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Label Changes for:

Viekira PAK (ombitasvir, paritaprevir and ritonavir tablets; dasabuvir tablets)

June 2016

Changes have been made to the PRECAUTIONS sections of the safety label.

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)  

June 2016

DRUG INTERACTIONS

Established and Other Potential Drug Interactions

Table 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)
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.
     

 

April 2016

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.

 

January 2016

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

 

October 2015

CONTRAINDICATIONS

  • bullet updated...VIEKIRA PAK is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B and C) due to risk of potential toxicity
  • bullet updated...Drugs that are moderate or strong inducers of CYP3A and strong inducers of CYP2C8 and may lead to reduced efficacy of VIEKIRA PAK.
  • Table updated with information regarding contraindication of Colchicine


WARNINGS AND PRECAUTIONS

Risk of Hepatic Decompensation and Hepatic Failure in Patients with Cirrhosis
  • Hepatic decompensation and hepatic failure, including liver transplantation or fatal outcomes, have been reported postmarketing in patients treated with VIEKIRA PAK. Most patients with these severe outcomes had evidence of advanced cirrhosis prior to initiating therapy with VIEKIRA PAK. Reported cases typically occurred within one to four weeks of initiating therapy and were characterized by the acute onset of rising direct serum bilirubin levels without ALT elevations in association with clinical signs and symptoms of hepatic decompensation. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
  • VIEKIRA PAK is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B and C).

For patients with cirrhosis:

  • Monitor for clinical signs and symptoms of hepatic decompensation (such as ascites, hepatic encephalopathy, variceal hemorrhage).
  • Hepatic laboratory testing including direct bilirubin levels should be performed at baseline and during the first 4 weeks of starting treatment and as clinically indicated.
  • Discontinue VIEKIRA PAK in patients who develop evidence of hepatic decompensation.


ADVERSE REACTIONS

  • added bullet...Risk of Hepatic Decompensation and Hepatic Failure in Patients with Cirrhosis
Post-Marketing Adverse Reactions

The following adverse reactions have been identified during post approval use of VIEKIRA PAK. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

  • Immune System Disorders: Hypersensitivity reactions (including angioedema).
  • Hepatobiliary Disorders: Hepatic decompensation, hepatic failure

PATIENT COUNSELING INFORMATION

Risk of ALT Elevations or Hepatic Decompensation and Failure
  • Inform patients to watch for early warning signs of liver inflammation or failure, such as fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice, onset of confusion, abdominal swelling, and discolored feces, and to consult their health care professional without delay if such symptoms occur

 

July 2015

CONTRAINDICATIONS

  • … Drugs that are moderate or strong inducers ….

DRUG INTERACTIONS

  • add quetiapine drug interaction information to Table 5

SPECIAL POPULATIONS

Pregnancy
  • update information regarding dasabuvir exposure in animals

 

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