Drug Safety-related Labeling Changes (SrLC)

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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.

VIEKIRA PAK (COPACKAGED) (NDA-206619)

(DASABUVIR SODIUM ; OMBITASVIR; PARITAPREVIR; RITONAVIR)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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12/06/2019 (SUPPL-20)

Approved Drug Label (PDF)

4 Contraindications

(additions underlined)

…

With drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events :
…
- Microsomal triglyceride transfer protein inhibitor: lomitapide
With drugs that are moderate or strong inducers of CYP3A and strong inducers of CYP2C8 and may lead to reduced efficacy of VIEKIRA XR:
- Androgen receptor inhibitor: apalutamide
  …

7 Drug Interactions

7.3 Established and Other Potential Drug Interactions

(additions underlined)

Clearance of HCV infection with direct-acting antivirals may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. For example, altered blood glucose control resulting in serious symptomatic hypoglycemia has been reported in diabetic patients in postmarketing case reports and published epidemiological studies.

Management of hypoglycemia in these cases required either discontinuation or dose modification of concomitant medications used for diabetes treatment.

Frequent monitoring of relevant laboratory parameters (e.g. International Normalized Ratio [INR] in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as CYP P450 substrates with a narrow

therapeutic index (e.g. certain immunosuppressants) is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary.

…

Table 4. Drug Interactions

(addition of the following to Table 4, please refer to label for more information)

ANTICANCER AGENTS/KINASE INHIBITORS

encorafenib

fostamatinib

ibrutinib

ivosidenib

GnRH RECEPTOR ANTAGONISTS

elagolix

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(additions underlined)

…

Do not take VIEKIRA XR if you:

have moderate to severe liver problems
take any of the following medicines:

…

apalutamide
…
lomitapide
...

07/23/2018 (SUPPL-18)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Post-Marketing Adverse Reactions

(addition underlined)

…

Immune System Disorders: Anaphylactic reactions and other hypersensitivity reactions (including angioedema).

…

7 Drug Interactions

7.3 Established and Other Potential Drug Interactions

(Table 5 updated to include information regarding Fentanyl)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Pregnancy

Advise patients that extreme care must be taken to avoid pregnancy during treatment with VIEKIRA PAK with ribavirin and within 6 months of stopping ribavirin in both female patients and in female partners of male patients. Inform patients to notify their health care provider immediately in the event of a pregnancy.

…

Administration

…

Advise patients not to remove tablets from the daily dose pack until they are ready to take them.

…

11/09/2017 (SUPPL-17)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Post-Marketing Adverse Reactions

(additions underlined)

…

Skin and Subcutaneous Tissue Disorders: Erythema multiforme (EM)

7 Drug Interactions

7.1 Potential for VIEKIRA PAK to Affect Other Drugs

(additions underlined)

…

Fluctuations in INR values may occur in patients receiving warfarin concomitant with HCV treatment, including treatment with VIEKIRA PAK. If VIEKIRA PAK is coadministered with warfarin, close monitoring of INR values is recommended during treatment and post-treatment follow-up.

03/22/2017 (SUPPL-13)

Approved Drug Label (PDF)

4 Contraindications

Table 2. Drugs that are Contraindicated with VIEKIRA PAK (Table has been revised; please refer to label)

7 Drug Interactions

7.3 Established and Other Potential Drug Interactions

Table 5. Established Drug Interactions Based on Drug Interaction Trials (Table has been revised; please refer to label)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Additions and/or revisions are underlined)

Who should not take VIEKIRA PAK?

Do not take VIEKIRA PAK if you:

take any of the following medicines:
- atorvastatin (Caduet, Lipitor, Liptruzet)
- everolimus (Afinitor, Zortress)
- sirolimus (Rapamune)
- tacrolimus (Astagraf XL, Envarsus XR, Prograf)

03/22/2017 (SUPPL-15)

Approved Drug Label (PDF)

4 Contraindications

Table 2. Drugs that are Contraindicated with VIEKIRA PAK (Table has been revised; please refer to label)

7 Drug Interactions

7.3 Established and Other Potential Drug Interactions

Table 5. Established Drug Interactions Based on Drug Interaction Trials (Table has been revised; please refer to label)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Additions and/or revisions are underlined)

Who should not take VIEKIRA PAK?

