QVIR Kit (Atazanavir/Ritonavir + Emtricitabine/Tenofovir)

Table of Content

A key challenge in the clinical management of HIV is facilitating ART adherence. According to research studies, a 95 percent adherence rate is associated with controlling HIV replication, which allows an optimal therapeutic response to the medications.

The QVIR Kit contains a combination of two fixed-dose combinations (FDCs) in a co-blister packing.

The 2 FDCs are:

  • 1 tablet of tenofovir 300 mg/emtricitabine 200 mg (Tenvir-EM)
  • 1 tablet of atazanavir 300 mg/ritonavir 100 mg (Synthivan)

Tenofovir/emtricitabine (TDF/FTC) inhibits the HIV reverse transcriptase, while atazanavir/ritonavir (ATV/r) inhibits the HIV protease enzyme. Both these enzymes are essential for HIV replication.

A regimen containing TDF/FTC plus ATV/r is recommended by WHO Guidelines 2018, and by DHHS 2018 and EACS 2018 as an alternative regimen.

Both these FDCs are packaged together in one strip, which represent a single day’s treatment.

The availability of the co-packaged regimen will increase convenience and compliance for the patients.

QVIR Kit is indicated for the treatment of HIV-infected adult patients, either as first-line or a second-line regimen, depending on what regimen was used in first-line.

QVIR Kit should be taken once-daily, orally, with food. 

QVIR Kit should not be administered to HIV treatment-experienced patients with end-stage renal disease managed with hemodialysis.

January 2019

 

Black Box Warnings

Co-administration of ritonavir with several classes of drugs including sedative hypnotics, anti-arrhythmics or ergot alkaloid preparations may result in potentially serious and/or life-threatening adverse events due to the possible effects of ritonavir on the hepatic metabolism of certain drugs. Review medications taken by patients prior to prescribing ritonavir or when prescribing other medications to patients already taking ritonavir (see contraindications and warnings and precautions sections).

 

Post Treatment Acute Exacerbation of Hepatitis B

Severe acute exacerbations of hepatitis B have been reported in hbv-infected patients who have discontinued emtricitabine/tenofovir disoproxil fumarate. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in HBV-infected patients who discontinue emtricitabine/tenofovir disoproxil fumarate. If appropriate, initiation of anti-hepatitis B therapy may be warranted (see warnings and precautions).

Composition

QVIR Kit

Each kit contains:

  1. One tablet of Atazanavir and Ritonavir

Atazanavir sulfate IP … 300 mg

Ritonavir IP……………100 mg

  1. One tablet of Tenofovir disoproxil fumarate and Emtricitabine

Tenofovir disoproxil fumarate IP…300 mg

Emtricitabine IP….200mg

Dosage form

Atazanavir/ritonavir–Oral fixed-dose tablet

Emtricitabine plus Tenofovir disoproxil fumarate-Oral fixed-dose tablet

Description

Each QVIR Kit contains two tablets – one fixed-dose combination tablet of atazanavir/ritonavir and one fixed-dose combination tablet of emtricitabine/tenofovir disoproxil fumarate.

Atazanavir and ritonavir belong to the class of protease inhibitors and act by inhibiting protease enzyme. Emtricitabine and tenofovir disoproxil fumarate belong to the class of nucleoside reverse transcriptase inhibitors and act by inhibiting the reverse transcriptase enzyme.

Pharmacology

Pharmacodynamics

Atazanavir

Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI). The compound selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing the formation of mature virions.

Cardiac Electrophysiology

Concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram (ECG) has been observed in healthy volunteers receiving atazanavir. In a placebo-controlled study (AI424-076), the mean (±SD) maximum change in the PR interval from the pre-dose value was 24 (±15) milliseconds (msec) following oral dosing with 400 mg of atazanavir (n=65) compared to 13 (±11) msec following dosing with placebo (n=67). The PR interval prolongations in this study were asymptomatic. There is limited information on the potential for a pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the ECG (see WARNINGS AND PRECAUTIONS, cardiac conduction Abnormalities).

Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy subjects. Oral doses of 400 mg (maximum recommended dose) and 800 mg (twice the maximum recommended dosage) were compared with placebo; there was no concentration-dependent effect of atazanavir on the QTc interval (using Fridericia’s correction). In 1793 HIV-infected patients receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy subject or HIV-infected patient had a QTc interval >500 msec (see WARNINGS AND PRECAUTIONS, Cardiac Conduction Abnormalities).

Ritonavir

Ritonavir is a peptidomimetic inhibitor of the HIV-1 protease. Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor which leads to production of non-infectious immature HIV particles.

Low doses of ritonavir (100 mg) have been used as a pharmacokinetic booster, to boost plasma levels of concomitantly administered protease inhibitors. Boosted protease inhibitors are currently considered the standard of care in HIV therapy.

Cardiac Electrophysiology

QTcF interval was evaluated in a randomized, placebo and active controlled (moxifloxacin 400 mg once-daily) crossover study in 45 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) time-matched difference in QTcF from placebo after baseline correction was 5.5 (7.6) milliseconds (msec) for 400 mg twice-daily ritonavir. Ritonavir 400 mg twice daily resulted in Day 3 ritonavir exposure that was approximately 1.5 fold higher than observed with ritonavir 600 mg twice-daily dose at steady state.

PR interval prolongation was also noted in subjects receiving ritonavir in the same study on Day 3. The maximum-mean (95% confidence interval) difference from placebo in the PR interval after baseline correction was 22 (25) msec for 400 mg twice-daily ritonavir (see WARNINGS AND PRECAUTIONS, PR Interval Prolongation).

Emtricitabine

Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase (RT) by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5′-triphosphate is a weak inhibitor of mammalian DNA polymerase alpha, beta, epsilon and mitochondrial DNA polymerase gamma.

Tenofovir disoproxil fumarate (Tenofovir DF)

Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase by competing with the natural substrate deoxyadenosine 5′-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases alpha  , beta, and mitochondrial DNA polymerase gamma.

Pharmacokinetics

Atazanavir/ritonavir

The pharmacokinetics of atazanavir/ritonavir was evaluated in healthy adult volunteers and in HIV-infected patients after administration of atazanavir 300 mg with ritonavir 100 mg once daily (see Table 1).

Table 1: Steady-state pharmacokinetics of atazanavir/ritonavir in healthy subjects or HIV-infected patients in the fed state

 

300 mg with ritonavir

100 mg once daily

Parameter

Healthy subjects

(n=28)

HIV-infected patients (n=10)

Cmax (ng/mL)

 

 

Geometric mean (CV %)

6129 (31)

4422 (58)

Mean (SD)

6450 (2031)

5233 (3033)

Tmax (h)

 

 

Median

2.7

3.0

AUC (ng•h/mL)

 

 

Geometric mean (CV %)

57039 (37)

46073 (66)

Mean (SD)

61435 (22911)

53761 (35294)

T-half (h)

 

 

Mean (SD)

18.1 (6.2)a

8.6 (2.3)

Cmin (ng/mL)

 

 

Geometric mean (CV %)

1227 (53)

636 (97)

Mean (SD)

1441 (757)

862 (838)

a n=26

Figure 1 displays the mean plasma concentrations of atazanavir at steady state after atazanavir 300 mg (as two 150 mg capsules) with ritonavir 100 mg once daily with a light meal in HIV-infected adult patients.

Absorption

Atazanavir

Atazanavir is rapidly absorbed with a Tmax of approximately 2.5 hours. Atazanavir demonstrates non-linear pharmacokinetics with greater than dose-proportional increases in AUC and Cmax values over the dose range of 200 to 800 mg once daily. Steady-state is achieved between Days 4 and 8, with an accumulation of approximately 2.3-fold.

Ritonavir

Under moderate fat conditions (857 kcal; 31% fat, 13% protein, 56% carbohydrates), when a single 100 mg ritonavir dose was administered as a tablet compared with a capsule, AUC(0-∞) met equivalence criteria but mean Cmax was increased by 26% (92.8% confidence intervals: ↑15 -↑39%).

Food Effect

Atazanavir

Administration of atazanavir with food enhances bioavailability and reduces pharmacokinetic variability. Co-administration of a single 300mg dose of atazanavir and a 100mg dose of ritonavir with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 33% increase in the AUC and a 40% increase in both the Cmax and the 24-hour concentration of atazanavir relative to the fasting state. Co-administration with a high-fat meal (951 kcal, 54.7 g fat, 35.9 g protein) did not affect the AUC of atazanavir relative to fasting conditions and the Cmax was within 11% of fasting values. The 24-hour concentration following a high-fat meal was increased by approximately 33% due to delayed absorption; the median Tmax increased from 2.0 to 5.0 hours. Co-administration of atazanavir with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately 25% compared to the fasting state.

Ritonavir

The bioavailability of ritonavir tablet is decreased under fed conditions as compared to fasted conditions.

Following the administration of a 100 mg tablet dose of ritonavir, Cmax and AUCinf of ritonavir were decreased by 21-23% under moderate fat (857 Kcal, 30% from fat) or high fat conditions (917 Kcal, 60% calories from fat) relative to fasting conditions.

Distribution

Atazanavir

Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively).

Metabolism

Atazanavir

Atazanavir is extensively metabolized in humans. The major biotransformation pathways of atazanavir in humans consisted of mono-oxygenation and dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. Two minor metabolites of atazanavir in plasma have been characterized. Neither metabolite demonstrated in vitro antiviral activity. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A.

Ritonavir (Full dose)

Nearly all of the plasma radioactivity after a single oral 600 mg dose of 14C-ritonavir oral solution (n=5) was attributed to unchanged ritonavir. Five ritonavir metabolites have been identified in human urine and feces. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent drug; however, the concentrations of this metabolite in plasma are low. In vitro studies utilizing human liver microsomes have demonstrated that cytochrome P450 3A (CYP3A) is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of M-2.

Elimination

Atazanavir

Following a single 400mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. The mean elimination half-life of atazanavir in healthy volunteers (n=214) and HIV-infected adult patients (n=13) was approximately 7 hours at steady state, following a dose of 400 mg daily with a light meal.

Ritonavir (Full dose): In a study of five subjects receiving a 600 mg dose of 14C-ritonavir oral solution, 11.3 + 2.8% of the dose was excreted into the urine, with 3.5 + 1.8% of the dose excreted as unchanged parent drug. In the study, 86.4 + 2.9% of the dose was excreted in the feces, with 33.8 + 10.8% of the dose excreted as unchanged parent drug. Upon multiple dosing, ritonavir accumulation is less than predicted from a single dose, possibly due to a time and dose-related increase in clearance.

Emtricitabine/Tenofovir DF

One tablet was comparable to one FTC capsule (200 mg) plus one TDF tablet (300 mg) following single-dose administration to fasting healthy subjects (N=39).

Emtricitabine

The pharmacokinetic properties of emtricitabine are summarized in Table 2. Following oral administration of emtricitabine, emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1–2 hours post-dose. Less than 4 % of emtricitabine binds to human plasma proteins in vitro and the binding is independent of concentration over the range of 0.02-200 μg/mL. Following administration of radiolabelled emtricitabine, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of emtricitabine include 3′-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of emtricitabine, the plasma emtricitabine half-life is approximately 10 hours.

Tenofovir Disoproxil Fumarate

The pharmacokinetic properties of tenofovir disoproxil fumarate are summarized in Table 2. Following oral administration of Tenofovir DF, maximum tenofovir serum concentrations are achieved in 1.0 ± 0.4 hour. Less than 0.7 % of tenofovir binds to human plasma proteins in vitro and the binding is independent of concentration over the range of 0.01–25 μg/mL. Approximately 70–80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of Tenofovir DF, the terminal elimination half-life of tenofovir is approximately 17 hours.

