
Clinical Comments: A dose decrease may be needed for these drugs when co-administered with ritonavir.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Patient Information (updated)
Do not take NORVIR with any of the following medicines:
· lurasidone (Latuda)