Do not take VIEKIRA PAK if you:

take any of the following medicines:
- atorvastatin (Caduet, Lipitor, Liptruzet)
- everolimus (Afinitor, Zortress)
- sirolimus (Rapamune)
- tacrolimus (Astagraf XL, Envarsus XR, Prograf)

02/14/2017 (SUPPL-14)

Approved Drug Label (PDF)

Boxed Warning

WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV

(Newly added section)

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with VIEKIRA PAK. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

5 Warnings and Precautions

5.1 Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV

(Newly added subsection)

Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive).

HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients.

HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.

Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti- HBc before initiating HCV treatment with VIEKIRA PAK. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with VIEKIRA PAK and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV

Inform patients that HBV reactivation can occur in patients coinfected with HBV during or after treatment of HCV infection. Advise patients to tell their healthcare provider if they have a history of hepatitis B virus infection.

MEDICATION GUIDE VIEKIRA PAK (vee-KEE-rah-pak) (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets)co-packaged for oral use

(Additions and/or revisions are underlined)

What is the most important information I should know about VIEKIRA PAK?

VIEKIRA PAK can cause serious side effects, including,

Hepatitis B virus reactivation: Before starting treatment with VIEKIRA PAK, your healthcare provider will do blood tests to check for hepatitis B virus infection. If you have ever had hepatitis B virus infection, the hepatitis B virus could become active again during or after treatment of hepatitis C virus with VIEKIRA PAK. Hepatitis B virus becoming active again (called reactivation) may cause serious liver problems including liver failure and death. Your healthcare provider will monitor you if you are at risk for hepatitis B virus reactivation during treatment and after you stop taking VIEKIRA PAK.

Before taking VIEKIRA PAK, tell your healthcare provider about all of your medical conditions, including if you:

• have ever had hepatitis B virus infection

06/21/2016 (SUPPL-11)

Approved Drug Label (PDF)

7 Drug Interactions

Drugs without Clinically Significant Interactions with VIEKIRA PAK

No dosage adjustments are recommended when Viekira Pak is co-administered with the following medications: addition of abacavir, dolutegravir, lamivudine, sofosbuvir, sulfamethoxazole, and trimethoprim.

Established and Other Potential Drug Interactions

able 5. Established Drug Interactions Based on Drug Interaction Trials

Two drug classes added; please refer to label.

ANTIDIABETIC DRUGS (metformin)
MUSCLE RELAXANTS (carisoprodol, and cyclobenzaprine)

The following two drug classes had drugs added; please refer to label.

NARCOTIC ANALGESICS (Hydrocodone/acetaminophen)
SEDATIVES/HYPNOTICS (Diazepam)

04/22/2016 (SUPPL-9)

Approved Drug Label (PDF)

8 Use in Specific Populations

Pregnancy

Animal data

Ombitasvir

Ombitasvir was administered orally to pregnant mice (0, 15, 50, or 150 mg/kg/day) and rabbits (0, 10 or 60 mg/kg/day) during the period of organogenesis (on gestation days (GD) 6 to 15, and GD 7 to 19, respectively). There were no ombitasvir-related embryofetal effects (malformations or fetal toxicity) at any dose level in either species. The systemic exposures at the highest doses were 28-times higher (mice) and 4-times higher (rabbits) than the exposures in humans at the recommended clinical dose.
In a pre- and postnatal developmental study in mice, ombitasvir was administered orally at 0, 10, 40, or 200 mg/kg/day from GD 6 to lactation day 20. There were no ombitasvir-related effects at maternal exposures 25-times higher than exposures in humans at the recommended clinical dose.
The major human metabolites of ombitasvir, M29 and M36, were tested in pregnant mice during the period of organogenesis from GD 6 to 15. M29 was administered orally at doses of 0, 1, 2.5 or 4.5 mg/kg/day. M36 was dosed orally at doses 1.5, 3, or 6 mg/kg/day. In both cases, there were no treatment related embryofetal effects (malformations or fetal toxicity) at any dose level. The highest doses produced exposures approximately 26-times higher than the exposures in humans at the recommended clinical dose.