Table 2: Single Dose Pharmacokinetic Parameters for Emtricitabine and Tenofovir in Adultsa
 

Emtricitabine

Tenofovir

Fasted oral bioavailabilityb (%)

92 (83.1-106.4)

25 (NC-45.0)

Plasma terminal elimination half-lifeb (hr)

10 (7.4-18.0)

17 (12.0-25.7)

Cmaxc (µg/mL)

1.8 ± 0.72d

0.30 ± 0.09

AUCc (µg·hr/mL)

10.0 ± 3.12d

2.29 ± 0.69

CL/Fc (mL/min)

302 ± 94

1043 ± 115

CLrenalc (mL/min)

213 ± 89

243 ± 33

a NC = Not calculated

b Median (range)

c Mean (± SD)

d Data presented as steady state values

Effects of Food on Oral Absorption

Emtricitabine/Tenofovir DF

Emtricitabine/tenofovir DF may be administered with or without food. Administration of emtricitabine/tenofovir DF following a high fat meal (784 kcal; 49 grams of fat) or a light meal (373 kcal; 8 grams of fat) delayed the time of tenofovir Cmax by approximately 0.75 hour. The mean increases in tenofovir AUC and Cmax were approximately 35% and 15%, respectively, when administered with a high fat or light meal, compared to administration in the fasted state. In previous safety and efficacy trials, Emtricitabine/tenofovir DF was taken under fed conditions. Emtricitabine systemic exposures (AUC and Cmax) were unaffected when emtricitabine/tenofovir DF was administered with either a high fat or a light meal.

Special Populations

Race

Ritonavir:

Pharmacokinetic differences due to race have not been identified.

Emtricitabine

No pharmacokinetic differences due to race have been identified following the administration of emtricitabine.

Tenofovir DF

There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of tenofovir DF.

Gender

Ritonavir

A study of ritonavir pharmacokinetics in healthy males and females showed no statistically significant differences in the pharmacokinetics of ritonavir.

Emtricitabine and Tenofovir DF

Emtricitabine and tenofovir pharmacokinetics are similar in male and female subjects.

Age

Ritonavir

No age-related pharmacokinetic differences have been observed in adult patients (18 to 63 years). Ritonavir pharmacokinetics have not been studied in older patients.

Patients with Renal Impairment

Atazanavir

 Atazanavir is not recommended for use in HIV-treatment-experienced patients with end stage renal disease managed with hemodialysis

Ritonavir

Ritonavir pharmacokinetics have not been studied in patients with renal impairment, however, since renal clearance is negligible, a decrease in total body clearance is not expected in patients with renal impairment.

Emtricitabine/Tenofovir DF

The pharmacokinetics of emtricitabine and tenofovir are altered in patients with renal impairment (see WARNINGS AND PRECAUTIONS). In adult subjects with creatinine clearance <50 mL/min, Cmax, and AUC0-∞ of emtricitabine and tenofovir were increased.

Patients with Hepatic Impairment

Atazanavir/ritonavir

Atazanavir is not recommended for use in patients with severe hepatic impairment. The pharmacokinetics of atazanavir in combination with ritonavir has not been studied in subjects with hepatic impairment; thus, coadministration of atazanavir with ritonavir is not recommended for use in patients with any degree of hepatic impairment

Emtricitabine/Tenofovir DF

The pharmacokinetics of tenofovir following a 300 mg dose of tenofovir DF have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. The pharmacokinetics of tenofovir/emtricitabine or emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.

Geriatric Patients

Emtricitabine/Tenofovir DF

Pharmacokinetics of emtricitabine and tenofovir has not been fully evaluated in the elderly (65 years of age and older).

Pregnancy

Atazanavir

The pharmacokinetic data from HIV-infected pregnant women receiving Atazanavir with ritonavir are presented in Table 4.

Table 4: Steady-State Pharmacokinetics of Atazanavir with Ritonavir in HIV-Infected Pregnant Women in the Fed State

Pharmacokinetic parameter

Atazanavir 300 mg with ritonavir 100 mg

2nd Trimester

(n=5a)

3rd Trimester

(n=20)

Postpartumb

(n=34)

Cmax ng/mL

3078.85

3291.46

5721.21

Geometric mean (CV%)

(50)

(48)

(31)

AUC ng x h/mL

27657.1

34251.5

61990.4

Geometric mean (CV%)

(43)

(43)

(32)

Cmin ng/mLc

538.70

668.48

1462.59

Geometric mean (CV%)

(46)

(50)

(45)

a Available data during the 2nd trimester are limited.

b Atazanavir peak concentrations and AUCs were found to be approximately 28% to 43% higher during the postpartum period (4-12 weeks) than those observed historically in HIV-infected, non-pregnant patients. Atazanavir plasma trough concentrations were approximately 2.2-fold higher during the postpartum period when compared to those observed historically in HIV-infected, non-pregnant patients.

c Cmin is concentration 24 hours post-dose.

Ritonavir

Based on evaluation of the published literature, ritonavir exposures are reduced during pregnancy relative to postpartum.

Indications

QVIR Kit is indicated for the treatment of HIV-1 infection in adults.

The following points should be considered when initiating therapy with QVIR Kit :

  • It is not recommended that emtricitabine/tenofovir DF be used as a component of a triple nucleoside regimen.
  • Emtricitabine/tenofovir DF should not be coadministered with emtricitabine/tenofovir DF/efavirenz, emtricitabine, tenofovir DF or lamivudine-containing products (see WARNINGS AND PRECAUTIONS).
  • In treatment experienced patients, the use of emtricitabine/tenofovir DF should be guided by laboratory testing and treatment history.

Dosage and Administration

Adults

One tablet of atazanavir/ritonavir (300/100mg) and one tablet of emtricitabine/tenofovir DF (200/300mg) once daily with food.

Overview

Atazanavir/ritonavir

  • The recommended oral dosage of atazanavir/ritonavir tablet depends on the treatment history of the patient and the use of other co-administered drugs. When co-administered with H2-receptor antagonists or proton-pump inhibitors, dose separation may be required.
  • Efficacy and safety of atazanavir with ritonavir in doses greater than 100 mg once daily have not been established. The use of higher ritonavir doses might alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and, therefore, is not recommended. Prescribers should consult the complete prescribing information for ritonavir when using this agent.

Testing Prior to Initiation and During Treatment with Atazanavir

Renal laboratory testing should be performed in all patients prior to initiation of atazanavir and continued during treatment with atazanavir. Renal laboratory testing should include serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination

Hepatic laboratory testing should be performed in patients with underlying liver disease prior to initiation of atazanavir and continued during treatment with atazanavir .

Tenofovir/Emtricitabine

Testing Prior to Initiation of tenofovir/emtricitabine for Treatment of HIV-1 Infection

Prior to or when initiating tenofovir/emtricitabine, test patients for hepatitis B virus infection.

Prior to initiation and during use of tenofovir/emtricitabine, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus.

Recommended Adult Dosage

Atazanavir/ritonavir

Table 5 also displays recommended dosage of Atazanavir and ritonavir when given concomitantly with other antiretroviral drugs and H2-receptor antagonists (H2RA). Ritonavir is required with several ataanavir dosage regimens (see the ritonavir complete prescribing information about the safe and effective use of ritonavir). The use of atazanavir in treatment-experienced adult patients without ritonavir is not recommended.

 Table 5: Recommended Atazanavir and Ritonavir Dosage in Adultsa

 

Atazanavir  Once Daily dosage

Ritonavir Once Daily  dosage

Treatment-Naive Adult Patients recommended regimen

300mg

100mg

Treatment-Experienced Adult Patients recommended regimen

300mg

100mg

a See Drug Interactions for instructions concerning coadministration of acid-reducing medications (eg, H2RA or proton pump inhibitors ), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine).

Recommended Dosage for Treatment of HIV-1 Infection in Adults

Tenofovir/emtricitabine

Tenofovir/emtricitabine is a two-drug fixed dose combination product containing emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). The recommended dosage of tenofovir/emtricitabine in adults is one tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food.

Renal Impairment

Atazanavir

For patients with renal impairment, including those with severe renal impairment who are not managed with hemodialysis, no dose adjustment is required for atazanavir. Treatment-naïve patients with end-stage renal disease managed with hemodialysis should receive atazanavir/ritonavir tablet. QVIR Kit should not be administered to HIV-treatment-experienced patients with end-stage renal disease managed with hemodialysis (see USE INSPECIAL POPULATIONS).

Tenofovir/Emtricitabine

Table 6 provides dosage interval adjustment for patients with renal impairment. No dose adjustment is necessary for HIV-1 infected patients with mild renal impairmen (creatinine clearance 50–80 mL/min). The safety and effectiveness of the dosing interval adjustment recommendations in patients with moderate renal impairment (creatinine clearance 30–49 mL/min) have not been clinically evaluated; therefore, clinical response to treatment and renal function should be closely monitored in these patients (see WARNINGS AND PRECAUTIONS) No data are available to make dose recommendations in pediatric patients with renal impairment.

Table 6: Dosage Adjustment for HIV-1 Infected Adult Patients with Altered Creatinine Clearance

 

Creatinine Clearance (mL/min)a

 

≥50

30-49

<30 (Including patients Requiring Hemodialysis)

Recommended Dosing interval

Every 24 hours

Every 24 hours

Tenofovir/Emtricitabine is not recommended

a. Calculated using ideal (lean) body weight

Hepatic Impairment

The coadministration of atazanavir with ritonavir in patients with any degree of hepatic impairment is not recommended. (see WARNINGS AND PRECAUTIONS).

Contraindications

QVIR Kit is contraindicated:

  • in patients with previously demonstrated clinically significant hypersensitivity (e.g, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product;
  • when co-administered with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events. Table 7 and 8.
  • when coadministered with drugs that strongly induce CYP3A and may lead to lower exposure and loss of efficacy of atazanavir sulphate.) Table 7
  • When co-administering ritonavir with other protease inhibitors, see the full prescribing information for that protease inhibitor including contraindication information
  • Ritonavir 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 7: Drugs that are contraindicated with atazanavir (Information in the table applies to atazanavir with or without ritonavir, unless otherwise indicated)

Drug class

Drugs Within Class That Are Contraindicated with Atazanavir

Clinical Comment

 

Alpha1-adrenoreceptor antagonist

Alfuzosin

Potential for increased alfuzosin concentrations, which can result in hypotension.

Antimycobacterials

Rifampin

Rifampin substantially decreases plasma concentrations of atazanavir, which may result in loss of therapeutic effect and development of resistance.

Antineoplastics

Irinotecan

 

Atazanavir inibits UGT1Al and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities.

Antipsychotics

Lurasidone

 

Pimozide

Potential for serious and/or life-threatening reactions if atazanavir is coadministered with ritonavir.

Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.

Benzodiazepines

Triazolam,

orally administered midazolama

Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Co-administration of triazolam or orally administered midazolam with atazanavir may cause large increases in the concentration of these benzodiazepines. Potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression.

Ergot Derivatives

dihydroergotamine, ergotamine, ergonovine, methylergonovine

Potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.

Gastrointestinal (GI) Motility Agent

cisapride

Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.

Hepatitis C Direct-Acting Antivirals

Elbasvir/grazoprevir

 

Glecapreir/pibretasvir

May increase risk of ALT elevations due to increase in significant increase in grazoprevir plasma concentrations.

