Side Effects of Daklinza (daclatasvir)

Daklinza (daclatasvir) is a direct-acting antiviral agent (DAA) used in combination with sofosbuvir (Sovaldi) to treat chronic hepatitis C genotype 1 or 3 infection. It may be used with or without ribavirin (Rebetol, Ribasphere).

Common side effects of Daklinza include

• fatigue,
• headache,
• anemia (when combined with ribavirin),
• nausea,
• elevated lipase,
• diarrhea,
• insomnia,
• drowsiness, and
• rash.

Serious side effects of Daklinza include

• severe reduction in heart rate in people who were treated with Daklinza and sofosbuvir while also being treated with amiodarone (Cordarone) and
• reactivation of hepatitis B virus (HBV) in people who are infected with HBV and HCV.

Drug interactions of Daklinza include rifampin, carbamazepine, phenytoin, and St. John's wort, which may reduce blood levels of Daklinza and reduce its effectiveness by increasing its metabolism (break-down) in the intestine.

• Other drugs that also may reduce blood levels of Daklinza include nafcillin, bosentan, nevirapine, dexamethasone, efavirenz, atazanavir, darunavir, lopinavir/ritonavir, etravirine, and modafinil.
• Drugs that increase blood levels of Daklinza by reducing its break down in the liver include atazanavir with ritonavir, nelfinavir, indinavir, saquinavir, clarithromycin, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole.
• Daklinza increases blood levels of atorvastatin, rosuvastatin, and other statins.
• Daklinza also increases blood levels of buprenorphine and digoxin.

Daklinza has not been adequately evaluated in pregnant women. However, ribavirin, which may be combined with Daklinza, should not be used by pregnant women or their male partners. 

It is unknown if Daklinza is secreted into breast milk. Consult your doctor before breastfeeding.

Common side effects include:

• Fatigue
• Headache
• Anemia (when combined with ribavirin)
• Nausea
• Elevated lipase

Other side effects include:

• Diarrhea
• Insomnia
• Drowsiness
• Rash

Serious side effects include:

• Severe reduction in heart rate (bradycardia) has occurred in people who were treated with daclatasvir and sofosbuvir while also being treated with amiodarone (Cordarone).
• Daclatasvir may cause reactivation of hepatitis B virus (HBV) in people who are infected with HBV and HCV.

If Daklinza and sofosbuvir are administered with ribavirin, refer to the prescribing information for ribavirin regarding ribavirin-associated adverse reactions.

The following serious adverse reaction is described below and elsewhere in the labeling:

• Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir and Amiodarone.

Clinical Trials Experience

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
• Approximately 2400 subjects with chronic HCV infection have been treated with the recommended dose of Daklinza in combination with other anti-HCV drugs in clinical trials.
• Six hundred seventy-nine subjects have received a Daklinza and sofosbuvir-based regimen.
• Safety experience from three clinical trials of Daklinza and sofosbuvir with or without ribavirin is presented.

Daklinza And Sofosbuvir

• In the ALLY-3 trial, 152 treatment-naive and treatment-experienced subjects with HCV genotype 3 infection were treated with Daklinza 60 mg once daily in combination with sofosbuvir for 12 weeks.
• The most common adverse reactions (frequency of 10% or greater) were headache and fatigue.
• All adverse reactions were mild to moderate in severity. No subjects discontinued therapy for adverse events.
• In the ALLY-2 trial, 153 treatment-naive and treatment-experienced subjects with HCV/HIV-1 coinfection were treated with Daklinza 60 mg once daily (dose-adjusted for concomitant antiretroviral use) in combination with sofosbuvir for 12 weeks.
• The most common adverse reaction (frequency of 10% or greater) was fatigue.
• The majority of adverse reactions were mild to moderate in severity.
• No subjects discontinued therapy for adverse events. Adverse reactions considered at least possibly related to treatment and occurring at a frequency of 5% or greater in ALLY-3 or ALLY-2 are presented in Table 4.