Paritaprevir/ritonavir

Paritaprevir/ritonavirwas administered orally to pregnant rats (0/0, 30/15, 100/15, 450/45 mg/kg/day) and mice (0/0, 30/30, 100/30, or 300/30 mg/kg/day) during the period of organogenesis (on GD 6 to 17, and GD 6 to 15, respectively). There were no test articlerelated embryofetal effects (malformations or fetal toxicity) at any dose level in either species. The highest systemic exposure of paritaprevir was 8-times higher (rats) and 98-times higher (mice) than the exposures in humans at the recommended clinical dose.
In a pre- and postnatal developmental study in rats, paritaprevir/ritonavir were administered orally at 0/0, 6/30, 30/30, or 300/30 mg/kg/day from GD 7 to lactation day 20. There were no treatment related effects at maternal exposures 17-times higher than exposures in humans at the recommended clinical dose.

Dasabuvir

Dasabuvir was administered orally to pregnant rats (0, 60, 300 and 800 mg/kg/day) and rabbits (0, 100, 200 or 400 mg/kg/day) during the period of organogenesis (on GD 6 to 17 and GD 7 to 20, respectively). There were no test article-related embryofetal effects (malformations or fetal toxicity) at any dose level in either species. The highest systemic exposure of dasabuvir was 24-times higher (rats) and 6-times higher (rabbits) than the
exposures in humans at the recommended clinical dose.
In a pre- and postnatal developmental study in rats, dasabuvir was administered orally at 0, 50, 200, or 800 mg/kg/day from GD 7 to lactation day 21. There were no treatment-related effects at maternal exposures 44-times higher than exposures in humans at the recommended clinical dose.

Lactation

Animal Data

Ombitasvir

No effects of ombitasvir on growth and postnatal development were observed in nursing pups at the highest dose tested (200 mg/kg/day) in mice. Maternal systemic exposure (AUC) to ombitasvir was approximately 25 times the exposure in humans at the recommended clinical dose. Although not measured directly, ombitasvir was likely present in the milk of lactating mice in this study, since systemic exposure was observed in nursing pups on postnatal day 21 (approximately 16% of maternal exposure).
When ombitasvir was administered to lactating rats (5 mg/kg on post-partum day 10 to 11), milk exposure (AUC) was 4 times higher than that in plasma, with unchanged parent drug (91%) accounting for the majority of drug-related material in milk.

Paritaprevir/ritonavir

No effects of paritaprevir/ritonavir on growth and postnatal development were observed in nursing pups at the highest dose tested (300/30 mg/kg/day) in rats. Maternal systemic exposure (AUC) to paritaprevir was approximately 17 times the exposure in humans at the recommended clinical dose. Although not measured directly, paritaprevir was likely present in the milk of lactating rats at the high dose in this study, since systemic exposure was observed in nursing pups on post-natal day 15 (approximately 0.3 % of maternal exposure).
When paritaprevir/ritonavirwas administered to lactating rats (30/15 mg/kg on post-partum day 10 to 11), milk exposure (AUC) was half that in plasma, with the hydrolysis product M13 (84%) and unchanged parent drug (16%) accounting for all paritaprevir-related material in milk.

Dasabuvir

No effects of dasabuvir on growth and postnatal development were observed in nursing pups at the highest dose tested (800 mg/kg/day) in rats. Maternal systemic exposure (AUC) to dasabuvir was approximately 44 times the exposure in humans at the recommended clinical dose. Although not measured directly, dasabuvir was likely present in the milk of lactating rats in this study, since systemic exposure was observed in nursing pups on post-natal day 14 (approximately 14% of maternal exposure).
When dasabuvir was administered to lactating rats (5 mg/kg on post-partum day 10 to 11), milk exposure (AUC) was 2 times higher than that in plasma, with unchanged parent drug (78%) accounting for the majority of drug-related material in milk.

Renal Impairment

No dosage adjustment of VIEKIRA PAK is required in patients with mild, moderate or severe renal impairment, including those on dialysis. For patients that require ribavirin, refer to the ribavirin prescribing information for information regarding use in patients with renal impairment.

01/28/2016 (SUPPL-10)

Approved Drug Label (PDF)

7 Drug Interactions

Established and Other Potential Drug Interactions

update the Table 5 with patient monitoring information with the concomitant use of angiotensin receptor blockers and calcium channel blockers