 

 

May increase risk of ALT elevations due to a increase in glecaprevir and pibrentasvir concentrations

Herbal Products

St. John's wort (Hypericum perforatum)

Coadministration of St. John's wort and atazanavir may result in loss of therapeutic effect and development of resistance.

HMG-CoA Reductase Inhibitors

Lovastatin, simvastatin

Potential for serious reactions such as myopathy, including rhabdomyolysis.

PDE5 Enzyme inhibitor

Sildenafilb, when dosed for the treatment of pulmonary arterial hypertension

Potential for sildenafil-associated adverse events (which include visual disturbance, hypotension, priapism, and syncope).

Protease Inhibitors

Indinavir

Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia.

Non-nucleoside Reverse Transcriptase Inhibitors

Nevirapine

Nevirapine substantially decreases atazanavir exposure which may result in loss of therapeutic effect and development of resistance. Potential risk for nevirapine-associated adverse reactions due to increased nevirapine exposures.

a See WARNINGS AND PRECAUTIONS, Drug Interactions, Table 8 for parenterally administered midazolam.

b See WARNINGS AND PRECAUTIONS, Drug Interactions, for sildenafil when dosed for erectile dysfunction.

Table 8:  Drugs that are contraindicated with ritonavir use (full dose)

Drug Class

Drugs Within Class That Are Contraindicated with ritonavir

Clinical comments

Alpha1-adrenoreceptor antagonist               

Alfuzosin HCL

Potential for hypotension

Antianginal

Ranolazine

Potential for serious and/or life-threatening reactions.

Anti-arrhythmics

amiodarone, dronedarone,flecainide, propafenone, quinidine

Potential for cardiac arrhythmias

Antifungal

Voriconazole

 

Co-administration of voriconazole with ritonavir 400 mg every 12 hours significantly decreases voriconazole plasma concentrations and may lead to loss of antifungal response.

Anti-gout

Colchicinea

Potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment.

Antipsychotics

Lurasidone

 

 

Pimozide

Potential for serious and/or life-threatening reactions.

 

Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.

Herbal Products

St. John’s Wort (hypericum perforatum)

May lead to loss of virologic response and possible resistance to ritonavir or to the class of protease inhibitors.

Ergot Derivatives

dihydroergotamine, ergotamine, methylergonovine

 

Potential for acute ergot toxicity characterized by vasopasm and ischemia of the extremities and other tissues, including the central nervous system.

HMG-CoA Reductase Inhibitors

Lovastatin, simvastatin

Potential for myopathy including rhabdomyolysis.

GI Motility Agent

cisapride

Potential for cardiac arrhythmias

Antipsychotics

pimozide

 

 

 

Lurasidone

 

Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.

 

 

Potential for serious and/or life-threatening reactions.

PDE5 enzyme inhibitor

Sildenafilb only when used for the treatment of pulmonary arterial hypertension (PAH)

Potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection and syncope

Sedative/hypnotics

Oral midazolamc, triazolam

 

Prolonged or increased sedation or respiratory depression

a see , Table 9 for colchicine doses in patients with normal hepatic and renal function.

b see , Table 9 for co-administration of sildenafil in patients with erectile dysfunction.

c see , Table 9 for parenterally administered midazolam.

Warnings and Precautions

Drug Interactions

Atazanavir

Potential for Atazanavir to Affect Other Drugs

Atazanavir is an inhibitor of CYP3A and UGT1A1. Co-administration of atazanavir and drugs primarily metabolized by CYP3A or UGT1A1 may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects.

Atazanavir is a weak inhibitor of CYP2C8. Use of atazanavir without ritonavir is not recommended when coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (eg, paclitaxel, repaglinide). When atazanavir with ritonavir is co-administered with substrates of CYP2C8, clinically significant interactions are not expected. 

The magnitude of CYP3A-mediated drug interactions on co-administered drug may change when atazanavir is co-administered with ritonavir. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir.

Potential for Other Drugs to Affect Atazanavir

Atazanavir is a CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease atazanavir plasma concentrations and reduce atazanavir’s therapeutic effect.

Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors, antacids, buffered medications, or H2-receptor antagonists are administered with atazanavir.

Established and Other Potentially Significant Drug Interactions

Table 9 provides dosing recommendations as a result of drug interactions with atazanavir. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.

Table 9: Established and other potentially significant drug interactions: Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interactions.

Concomitant Drug Class: Specific Drugs

Effect on Concentration of Atazanavir on Concomitant Drug

Clinical Comment

HIV Antiviral Agents

Nucleoside Reverse Transcriptase Inhibitors (NRTIs): didanosine buffered formulations enteric-coated (EC) capsules

↓ atazanavir

↓ didanosine

Co-administration of atazanavir with didanosine buffered tablets resulted in a marked decrease in atazanavir exposure. It is recommended that atazanavir be given (with food) 2 h before or 1 h after didanosine buffered formulations.  Simultaneous administration of didanosine EC and atazanavir with food results in a decrease in didanosine exposure. Thus, atazanavir and didanosine EC should be administered at different times.

Nucleotide Reverse Transcriptase Inhibitors: tenofovir disoproxil fumarate

↓ atazanavir

↑ tenofovir

Tenofovir may decrease the AUC and Cmin of atazanavir. When co-administered with tenofovir, it is recommended that atazanavir 300 mg be given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food). Atazanavir without ritonavir should not be co-administered with tenofovir. Atazanavir increases tenofovir concentrations. The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders. Patients receiving atazanavir and tenofovir should be monitored for tenofovir-associated adverse reactions.

Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): efavirenz

↓ atazanavir

Efavirenz decreases atazanavir exposure.

 

In treatment-naïve patients: If atazanavir is combined with efavirenz, atazanavir 400 mg (two 200mg capsules) with ritonavir 100 mg should be administered once daily all as a single dose with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime.

 

In treatment-experienced patients: Do not co-administer atazanavir with efavirenz in treatment-experienced patients due to decreased atazanavir exposure.

Protease Inhibitors: saquinavir (soft gelatin capsules)

↑ saquinavir

Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg co-administered with atazanavir 400 mg and tenofovir 300 mg (all given once daily) plus nucleoside analog reverse transcriptase inhibitors did not provide adequate efficacy.

ritonavir

↑ atazanavir

If atazanavir is co-administered with ritonavir, it is recommended that atazanavir 300 mg once daily be given with ritonavir 100 mg once daily with food. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir.

others

↑ other protease inhibitor

Atazanavir/ritonavir: Although not studied, the co-administration of atazanavir/ritonavir and an additional protease inhibitors would be expected to increase exposure to the other protease inhibitor. Such co-administration is not recommended.

HCV Antiviral Agents

 

 

Protease Inhibitors: Boceprevir

 

 

sofosbuvir, velpatasvir, voxilaprevir

 

 

↓ atazanavir

↓ ritonavir

 

 

↑voxilaprevir

Concomitant administration of boceprevir and atazanavir/ritonavir resulted in reduced steady-state exposures to atazanavir and ritonavir. Coadministration of atazanavir/ritonavir and boceprevir is not recommended.

Coadministration with atazanavir is not recommended.

Other Agents

 

 

Antacids and buffered medications

↓ atazanavir

Reduced plasma concentrations of atazanavir are expected if antacids, including buffered medications, are administered with atazanavir. Atazanavir should be administered 2 hours before or 1 hour after these medications.

Anti-arrhythmics: amiodarone, bepridil, lidocaine (systemic), quinidine

↑ amiodarone, bepridil, lidocaine (systemic), quinidine

Co-administration with atazanavir has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with atazanavir sulfate.

Anticoagulants: warfarin

↑ warfarin

Co-administration with atazanavir has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that International Normalized Ratio (INR) be monitored.

Antidepressants: tricyclic antidepressants

 

 

 

 

 

trazodone

↑tricyclic antidepressants

 

 

 

 

 

 

↑ trazodone

Co-administration with atazanavir has the potential to produce serious and/or life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with atazanavir.

 

Concomitant use of trazodone and atazanavir with or without ritonavir may increase plasma concentrations of trazodone. Nausea, dizziness, hypotension, and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as atazanavir, the combination should be used with caution and a lower dose of trazodone should be considered.

Antiepileptics: carbamazepine

↓ atazanavir

↑ carbamazepine

Plasma concentrations of atazanavir may be decreased when carbamazepine is administered with atazanavir without ritonavir. Coadministration of carbamazepine and atazanavir without ritonavir is not recommended. Ritonavir may increase plasma levels of carbamazepine. If patients beginning treatment with atazanavir/ritonavir have been titrated to a stable dose of carbamazepine, a dose reduction for carbamazepine may be necessary.

phenytoin, phenobarbital

↓ atazanavir

↓ phenytoin

↓ phenobarbital

Plasma concentrations of atazanavir may be decreased when phenytoin or phenobarbital is administered with atazanavir without ritonavir. Coadministration of phenytoin or phenobarbital and atazanavir without ritonavir is not recommended. Ritonavir may decrease plasma levels of phenytoin and phenobarbital. When atazanavir with ritonavir is coadministered with either phenytoin or phenobarbital, a dose adjustment of phenytoin or phenobarbital may be required.

Lamotrigine

↓ lamotrigine

Coadministration of lamotrigine and atazanavir with ritonavir may decrease lamotrigine plasma concentrations. Dose adjustment of lamotrigine may be required when coadministered with atazanavir and ritonavir. Coadministration of lamotrigine and atazanavir without ritonavir is not expected to decrease lamotrigine plasma concentrations. No dose adjustment of lamotrigine is required when coadministered with atazanavir without ritonavir.

Antifungals: ketoconazole, itraconazole

Atazanavir/ritonavir

↑ ketoconazole

↑ itraconazole

Co-administration of ketoconazole has only been studied with atazanavir without ritonavir (negligible increase in atazanavir AUC and Cmax). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously with atazanavir/ritonavir.

voriconazole

Atazanavir/ritonavir

in subjects with a

functional CYP2C19

allele:

↓ voriconazole

↓ atazanavir

 

Atazanavir/ritonavir

in subjects without a functional CYP2C19

allele:

↑ voriconazole

↓ atazanavir

The use of voriconazole in patients receiving atazanavir/ritonavir is not recommended unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Patients should be carefully monitored for voriconazole-associated adverse reactions and loss of either voriconazole or atazanavir efficacy during the coadministration of voriconazole and atazanavir/ritonavir. Coadministration of voriconazole with atazanavir (without ritonavir) may affect atazanavir concentrations; however, no data are available.

Anti-gout:

Colchicine

↑colchicine

The coadministration of atazanavir with colchicine to patients with renal or hepatic impairment is not recommended.

Recommended dosage of colchicine when administered with atazanavir:

Treatment of gout flares: 0.6 mg (1 tablet) for one dose, followed by 0.3 mg (half tablet), 1 hour later. Not to be repeated before 3 days.

Prophylaxis of gout flares:  If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF): maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)

Antimycobacterials: rifabutin

↑ rifabutin

A rifabutin dose reduction of up to 75% (e.g., 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted

Antipsychotics: quetiapine and lurasidone

↑ quetiapine

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Atazanavir/ritonavir

↑ lurasidone

Initiation of atazanavir with ritonavir in patients taking quetiapine:

Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.

Initiation of quetiapine in patients taking atazanavir with ritonavir:

Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.

 

Atazanavir/ritonavir

Use of Lurasidone is contraindicated

Benzodiazepines: parenterally administered midazolama

↑ midazolam

Concomitant use of parenteral midazolam with atazanavir may increase plasma concentrations of midazolam.

Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation.

Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with atazanavir is CONTRAINDICATED.

Calcium channel blockers: diltiazem

 

 

 

 

 

felodipine, nifedipine, nicardipine, and verapamil

↑ diltiazem and desacetyl-diltiazem

 

 

 

 

 

↑ calcium channel blocker

Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Co-administration of atazanavir/ritonavir with diltiazem has not been studied.

 

Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended.

Endothelin receptor antagonists: Bosentan

↓ atazanavir

↓ atazanavir

↑ bosentan

↑ bosent

Plasma concentrations of atazanavir may be decreased when bosentan is administered with atazanavir without ritonavir. Co-administration of bosentan and atazanavir without ritonavir is not recommended

Co-administration of bosentan in patients on atazanavir/ritonavir Tablets: For those patients who have been receiving atazanavir/ritonavir tablets for at least 10 days, start bosentan at 62.5 mg once daily or every other day, based on individual tolerability.

Co-administration of atazanavir/ritonavir tablets in patients on bosentan: Discontinue bosentan at least 36 hours before starting atazanavir/ritonavir tablets. At least 10 days after starting atazanavir/ritonavir tablets, resume bosentan at 62.5 mg once daily or every other day, based on individual tolerability.

HMG-CoA reductase inhibitors: atorvastatin, rosuvastatin

↑ atorvastatin

↑ rosuvastatin

Titrate atorvastatin dose carefully and use the lowest necessary dose. Rosuvastatin dose should not exceed 10 mg/day. The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including atazanavir, are used in combination with these drugs.

H2-Receptor antagonists

↓ atazanavir

Plasma concentrations of atazanavir were substantially decreased when atazanavir 400 mg once daily was administered simultaneously with famotidine 40 mg twice daily, which may result in loss of therapeutic effect and development of resistance.

 

In treatment-naïve patients: Atazanavir/ritonavir (300/100mg) tablets once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H2-receptor antagonist. An H2-receptor antagonist dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with atazanavir 300 mg along with ritonavir 100 mg in treatment-naïve patients.

OR

For patients unable to tolerate ritonavir, atazanavir 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H2-receptor antagonist. No single dose of the H2-receptor antagonist should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg.

 

In treatment-experienced patients:

Whenever an H2-receptor antagonist is given to a patient receiving atazanavir with ritonavir, the H2-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the atazanavir and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2-receptor antagonist.

  • Atazanavir/ritonavir 300/100 mg tablets once daily with food if taken with an H2-receptor antagonist.
  • atazanavir 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir and an H2-receptor antagonist.
  • Atazanavir 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with either tenofovir DF or an H2RA for pregnant women during the second and third trimester. Atazanavir is not recommended for pregnant women during the second and third trimester taking Atazanavir with both tenofovir DF and an H2RA.

 

Immunosuppressants: cyclosporin, sirolimus, tacrolimus

↑ immunosuppressants

Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with atazanavir sulfate.

Inhaled beta agonist:

salmeterol

↑ salmeterol

Coadministration of salmeterol with atazanavir is not recommended. Concomitant use of salmeterol and atazanavir may result in increased risk of cardiovascular adverse reactions associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.

Inhaled/nasal steroid: fluticasone

atazanavir/ritonavir

↑ fluticasone

Concomitant use of fluticasone propionate and atazanavir/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and atazanavir/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects .

Macrolide antibiotics: clarithromycin

↑ clarithromycin

↓14-OH clarithromycin

↑ atazanavir

Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is co-administered with atazanavir. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Co-administration of atazanavir/ritonavir with clarithromycin has not been studied.

Hormonal contraceptives: ethinyl estradiol and norgestimate or norethindrone

↓ ethinyl estradiol

↑ norgestimateb

 

 

 

 

 

 

 

↑ ethinyl estradiol

↑ norethindronec

Use with caution if co-administration of atazanavir or atazanavir/ritonavir with oral contraceptives is considered. If an oral contraceptive is administered with atazanavir/ritonavir tablets, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol.

 

Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne.

 

Co-administration of atazanavir or atazanavir/ritonavir with other hormonal contraceptives (e.g., contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestagens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended.

Opioids: Buprenorphine

↑ buprenorphine             ↑ norbuprenorphine

 

Co-administration of buprenorphine and atazanavir/ritonavir tablets increases the plasma concentration of buprenorphine and norbuprenorphine. Co-administration of atazanazir/ritonavir tablets with buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. Co- administration of buprenorphine and atazanavir with ritonavir is not expected to decrease atazanavir plasma concentrations. Coadministration of buprenorphine and atazanavir without ritonavir may decrease atazanavir plasma concentrations.

PDE5 inhibitors: sildenafil, tadalafil, vardenafil

↑ sildenafil

↑ tadalafil

↑ vardenafil

Co-administration with atazanavir has not been studied but may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism.

 

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

Use of sildenafil for the treatment of pulmonary hypertension (PAH) is contraindicated with atazanavir.

The following dose adjustments are recommended for the use of tadalafil with atazanavir:

 

Coadministration of tadalafil in patients on atazanavir (with or without ritonavir):

  • For patients receiving atazanavir (with or without ritonavir) for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.

 

Coadministration of atazanavir (with or without ritonavir) in patients on tadalafil:

  • Avoid the use of tadalafil when starting atazanavir (with or without ritonavir). Stop tadalafil at least 24 hours before starting atazanavir (with or without ritonavir). At least one week after starting atazanavir (with or without ritonavir), resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.

 

Use of PDE5 inhibitors for erectile dysfunction:

Use sildenafil with caution at reduced doses of 25 mg every 48 hours, with increased monitoring for adverse events.

 

Use tadalafil with caution at reduced doses of 10 mg every 72 hours, with increased monitoring for adverse events.

 

Atazanavir/ritonavir: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours, with increased monitoring for adverse events.

Proton-pump inhibitors:

omeprazole

↓ atazanavir

Plasma concentrations of atazanavir were substantially decreased when atazanavir 400 mg or atazanavir 300 mg/ritonavir 100 mg once daily was administered with omeprazole 40 mg once daily, which may result in loss of therapeutic effect and development of resistance.

 

In treatment-naïve patients: The proton-pump inhibitor dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to atazanavir/ritonavir tablets.

 

In treatment-experienced patients: Proton-pump inhibitors should not be used in treatment-experienced patients receiving atazanavir.

a See Contraindications, Table 5 for orally administered midazolam.

b In combination with atazanavir 300 mg and ritonavir 100 mg once daily.

c In combination with atazanavir 400 mg once daily.

Drugs with No Observed or Predicted Interactions with atazanavir:

No clinically significant drug interactions were observed when atazanavir was co-administered with methadone, fluconazole, acetaminophen or atenolol, or the nucleoside reverse transcriptase inhibitors lamivudine or zidovudine.

Ritonavir

When co-administering ritonavir with other protease inhibitors (atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir), see the full prescribing information for that protease inhibitor including important information for drug interactions.

Potential for ritonavir to Affect Other Drugs

Ritonavir has been found to be an inhibitor of cytochrome P450 3A (CYP3A) and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (> 3-fold) when co-administered with ritonavir. Thus, co-administration of ritonavir with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 10.

Ritonavir also inhibits CYP2D6 to a lesser extent. Co-administration of substrates of CYP2D6 with ritonavir could result in increases (up to 2-fold) in the AUC of the other agent, possibly requiring a proportional dosage reduction. Ritonavir also appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6 as well as other enzymes, including glucuronosyl transferase.

Established and Other Potentially Significant Drug Interactions:

Table 10 provides a list of established or potentially clinically significant drug interactions with ritonavir.

Table 10: Established and other potentially significant drug interactions of ritonavir (full dose)

Concomitant Drug Class: Drug Name

Effect on Concentration of Ritonavir or Concomitant Drug

Clinical Comment

 

         HIV-Antiviral Agents

HIV-1 Protease Inhibitor: atazanavir

Darunavir

Fosamprenavir

↑ atazanavir

↑ amprenavir

↑ darunavir

See the complete prescribing information for fosamprenavir, atazanavir, darunavir for details on co-administration with ritonavir.

HIV-1 Protease Inhibitor:

Indinavir

↑ indinavir

Appropriate doses for this combination, with respect to efficacy and safety, have not been established.

HIV-1 Protease Inhibitor: saquinavir

 

↑ saquinavir

 

See the complete prescribing information for saquinavir for details on co-administration of saquinavir and ritonavir 100 mg.

Saquinavir/ritonavir in combination with rifampin is not recommended due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together.

HIV-1 Protease Inhibitor: tipranavir

 

↑ tipranavir

See the complete prescribing information for tipranavir for details on co-administration of tipranavir and ritonavir.

Non-Nucleoside Reverse Transcriptase Inhibitor: delavirdine

 

↑ ritonavir

 

Appropriate doses of this combination with respect to safety and efficacy have not been established.

HIV-1 CCR5 – antagonist: maraviroc

↑ maraviroc

 

See the complete prescribing information for maraviroc for details on co-administration of maraviroc and ritonavir-containing protease inhibitors.

Ìntegrase Inhibitor: Raltegravir

↓ raltegravir

The effects of ritonavir on raltegravir with ritonavir dosage regimens greater than 100 mg twice daily have not been evaluated, however raltegravir concentrations may be decreased with ritonavir coadministration.

Other Agents

Analgesics, Narcotic: tramadol, propoxyphene, methadone, fentanyl

 

↑ analgesics

 

 

↓ methadone

 

 

↑ fentanyl

 

 

A dose decrease may be needed for these drugs when co-administered with ritonavir.

 

Dosage increase of methadone may be considered.

 

Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with ritonavir.

Anesthetic: meperidine

 

↓ meperidine/                 

↑ normeperidine (metabolite)

 

Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures).

Antialcoholics: disulfiram/ metronidazole

 

 

Ritonavir formulations contain alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).

Antiarrhythmics: disopyramide, lidocaine, mexiletine

 

↑ antiarrhythmics

 

For contraindicated antiarrhythmics

Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when co-administered with ritonavir, if available.

Anticancer Agents:

dasatinib, nilotinib,

vincristine, vinblastine

 

↑ anticancer agents

 

 

For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when ritonavir is administered concurrently with vincristine or vinblastine. Clinicians should be aware that if the ritonavir containing regimen is withheld for a prolonged period, consideration should be given to altering the regimen to not include a CYP3A or P-gp inhibitor in order to control HIV-1 viral load.

A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as ritonavir. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.

Anticoagulant: warfarin

 

 

 ↓↑ warfarin

 

Initial frequent monitoring of the INR during ritonavir and warfarin co­administration isrecommended.

Anticoagulant:

rivaroxaban

↑ rivaroxaban

Avoid concomitant use of rivaroxaban and ritonavir. Co-administration of ritonavir and rivaroxaban may lead to risk of increased bleeding.

Anticonvulsants: carbamazepine, clonazepam, ethosuximide

 

↑ anticonvulsants

 

A dose decrease may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.

Anticonvulsants: divalproex, lamotrigine, phenytoin

 

↓ anticonvulsants

 

A dose increase may be needed for these drugs when co­administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available

Antidepressants: nefazodone, selective serotonin reuptake inhibitors (SSRIs)

e.g. fluoxetine, paroxetine, tricyclics: e.g. amitriptyline, nortriptyline

↑ antidepressants

 

A dose decrease may be needed for these drugs when co-administered with ritonavir.

 

Antidepressant: bupropion

 

↓ bupropion

↓ active metabolite, hydroxybupropion

Patients receiving ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion.