Table 4: Adverse Reactions (All Severity) Reported at ≥5% Frequency, Daklinza + Sofosbuvir, Studies ALLY-3 and ALLY-2

Daklinza, Sofosbuvir, And Ribavirin

• In the ALLY-1 trial, 113 subjects with chronic HCV infection, including 60 subjects with Child-Pugh A, B, or C cirrhosis and 53 subjects with recurrence of HCV after liver transplantation, were treated with Daklinza 60 mg once daily in combination with sofosbuvir and ribavirin for 12 weeks.
• The most common adverse reactions (frequency of 10% or greater) among the 113 subjects were
  • headache,
  • anemia,
  • fatigue, and
  • nausea.
• The majority of adverse reactions were mild to moderate in severity.
• Of the 15 (13%) subjects who discontinued study drug for adverse events, 13 (12%) subjects discontinued ribavirin only and 2 (2%) subjects discontinued all study drugs.
• During treatment, 4 subjects in the cirrhotic cohort underwent liver transplantation.
• Adverse reactions considered at least possibly related to treatment and occurring at a frequency of 5% or greater in either treatment cohort in ALLY-1 are presented in Table 5.

Table 5: Adverse Reactions (All Severity) Reported at ≥5% Frequency in Either Treatment Cohort, Daklinza + Sofosbuvir + Ribavirin, Study ALLY-1

Laboratory Abnormalities

Selected Grade 3 and 4 treatment-emergent laboratory abnormalities observed in clinical trials of Daklinza in combination with sofosbuvir with or without ribavirin are presented in Table 6.

Table 6: Selected Grade 3 and 4 Laboratory Abnormalities in Clinical Trials of Daklinza + Sofosbuvir ± Ribavirin, Studies ALLY-3, ALLY2, and ALLY-1

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Daklinza. 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.

Cardiac Disorders

• Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with a sofosbuvir-containing regimen.

Potential For Other Drugs To Affect Daklinza

• Daclatasvir is a substrate of CYP3A. Therefore, moderate or strong inducers of CYP3A may decrease the plasma levels and therapeutic effect of daclatasvir.
• Strong inhibitors of CYP3A (eg, clarithromycin, itraconazole, ketoconazole, ritonavir) may increase the plasma levels of daclatasvir.

Potential For Daklinza To Affect Other Drugs

• Daclatasvir is an inhibitor of P-glycoprotein transporter (P-gp), organic anion transporting polypeptide (OATP) 1B1 and 1B3, and breast cancer resistance protein (BCRP).
• Administration of Daklinza may increase systemic exposure to medicinal products that are substrates of P-gp, OATP 1B1 or 1B3, or BCRP, which could increase or prolong their therapeutic effect or adverse reactions (see Table 7).

Established And Other Potentially Significant Drug Interactions

• 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 cytochrome 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.
• Refer to the prescribing information for other agents in the regimen for drug interaction information. The most conservative recommendation should be followed.
• Please also refer to Section 4 (Contraindications) and Section 12.3 (Pharmacokinetics) for complete information on all drug interactions.
• Table 7 provides clinical recommendations for established or potentially significant drug interactions between Daklinza and other drugs. Clinically relevant increase in concentration is indicated as “?” and clinically relevant decrease as “?” for drug interaction data.

Table 7: Established and Other Potentially Significant Drug Interactions

Drugs Without Clinically Significant Interactions With Daklinza

• Please see prescribing information for information regarding anticipated interactions that are not clinically relevant.
• Based on the results of drug interaction trials, no clinically relevant changes in exposure were observed for cyclosporine, darunavir (with ritonavir), dolutegravir, escitalopram, ethinyl estradiol/norgestimate, lopinavir (with ritonavir), methadone, midazolam, tacrolimus, or tenofovir with concomitant use of daclatasvir.
• No clinically relevant changes in daclatasvir exposure were observed with cyclosporine, darunavir (with ritonavir), dolutegravir, escitalopram, famotidine, lopinavir (with ritonavir), omeprazole, sofosbuvir, tacrolimus, or tenofovir.
• No dosage adjustment for daclatasvir is necessary with darunavir/cobicistat or moderate CYP3A inhibitors, including atazanavir (unboosted), fosamprenavir, ciprofloxacin, diltiazem, erythromycin, fluconazole, or verapamil.