Antidepressant: desipramine

↑ desipramine

 

Dosage reduction and concentration monitoring of desipramine is recommended.

Antidepressant: trazodone

 

↑ trazodone

 

Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. A lower dose of trazodone should be considered.

Antiemetic: dronabinol

↑ dronabinol

 

A dose decrease of dronabinol may be needed when co-administered with ritonavir.

Antifungals: ketoconazole itraconazole, voriconazole

 

↑ ketoconazole

↑ itraconazole

↓ voriconazole

 

For contraindicated antifungals,

High doses of ketoconazole or itraconazole (> 200 mg/day) are not recommended.

Coadministration of voriconazole and ritonavir doses of 400 mg every 12 hours or greater is contraindicated. Coadministration of voriconazole and ritonavir 100 mg should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.

Anti-gout: colchicine

 

↑ colchicine

 

Concomitant administration with colchicine is

contraindicated in patients with renal and/or hepatic impairment .

 

For patients with normal renal or hepatic function:

 

Treatment of gout flares-co­administration of colchicine in patients on ritonavir:

 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

 

Prophylaxis of gout flares-co­administration of colchicine in patients on ritonavir:

If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

 

Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on ritonavir:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).

Anti-infective: clarithromycin

 

↑ clarithromycin

 

For patients with renal impairment adjust clarithromycin dose as follows:

  • For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%.
  • For patients with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%.

 

No dose adjustment for patients with normal renal function is necessary.

Antimycobacterial: bedaquiline

↑ bedaquiline

Bedaquiline should only be used with ritonavir if the benefit of co-administration outweighs the risk.

Antimycobacterial: rifabutin

 

↑ rifabutin and rifabutin metabolite

 

Dosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg/day is recommended (e.g., 150 mg every other day or three times a week). Further dosage reduction may be necessary.

Antimycobacterial: rifampin

↓ ritonavir

May lead to loss of virologic response. Alternate antimycobacterial agents such as rifabutin should be considered

Antiparasitic: atovaquone

↓ atovaquone

Clinical significance is unknown; however, increase in atovaquone dose may be needed.

Antiparasitic: quinine

↑ quinine

A dose decrease of quinine may be needed when co-administered with ritonavir.

Antipsychotics: perphenazine, risperidone, thioridazine

↑ antipsychotics

For contraindicated antipsychotics, .

A dose decrease may be needed for these drugs when co-administered with ritonavir.

Antipsychotics:

Quetiapine

↑ quetiapine

Initiation of ritonavir in patients taking quetiapine:

Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.

Initiation of quetiapine in patients taking ritonavir:

Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.

β-Blockers: metoprolol, timolol

↑ Beta-Blockers

Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co­administered with ritonavir.

Bronchodilator: theophylline

↓ theophylline

Increased dosage of theophylline may be required; therapeutic monitoring should be considered.

Calcium channel blockers: diltiazem, nifedipine, verapamil

↑ calcium channel blockers

Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co­administered with ritonavir.

Digoxin

↑ digoxin

Concomitant administration of ritonavir with digoxin may increase digoxin levels. Caution should be exercised when coadministering ritonavir with digoxin, with appropriate monitoring of serum digoxin levels.

Endothelin receptor antagonists: bosentan

↑ bosentan

Co-administration of bosentan in patients on ritonavir:

In patients who have been receiving ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

 

Co-administration of ritonavir in patients on bosentan:

Discontinue use of bosentan at least 36 hours prior to initiation of ritonavir.

After at least 10 days following the initiation of ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

HCV direct acting antiviral Direct acting ntivr: simeprevir

↑ simeprevir

It is not recommended to co-administer ritonavir with simeprevir.

HMG-CoA Reductase Inhibitor: atorvastatin rosuvastatin

↑ atorvastatin

 

↑ rosuvastatin

For contraindicated HMG-CoA reductase inhibitors, .

Titrate atorvastatin and rosuvastatin dose carefully and use the lowest necessary dose.

If ritonavir is used with another protease inhibitor, see the complete prescribing information for the concomitant protease inhibitor for details on co-administration with atorvastatin and rosuvastatin.

Immunosuppressants: cyclosporine, tacrolimus, sirolimus (rapamycin)

↑ immunosuppressants

Therapeutic concentration monitoring is recommended for immunosuppressant agents when co­administered with ritonavir.

Long-acting beta­adrenoceptor agonist: salmeterol

 

↑ salmeterol

 

Concurrent administration of salmeterol and ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.

Oral Contraceptives or Patch Contraceptives: ethinyl estradiol

 

↓ ethinyl estradiol

 

Alternate methods of contraception should be considered.

PDE5 Inhibitors: avanafil, sildenafil, tadalafil, vardenafil

 

↑ avanafil

↑ sildenafil

↑ tadalafil

↑ vardenafil

 

For contraindicated PDE5 inhibitors, .

Do not use ritonavir with avanafil because a safe and effective avanafil dosage regimen has not been established.

 

Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patients receiving ritonavir. Co-administration of ritonavir with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse events, including hypotension,syncope, visual changes, and prolonged erection.

 

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

Sildenafil is contraindicated .

 

The following dose adjustments are recommended for use of tadalafil with ritonavir:

 

 Co-administration of tadalafil in patients on ritonavir:

In patients receiving ritonavir for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

 

Co-administration of ritonavir in patients on tadalafil:

Avoid use of tadalafil during the initiation of ritonavir. Stop tadalafil at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for the treatment of erectile dysfunction:

 It is recommended not to exceed the following doses:

  • Sildenafil: 25 mg every 48 hours
  • Tadalafil: 10 mg every 72 hours
  • Vardenafil: 2.5 mg every 72 hours.

 

Use with increased monitoring for adverse events.

Sedative/hypnotics: buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem

↑ sedative/hypnotics

 

A dose decrease may be needed for these drugs when co-administered with ritonavir.

Sedative/hypnotics: Parenteral midazolam

 

↑ midazolam

 

For contraindicated sedative/hypnotics, .

Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.

Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids:  e.g.  betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone prednisone triamcinolone

↑ glucocorticoids

 

Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression.

 

Alternative corticosteroids including beclomethasone and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use.

Stimulant:

methamphetamine

 

↑ methamphetamine

 

Use with caution. A dose decrease of methamphetamine may be needed when co-administered with ritonavir.

 

Emtricitabine/Tenofovir DF:

r.

Drugs Affecting Renal Function

FTC and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of tenofovir/emtricitabine with drugs that are eliminated by active tubular secretion may increase concentrations of FTC, tenofovir, and/or the coadministered drug. Some examples include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs Drugs that decrease renal function may increase concentrations of FTC and/or tenofovir.

Established and Significant Interactions

Table 11 provides a listing of established or clinically significant drug interactions. The drug interactions described are based on studies conducted with either TDF/FTC, the components FTC and TDF as individual agents and/or in combination, or are predicted drug interactions that may occur with  tenofovir/FTC combination.

Table 11 : Established and Significanta Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials

Concomitant Drug Class: Drug Name

Effect on Concentration

Clinical Comment

NRTI:

didanosinec

 

↑ didanosine

Patients receiving TDF/FTC combination and didanosine should be monitored closely for didanosine-associated adverse reactions. Discontinue didanosine in patients who develop didanosine-associated adverse reactions. Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis, and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving TDF with didanosine 400 mg daily.

 

In patients weighing greater than 60 kg, reduce the didanosine dose to 250 mg when it is coadministered with TDF/FTC combination. Data are not available to recommend a dose adjustment of didanosine for adult or pediatric patients weighing less than 60 kg. When coadministered, TDF/FTC combination and  didanosine -EC may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat).

HIV-1 Protease Inhibitors: atazanavirc

 

lopinavir/ritonavirc atazanavir/ritonavirc darunavir/ritonavirc

↓ atazanavir

 

 

 

 

↑ tenofovir

When coadministered with TDF/FTC combination, atazanavir 300 mg should be given with ritonavir 100 mg.

 

Monitor patients receiving TDF/FTC combination concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir boosted darunavir for TDF-associated adverse reactions.

 

Discontinue TDF/FTC combination in patients who develop TDF-associated adverse reactions.

Hepatitis C Antiviral Agents: sofosbuvir/velpatasvirc sofosbuvir/velpatasvir/ voxilaprevirc ledipasvir/sofosbuvirc

↑ tenofovir

Monitor patients receiving TDF/FTC combination concomitantly with sofosbuvir/velpatasvir or sofosbuvir/velpatasvir/voxilaprevir for adverse reactions associated with TDF.

 

Monitor patients receiving TDF/FTC combination concomitantly with ledipasvir/sofosbuvir without an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination for adverse reactions associated with TDF. In patients receiving TDF/FTC combination concomitantly with ledipasvir/sofosbuvir and an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, consider an alternative HCV or antiretroviral therapy, as the safety of increased tenofovir concentrations in this setting has not been established. If coadministration is necessary, monitor for adverse reactions associated with TDF.

a. This table is not all inclusive.

b. ↑=Increase, ↓=Decrease

c. Indicates that a drug-drug interaction trial was conducted.

Atazanavir/ritonavir

Cardiac conduction Abnormalities

Atazanavir has been shown to prolong the PR interval of the electrocardiogram in some patients. In healthy volunteers and in patients, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been rare reports of second-degree AV block and other conduction abnormalities . In clinical trials that included electrocardiograms, asymptomatic first-degree AV block was observed in 5.9% of atazanavir-treated patients (n=920), 5.2% of lopinavir/ritonavir-treated patients (n=252), 10.4% of nelfinavir-treated patients (n=48), and 3.0% of efavirenz-treated patinets (n=329). In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir/ritonavir-treated patients and 5% (6/116) of lopinavir/ritonavir-treated patients who had on-study electrocardiogram measurements. Because of limited clinical experience in patients with preexisting conduction system disease (eg, marked first-degree AV block or second- or third-degree AV block). ECG monitoring should be considered in these patients.    

Severe Skin Reactions

In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately 20% of patients treated with atazanavir. The median time to onset of rash was 7.3 weeks and the median duration of rash was 1.4 weeks. Rashes were generally mild-to-moderate maculopapular skin eruptions. Treatment-emergent adverse reactions of moderate or severe rash (occurring at a rate of ≥2%) are presented for the individual clinical studies . Dosing with atazanavir was often continued without interruption in patients who developed rash. The discontinuation rate for rash in clinical trials was <1%.  Atazanavir should be discontinued if severe rash develops. Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug rash, eosinophilia and systemic symptoms (DRESS) syndrome, have been reported in patients receiving atazanavir .

Hyperbilirubinemia

Most patients taking atazanavir experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT). This hyperbilirubinemia is reversible upon discontinuation of atazanavir. Hepatic transaminase elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies. No long-term safety data are available for patients experiencing persistent elevations in total bilirubin >5 times the upper limit of normal (ULN). Alternative antiretroviral therapy to atazanavir may be considered if jaundice or scleral icterus associated with bilirubin elevations presents cosmetic concerns for patients. Dose reduction of atazanavir is not recommended since long-term efficacy of reduced doses has not been established (see UNDESIRABLE EFFECTS, Laboratory Abnormalities).

Hepatotoxicity

Patients with underlying hepatitis B or C viral infections or marked elevations in transaminases before treatment may be at increased risk for developing further transaminase elevations or hepatic decompensation. In these patients, hepatic laboratory testing should be conducted prior to initiating therapy with atazanavir and during treatment .

Chronic Kidney Disease

Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. Reports included biopsy-proven cases of granulomatous interstitial nephritis associated with the deposition of atazanavir drug crystals in the renal parenchyma. Consider alternatives to atazanavir in patients at high risk for renal disease or with preexisting renal disease. Renal laboratory testing (including serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination) should be conducted in all patients prior to initiating therapy with atazanavir and continued during treatment with atazanavir. Expert consultation is advised for patients who have confirmed renal laboratory abnormalities while taking atazanavir. In patients with progressive kidney disease, discontinuation of atazanavir may be considered .

Nephrolithiasis and Choelithiasis

Cases of nephrolithiasis and /or choelithiasis were reported during post-marketing surveillance in HIV-infected patients receiving atazanavir therapy. Some patients required hospitalization for additional management and some had complications. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis and/or cholelithiasis occur, temporary interruption or discontinuation of therapy may be considered .

Hemophilia

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.

Resistance/Cross-Resistance

Various degrees of cross-resistance among protease inhibitors have been observed. Resistance to atazanavir may not preclude the subsequent use of other protease inhibitors.

Fat Redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including atazanavir, lamivudine, ritonavir and tenofovir. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

Risk of Serious Adverse Reactions Due to Drug Interactions

Initiation of atazanavir with ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving atazanavir with ritonavir, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of atazanavir with ritonavir, 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 atazanavir with ritonavir.
  • loss of therapeutic effect of atazanavir with ritonavir and possible development of resistance.

Consider the potential for drug interactions prior to and during atazanavir/ritonavir therapy; review concomitant medications during atazanavir/ritonavir therapy; and monitor for the adverse reactions associated with the concomitant medications .

Diabetes Mellitus/Hyperglycemia

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 ritonavir.

Ritonavir

Hepatotoxicity

Hepatic transaminase elevations exceeding 5 times the upper limit of normal, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir alone or in combination with other antiretroviral drugs. There may be an increased risk for transaminase elevations in patients with underlying hepatitis B or C. Therefore, caution should be exercised when administering ritonavir to patients with pre-existing liver diseases, liver enzyme abnormalities, or hepatitis. Increased AST/ALT monitoring should be considered in these patients, especially during the first three months of ritonavir treatment .

There have been postmarketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients taking multiple concomitant medications and/or with advanced AIDS.

Allergic Reactions/hypersensitivity

Allergic reactions, including urticaria, mild skin eruptions, bronchospasm, and angioedema have been reported with ritonavir. Cases of anaphylaxis, toxic epidermal necrolysis (TEN), and Stevens-Johnson syndrome have also been reported. Discontinue treatment if severe reactions develop.

Pancreatitis

Pancreatitis has been observed in patients receiving ritonavir therapy, including those who developed hypertriglyceridemia.  In some cases, fatalities have been observed.  Patients with advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis. Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur.  Patients who exhibit these signs or symptoms should be evaluated and ritonavir therapy should be discontinued if a diagnosis of pancreatitis is made.

Lipid Disorders

Treatment with ritonavir therapy alone or in combination with saquinavir has resulted in substantial increases in the concentration of total triglycerides and cholesterol.  Triglycerides and cholesterol testing should be performed prior to initiating ritonavir therapy and at periodic intervals during therapy.  Lipid disorders should be managed as clinically appropriate taking into account any potential drug-drug interactions with ritonavir and HMG CoA reductase inhibitors .

Laboratory Tests

Ritonavir has been shown to increase triglycerides, cholesterol, SGOT (AST), SGPT (ALT), GGT, CPK, and uric acid. Appropriate laboratory testing should be performed prior to initiating ritonavir therapy and at periodic intervals or if any clinical signs or symptoms occur during therapy.

PR Interval Prolongation

Ritonavir prolongs the PR interval in some patients. Postmarketing cases of second- or third-degree atrioventricular block have been reported in patients. Ritonavir should be used with caution in patients with underlying structural heart disease, pre-existing conduction system abnormalities, ischemic heart disease cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities. The impact on the PR interval of co-administration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As a result, co-administration of ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A.

Clinical monitoring is recommended. .

Tenofovir/Emtricitabine

Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir DF a component of QVIR KIT, in combination with other antiretrovirals. Treatment with emtricitabine/tenofovir DF tablets should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Severe Acute Exacerbation of Hepatitis B in Patients with HBV Infection

All patients should be tested for the presence of chronic hepatitis B virus (HBV) before or when initiating tenofovir/emtricitabine.

Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in HBV-infected patients who have discontinued TDF/FTC. Patients infected with HBV who discontinue TDF/FTC should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure. HBV-uninfected individuals should be offered vaccination.

New Onset or Worsening of Renal Impairment

Emtricitabine and tenofovir are principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir DF (see UNDESIRABLE EFFECTS).

Prior to initiation and during use of TDF/FTC, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus.

Emtricitabine/tenofovir disoproxil fumarate should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs)). Cases of acute renal failure after initiation of high dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir DF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.

Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.

Treatment of HIV-1 Infection

Dosing interval adjustment of emtricitabine/tenofovir DF tablets and close monitoring of renal function are recommended in all patients with creatinine clearance 30-49 mL/min. (see DOSAGE AND ADMINISTRATION). No safety or efficacy data are available in patients with renal impairment who received tenofovir DF and emtricitabine using these dosing guidelines, so the potential benefit of tenofovir/emtricitabine therapy should be assessed against the potential risk of renal toxicity. Emtricitabine/tenofovir DF tablets should not be administered to patients with creatinine clearance <30 mL/min or patients requiring hemodialysis.

Risk of Adverse Reactions Due to Drug Interactions

The concomitant use of TDF/FTC and other drugs may result in known or potentially significant drug interactions, some of which may lead to possible clinically significant adverse reactions from greater exposures of concomitant drugs .

See Table 11 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 therapy withTDF/FTC; review concomitant medications during therapy withTDF/FTC; and monitor for adverse reactions associated with the concomitant drugs.

Bone Loss and Mineralization Defects

Bone Mineral Density

In clinical trials in HIV-1 infected adults and in a clinical trial of HIV-1 uninfected individuals, tenofovir DF was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1, 25 Vitamin D levels were also higher in subjects receiving tenofovir DF.

Clinical trials evaluating tenofovir DF in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the tenofovir DF treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis B infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected. For more information, please consult the tenofovir disoproxil fumarate prescribing information.

The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial. If bone abnormalities are suspected then appropriate consultation should be obtained.

Mineralization Defects

Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of tenofovir DF. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-1 infected patients treated with combination antiretroviral therapy, including tenofovir/Emtricitabine. During the initial phase of combination antiretroviral treatment, HIV-1 infected patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections , which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

Pregnancy

Atazanavir/ritonavir

Risk Summary

Atazanavir has been evaluated in a limited number of women during pregnancy. Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate . 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. No treatment-related malformations were observed in rats and rabbits, for which the atazanavir exposures were 0.7-1.2 times of those at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). When atazanavir was administered to rats during pregnancy and throughout lactation, reversible neonatal growth retardation was observed.

Clinical Considerations

Dose Adjustments during Pregnancy and the Postpartum Period

  • Atazanavir must be administered with ritonavir in pregnant women.
  • For pregnant patients, no dosage adjustment is required for Atazanavir with the following exceptions:
    • For treatment-experienced pregnant women during the second or third trimester, when atazanavir is coadministered with either an H2-receptor antagonist or tenofovir DF, atazanavir 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend a atazanavir dose for use with both an H2-receptor antagonist and tenofovir DF in treatment-experienced pregnant women.
  • No dosage adjustment is required for postpartum patients. However, patients should be closely monitored for adverse events because atazanavir exposures could be higher during the first 2 months after delivery .

Maternal Adverse Reactions

Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using Atazanavir in combination with nucleoside analogues, which are associated with an increased risk of lactic acidosis syndrome.

  • Hyperbilirubinemia occurs frequently in patients who take Atazanavir .

Advise pregnant women of the potential risks of lactic acidosis syndrome and hyperbilirubinemia.

Fetal/Neonatal Adverse Reactions

All infants, including neonates exposed to atazanavir in utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life.

Data

Human Data

In clinical trial AI424-182, Atazanavir/ritonavir (300/100 mg) in combination with zidovudine/lamivudine was administered to 41 HIV-infected pregnant women during the second or third trimester. Among the 39 women who completed the study, 38 women achieved an HIV RNA less than 50 copies/mL at time of delivery. Six of 20 (30%) women on Atazanavir/ritonavir 300/100 mg experienced hyperbilirubinemia (total bilirubin greater than or equal to 2.6 times ULN). There were no cases of lactic acidosis observed in clinical trial AI424-182.

Atazanavir drug concentrations in fetal umbilical cord blood were approximately 12% to 19% of maternal concentrations. Among the 40 infants born to 40 HIV-infected pregnant women, all had test results that were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. All 40 infants received antiretroviral prophylactic treatment containing zidovudine. No evidence of severe hyperbilirubinemia (total bilirubin levels greater than 20 mg/dL) or acute or chronic bilirubin encephalopathy was observed among neonates in this study. However, 10/36 (28%) infants (6 greater than or equal to 38 weeks gestation and 4 less than 38 weeks gestation) had bilirubin levels of 4 mg/dL or greater within the first day of life.

Lack of ethnic diversity was a study limitation. In the study population, 33/40 (83%) infants were Black/African American, who have a lower incidence of neonatal hyperbilirubinemia than Caucasians and Asians. In addition, women with Rh incompatibility were excluded, as well as women who had a previous infant who developed hemolytic disease and/or had neonatal pathologic jaundice (requiring phototherapy).

Additionally, of the 38 infants who had glucose samples collected in the first day of life, 3 had adequately collected serum glucose samples with values of less than 40 mg/dL that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis.

Based on prospective reports from the APR of approximately 1600 live births following exposure to atazanavir-containing regimens (including 1037 live births in infants exposed in the first trimester and 569 exposed in second/third trimesters), there was no difference between atazanavir and overall birth defects compared with the background birth defect rate. In the U.S. general population, the estimated background risk of major birth defects in clinically recognized pregnancies is 2-4%.

Animal Data

In animal reproduction studies, there was no evidence of mortality or teratogenicity in offspring born to animals at systemic drug exposure levels (AUC) 0.7 (in rabbits) to 1.2 (in rats) times those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). In pre-and postnatal development studies in the rat, atazanavir caused neonatal growth retardation during lactation that reversed after weaning. Maternal drug exposure at this dose was 1.3 times the human exposure at the recommended clinical exposure. Minimal maternal toxicity occurred at this exposure level.

Ritonavir

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.

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.

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 1/2 of the recommended daily dose, based on a body surface area conversion factor.

Tenofovir/Emtricitabine

Risk Summary

Data on the use of tenofovir/emtricitabine during pregnancy from observational studies have shown no increased risk of major birth defects..

Available data from the APR show no increase in the overall risk of major birth defects with first trimester exposure for emtricitabine (FTC) (2.3%) or tenofovir disoproxil fumarate (TDF) (2.1%) compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage for individual drugs is not reported in the APR. In the U.S. general population, the estimated background risk of miscarriage in clinically recognized pregnancies is 15–20%.

In animal reproduction studies, no adverse developmental effects were observed when the components of  tenofovir/emtricitabine  were administered separately at doses/exposures ≥60 (FTC), ≥14 (TDF)  and 2.7 (tenofovir) times those of the recommended daily dose of  tenofovir/emtricitabine.

Data

Human Data

Emtricitabine: Based on prospective reports to the APR of 3,749 exposures to FTC-containing regimens during pregnancy resulting in live births (including 2,614 exposed in the first trimester and 1,135 exposed in the second/third trimester), there was no increase in overall major birth defects with FTC compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of major birth defects in live births was 2.3% (95% CI: 1.8% to 2.9%) with first trimester exposure to FTC-containing regimens and 2.1% (95% CI: 1.4% to 3.1%) with the second/third trimester exposure to FTC-containing regimens.

Tenofovir Disoproxil Fumarate: Based on prospective reports from the APR of 4,817 exposures to TDF-containing regimens during pregnancy resulting in live births (including 3,342 exposed in the first trimester and 1,475 exposed in the second/third trimester), there was no increase in overall major birth defects with TDF compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of major birth defects in live births was 2.3% (95% CI: 1.8% to 2.8%) with first trimester exposure to TDF-containing regimens, and 2.1% (95% CI: 1.4% to 3.0%) with the second/third trimester exposure to TDF-containing regimens.

Methodologic limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation. 

Additionally, published observational studies on emtricitabine and tenofovir exposure in pregnancy have not shown an increased risk for major malformations.

Animal Data

Emtricitabine: FTC was administered orally to pregnant mice (at 0, 250, 500, or 1,000 mg/kg/day), and rabbits (at 0, 100, 300, or 1,000 mg/kg/day) through organogenesis (on gestation days 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with FTC in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 120 times higher than human exposures at the recommended daily dose. In a pre/postnatal development study in mice, FTC was administered orally at doses up to 1,000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the recommended daily dose.

Tenofovir Disoproxil Fumarate: TDF was administered orally to pregnant rats (at 0, 50, 150, or 450 mg/kg/day) and rabbits (at 0, 30, 100, or 300 mg/kg/day) through organogenesis (on gestation days 7 through 17, and 6 through 18, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with TDF in rats at doses up to 14 times the human dose based on body surface area comparisons and in rabbits at doses up to 19 times the human dose based on body surface area comparisons. In a pre/postnatal development study in rats, TDF was administered orally through lactation at doses up to 600 mg/kg/day; no adverse effects were observed in the offspring at tenofovir exposures of approximately 2.7 times higher than human exposures at the recommended daily dose of TDF/FTC.

QVIR Kit should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation

Atazanavir/ritonavir and Emtricitabine/tenofovir DF

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.

Atazanavir has been detected in human milk. No data are available regarding atazanavir effects on milk production. Atazanavir was present in the milk of lactating rats and was associated with neonatal growth retardation that reversed after weaning.

Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed. 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. Based on published data, FTC and tenofovir have been shown to be present in human breast milk. It is not known if the components of tenofovir/emtricitabine affect milk production or have effects on the breastfed child. .

Because of the potential for: (1) HIV transmission (in HIV-negative infants); (2) developing viral resistance (in HIV-positive infants); and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are taking atazanavir/ritonavir and TDF/FTC for the treatment of HIV-1.

Ritonavir

Females and Males of Reproductive Potential

Contraception

Use of ritonavir 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 .

Pediatric use

Atazanavir

Atazanavir in combination with other antiretroviral agents for the treatment of HIV-1 infection in pediatric patients 3 months of age and older weighing at least 5 kg. Atazanavir is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus. All Atazanavir contraindications, warnings, and precautions apply to pediatric patients .

The safety, pharmacokinetic profile, and virologic response of atazanavir in pediatric patients at least 3 months of age and older weighing at least 5 kg were established in three open-label, multicenter clinical trials: PACTG 1020A, AI424-451, and AI424-397. The safety profile in pediatric patients was generally similar to that observed in adults .

Ritonavir

In HIV-infected patients age greater than 1 month to 21 years, the antiviral activity and adverse event profile seen during clinical trials and through postmarketing experience were similar to that for adult patients.

Tenofovir DF/emtricitabine

Treatment of HIV-1 Infection

No pediatric clinical trial was conducted to evaluate the safety and efficacy of tenofovir DF/emtricitabine. Data from previously conducted trials with the individual drug products, emtricitabine and tenofovir DF were relied upon to support dosing recommendations for tenofovir DF/emtricitabine. For additional information, consult the prescribing information for emtricitabine and tenofovir DF.

Tenofovir DF/emtricitabine should only be administered to HIV-1 infected pediatric patients with body weight greater than or equal to 17 kg and who are able to swallow a whole tablet. Because it is a fixed-dose combination tablet, tenofovir DF/emtricitabine cannot be adjusted for patients of lower weight (see WARNINGS AND PRECAUTIONS, UNDISERABLE EFFECTS). Tenofovir DF/emtricitabine has not been evaluated for use in pediatric patients weighing less than 17 kg.

Geriatric use

Atazanavir

Clinical studies of atazanavir did not include sufficient numbers of patients aged 65 and over to  determine whether they respond differently from younger patients. Based on a comparison of mean single-dose pharmacokinetic values for Cmax and AUC, a dose adjustment based upon age is not recommended. In general, appropriate caution should be exercised in the administration and monitoring of atazanavir in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Ritonavir

Clinical studies of ritonavir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Tenofovir DF/Emtricitabine

Clinical studies of emtricitabine/tenofovir DF tablets did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of atazanavir/ritonavir in elderly patients, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Age/Gender

Atazanavir

A study of the pharmacokinetics of atazanavir was performed in young (n=29; 18 to 40 years of age) and elderly (n=30; ≥65 years of age) healthy subjects. There were no clinically important pharmacokinetic differences observed due to age or gender.

Impaired Renal Function

Atazanavir/ritonavir

Atazanavir is not recommended for use in HIV-treatment-experienced patients with end-stage renal disease managed with hemodialysis .

Emtricitabine/tenofovir DF

The dosing interval for emtricitabine/tenofovir DF tablets should be modified in patients with creatinine clearance 30–49 mL/min. Emtricitabine/tenofovir DF tablets is not recommended in patients with creatinine clearance below 30 mL/min and in patients with end-stage renal disease requiring dialysis (see DOSAGE AND ADMINISTRATION).

Impaired Hepatic Function

Atazanavir/ritonavir:

Atazanavir is not recommended for use in patients with severe hepatic impairment. Atazanavir/ritonavir is not recommended for use in patients with any degree of hepatic impairment .

Undesirable Effects

Atazanavir

The following adverse reactions are discussed in greater detail in other sections of the labeling:

  • cardiac conduction abnormalities
  • rash
  • hyperbilirubinemia
  • Chronic Kidney Disease
  • nephrolithiasis and Cholelithiasis

Clinical Trial 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.

Clinical Trial Experience in Adults

Adverse Reactions in Treatment-Naïve Patients:

The safety profile of atazanavir in treatment-naïve adults is based on 1625 HIV-1-infected patients in clinical trials, wherein 536 patients received atazanavir 300 mg with ritonavir 100 mg and 1089 patients received atazanavir 400 mg or higher (without ritonavir).

The most common adverse reactions were nausea, jaundice/scleral icterus, and rash.

Selected clinical adverse reactions of moderate or severe intensity reported in ≥2% of treatment-naïve patients receiving combination therapy, including atazanavir 300 mg with ritonavir 100 mg, are presented in Table 12.

Table 12: Selected treatment-emergent adverse reactionsa of moderate or severe intensity reported in ≥2% of adult treatment-naïve patientb (Study AI424-138)

 

96 weeksc

atazanavir 300 mg with ritonavir 100 mg (once daily) and tenofovir with emtricitabined

(n=441)

96 weeksc

lopinavir 400 mg with ritonavir 100 mg (twice daily) and tenofovir with emtricitabined

(n= 437)

Digestive System

 

 

     Nausea

4%

8%

     Jaundice/scleral icterus

5%

*

     Diarrhea

2%

12 %

Skin and Appendages

 

 

     Rash

3%

2%

* None reported in this treatment arm.

a Includes events of possible, probable, certain or unknown relationship to the treatment  regimen.

b Based on regimens containing atazanavir.

c Median time on therapy.

d As a fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily.

Adverse Events in Treatment-Experienced Adult Patients:

The safety profile of atazanavir in treatment-experienced adults is based on 119 HIV-1-infected patients in clinical trials.The most common adverse reactions were jaundice/scleral icterus and myalgia.

Selected clinical adverse events of moderate or severe intensity in ≥2% of treatment-experienced patients receiving atazanavir/ritonavir are presented in Table 13.

Table 13: Selected treatment-emergent adverse eventsa of moderate or severe intensity reported in ≥2% of adult treatment-experienced patientsb (Study AI424-045)

 

48 weeksc

Atazanavir/ritonavir 300/100 mg once daily + tenofovir + NRTI

(n=119)

48 weeksc

lopinavir/ritonavir 400/100 mg twice dailyd + tenofovir + NRTI

(n=118)

Body as a Whole

 

 

Fever

2%

*

Digestive System

 

 

Jaundice/scleral icterus

9%

*

Diarrhea

3%

11%

Nausea

3%

2%

Nervous System

 

 

Depression

2%

<1%

Musculoskeletal System

 

 

Myalgia

4%

*

* None reported in this treatment arm.

a Includes events of possible, probable, certain, or unknown relationship to the treatment regimen.

b Based on the regimen containing atazanavir.

c Median time on therapy.

d As a fixed-dose combination.

Laboratory Abnormalities in Treatment-Naïve Patients:

The percentages of adult treatment-naïve patients treated with combination therapy, including atazanavir sulfate 300 mg with ritonavir 100 mg, having Grade 3–4 laboratory abnormalities are presented in Table 14.

Table 14: Grade 3–4 laboratory abnormalities reported in ≥2% of adult treatment-naïve patientsa (Study AI424-138)

 

 

 

 

 

Variable

 

 

 

 

 

Limitc

96 weeksb

atazanavir 300 mg with ritonavir 100 mg (once daily) and tenofovir with emtricitabined

(n=441)

96 weeksb

lopinavir 400 mg with ritonavir 100 mg (twice daily) and tenofovir with emtricitabined

(n=437)

Chemistry

High

 

 

  SGOT/AST

≥5.1 x ULN

3%

1%

  SGPT/ALT

≥5.1 x ULN

3%

2%

  Total bilirubin

≥2.6 x ULN

44%

<1%

  Lipase

≥2.1 x ULN

2%

2%

  Creatine kinase

≥5.1 x ULN

8%

7%

  Total cholesterol

≥240 mg/dL

11%

25%

Hematology

Low

 

 

  Neutrophils

<750 cells/mm3

5%

2%

 

a Based on the regimen containing atazanavir.

b Median time on therapy.

c ULN = upper limit of normal.

d As a fixed-dose combination: 300 mg tenofovir, 200 mg emtricitabine once daily

Change in Lipids,from Baseline in Treatment-Naïve Patients:

For Study AI424-138, changes from baseline in fasting LDL-cholesterol, HDL-cholesterol, total cholesterol, and fasting triglycerides are shown in Table 15.

Table 15: Lipid values, mean change from baseline (Study AI424-138)

 

Atazanavir/Ritonavir a,b

Lopinavir/ritonavir b,c

Baseline

Week 48

Week 96

Baseline

Week 48

Week 96

mg/dl
(n=428e)

mg/dl

(n=372e)

Changed

(n=372e)

mg/dL

(n=342e)

Changed

(n=335)

mg/dl

(n=424e)

mg/dl

(n=335e)

Changed

(n=335e)

mg/dL

(n=291e)

Changed (n=291e)

LDL-cholesterolf

92

105

+14%

105

+14%

93

111

+19%

110

+17%

HDL-cholesterolf

37

46

+29%

44

+21%

36

48

+37%

46

+29%

Total cholesterolf

149

169

+13%

169

+13%

150

187

+25%

186

+25%

Triglyceridesf

126

145

+15%

140

+13%

129

194

+52%

184

+50%

a Atazanavir 300 mg with ritonavir 100 mg once daily with the fixed-dose combination : 300 mg tenofovir, 200 mg emtricitabine once daily.

b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid- reducing agents were used in 1% of patients in the lopinavir/ritonavir treatment arm and 1% in the atazanavir/ritonavir arm. Through week 48, serum lipid-reducing agents were used in 8% of patients in the lopinavir/ritonavir treatment arm and 2% in the atazanavir/ritonavir arm. Through Week 96, serum lipid-reducing agents were used in 10% in the lopinavir/ritonavir treatment arm and 3% in the atazanavir/ritonavir arm.

c Lopinavir 400 mg with ritonavir 100 mg twice daily with the fixed-dose combination of 300 mg tenofovir, 200 mg emtricitabine once daily.

d The change from baseline is the mean of within-patient changes from baseline for  patients with both baseline and week 48 or week 96 values and is not a simple difference of the baseline and week 48 or week 96 mean values, respectively.

e Number of patients with LDL-cholesterol measured.

f   Fasting.

Laboratory Abnormalities in Treatment-Experienced Adult Patients:

The percentages of adult treatment-experienced patients treated with combination therapy, including atazanavir/ritonavir, and having Grade 3–4 laboratory abnormalities are presented in Table 16.

Table 16: Grade 3–4 laboratory abnormalities reported in ≥2% of adult treatment-experienced patients (Study AI424-045)a

Variable

Limitc

48 weeksb

atazanavir/ritonavir 300/100 mg once daily + tenofovir + NRTI

(n=119)

48 weeksb

lopinavir/ritonavir 400/100 mg twice dailyd + tenofovir + NRTI

(n=118)

Chemistry

High

 

 

  SGOT/AST

≥5.1 x ULN

3%

3%

  SGPT/ALT

≥5.1 x ULN

4%

3%

  Total bilirubin

≥2.6 x ULN

49%

<1%

  Lipase

≥2.1 x ULN

5%

6%

  Creatine kinase

≥5.1 x ULN

8%

8%

  Total cholesterol

≥240 mg/dL

25%

26%

  Triglycerides

≥751 mg/dL

8%

12%

  Glucose

≥251 mg/dL

5%

<1%

Hematology

Low

 

 

  Platelets

<50,000 cells/mm3

2%

3%

  Neutrophils

<750 cells/mm3

7%

8%

a Based on regimen(s) containing atazanavir.

b Median time on therapy.

c ULN = upper limit of normal.

d As a fixed-dose combination.

Lipids, Change from Baseline in Treatment-Experienced Adult Patients:

For Study AI424-045, changes from baseline in fasting LDL-cholesterol, HDL-cholesterol, total cholesterol, and fasting triglycerides are shown in Table 16. The observed magnitude of dyslipidemia was less with atazanavir/ritonavir than with lopinavir/ritonavir. However, the clinical impact of such findings has not been demonstrated.

Table 16: Lipid values, mean change from baseline (Study AI424-045)

 

Atazanavir/ritonavira,b

Lopinavir/ritonavirb,c

Baseline mg/dl

(n=111e)

Week 48 mg/dl

(n=75e)

Week 48 Changed

(n=74e)

Baseline mg/dl

(n=108e)

Week 48 mg/dl

(n=76e)

Week 48 Changed

(n=73e)

LDL-cholesterolf

108

98

–10%

104

103

+1%

HDL-cholesterol

40

39

–7%

39

41

+2%

Total cholesterol

188

170

–8%

181

187

+6%

Triglyceridesf

215

161

–4%

196

224

+30%

a atazanavir 300 mg once daily + ritonavir + tenofovir + 1 NRTI.

b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 4% in the lopinavir/ritonavir treatment arm and 4% in the atazanavir/ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 19% in the lopinavir/ritonavir treatment arm and 8% in the atazanavir/ritonavir arm.

c  Lopinavir/ritonavir (400/100 mg) b.i.d. + tenofovir + 1 NRTI.

d The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and week 48 values and is not a simple difference of the baseline and week 48 mean values.

e  Number of patients with LDL-cholesterol measured.

f   Fasting.

Adverse reactions in Patients Co-infected with Hepatitis B and/or Hepatitis C Virus:

In study AI424-138, 60 patients treated with atazanavir/ritonavir 300 mg/100 mg once daily, and 51 patients treated with lopinavir/ritonavir 400 mg/100 mg twice daily, each with fixed-dose tenofovir-emtricitabine, were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times the ULN developed in 10% (6/60) of the atazanavir/ritonavir-treated patients and 8% (4/50) of the lopinavir/ritonavir-treated patients. AST levels >5 times the ULN developed in 10% (6/60) of the atazanavir/ritonavir-treated patients and none (0/50) of the lopinavir/ritonavir-treated patients.

In study AI424-045, 20 patients treated with atazanavir/ritonavir 300 mg/l00 mg once daily, and 18 patients treated with lopinavir/ritonavir 400 mg/100 mg twice daily, were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times the ULN developed in 25% (5/20) of the atazanavir/ritonavir-treated patients and 6% (1/18) of the lopinavir/ritonavir-treated patients. AST levels >5 times the ULN developed in 10% (2/20) of the atazanavir/ritonavir-treated patients and 6% (1/18) of the lopinavir/ritonavir-treated patients. AST levels >5 times ULN developed in 10% (2/20) of the atazanavir/ritonavir-treated patients and 6% (1/18) of the lopinavir/ritonavir-treated patients.

Postmarketing experience

The following events given below have been identified during the postmarketing use of atazanavir. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: edema

Cardiovascular System: second-degree AV block, third-degree AV block, left bundle branch block, QTc prolongation (see WARNINGS AND PRECAUTIONS)

Hepatobilary Disorders: Cholelithiasis, cholecystitis, cholestasis

Gastrointestinal System: pancreatitis

Hepatic System: hepatic function abnormalities

Hepatobiliary Disorders: cholelithiasis , cholecystitis, cholestasis

Metabolic System and Nutrition Disorders: hyperglycemia, diabetes mellitus (see WARNINGS and PRECAUTIONS, Diabetes Mellitus/Hyperglycemia)

Musculoskeletal System: arthralgia

Renal System: nephrolithiasis (see WARNINGS and PRECAUTIONS, Nephrolithiasis), interstitial nephritis, granulomatous interstitial nephritis, chronic kidney disease

Skin and Appendages: alopecia, maculopapular rash (see WARNINGS and PRECAUTIONS, Rash), pruritus, angioedema

Emtricitabine/Tenofovir DF

The following are the adverse reactions:

  • Lactic Acidosis/Severe Hepatomegaly with Steatosis (see BOXED WARNING, WARNINGS  AND PRECAUTIONS)
  • Severe Acute Exacerbations of hepatitis B (see BOXED WARNING, WARNINGS AND PRECAUTIONS)
  • New Onset or Worsening Renal Impairment (see WARNINGS AND PRECAUTIONS)
  • Bone Bone Loss and Mineralization Defects (see WARNINGS AND PRECAUTIONS)
  • Immune Reconstitution Syndrome (see WARNINGS AND PRECAUTIONS)

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.

Adverse Reactions from Clinical Trials Experience HIV-1 Infected Subjects:

Clinical Trials in Adult Subjects

In Study 934, 511 antiretroviral-naïve subjects received efavirenz (EFV) administered in combination with either FTC+TDF (N=257) or zidovudine (AZT)/lamivudine (3TC) (N=254) for 144 weeks .The most common adverse reactions (incidence ≥ 10%, any severity) occurring in Study 934, an active-controlled clinical trial of efavirenz, emtricitabine, and tenofovir disoproxil fumarate, include diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. See also Table 15 for the frequency of treatment-emergent adverse reactions (Grade 2-4) occurring in ≥ 5% of patients treated with efavirenz, emtricitabine, and tenofovir disoproxil fumarate in this trial.

Skin discoloration, manifested by hyperpigmentation, occurred in 3% of subjects taking FTC+TDF, and was generally mild and asymptomatic. The mechanism and clinical significance are unknown.

Study 934 - Treatment Emergent Adverse Reactions: In Study 934, 511 antiretroviral naïve subjects received either tenofovir DF + emtricitabine administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254). Adverse reactions observed in this trial were generally consistent with those seen in other trials in treatment-experienced or treatment-naïve subjects receiving tenofovir DF and/or emtricitabine (Table 18).

Table 18: Selected Treatment-Emergent Adverse Reactionsa (Grades 2–4) Reported in ≥5% in Any Treatment Group in Study 934 (0–144 Weeks)

 

FTC + TDF + EFVb

AZT/3TC + EFV

 

N=257

N=254

Gastrointestinal Disorder

Diarrhea

Nausea

Vomiting

 

9%

9%

2%

 

5%

7%

5%

General Disorders and Administration Site Condition

Fatigue

 

 

9%

 

 

8%

Infections and Infestations

Sinusitis

Upper respiratory tract infections

Nasopharyngitis

 

8%

8%

5%

 

4%

5%

3%

Nervous System Disorders

Headache

Dizziness

 

6%

8%

 

5%

7%

Psychiatric Disorders

Depression

Insomnia

 

9%

5%

 

7%

7%

Skin and Subcutaneous Tissue Disorders

Rash eventc

 

7%

 

9%

a Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug.

b From Weeks 96 to 144 of the trial, subjects received emtricitabine/tenofovir DF with efavirenz in place of Tenofovir DF + Emtricitabine with efavirenz.

c Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular.

Laboratory Abnormalities:

Laboratory abnormalities observed in this trial were generally consistent with those seen in other trials of emtricitabine/ tenofovir DF (Table 19).

Table 19: Significant Laboratory Abnormalities Reported in ≥1% of Subjects in Any Treatment Group in Study 934 (0–144 Weeks)

 

FTC + TDF + EFVa

AZT/3TC + EFV

N=257

N=254

Any ≥ Grade 3 Laboratory Abnormality

30%

26%

Fasting Cholesterol (>240mg/dL)

22%

24%

Creatinine Kinase

(M: >990 U/L)

(F: >845 U/L)

 

9%

 

7%

Serum Amylase (>175 U/L)

8%

4%

Alkaline Phosphatase (>550 U/L)

1%

0%

AST

(M: >180 U/L)

(F: >170 U/L)

 

3%

 

3%

ALT

(M: >215 U/L)

(F: >170 U/L)

2%

3%

Hemoglobin (<8.0 mg/dL)

0%

4%

Hyperglycemia (>250 mg/dL)

2%

1%

Hematuria (>75 RBC/HPF)

3%

2%

Glycosuria (≥ 3+)

< 1%

1%

Neutrophils (<750/mm3)

3%

5%

Fasting Triglycerides (>750 mg/dL)

4%

2%

a From Weeks 96 to 144 of the trial, subjects received emtricitabine/ tenofovir DF with efavirenz in place of Tenofovir DF + Emtricitabine with efavirenz.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of tenofovir. No additional adverse reactions have been identified during postapproval use of emtricitabine. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causual relationship to drug exposure.

Immune system disorders: allergic reaction, including angiodema

Metabolism and nutrition disorders: lactic acidosis, hypokalemia, hypophosphatemia

Respiratory, thoracic, and mediastinal disorders: dyspnea

Gastrointestinal disorders: pancreatitis, increased amylase, abdominal pain

Hepatobiliary Disorders: hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT)

Skin and Subcutaneous Tissue Disorders: rash

Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy

Renal and Urinary disorders: acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria.

General Disorders and Administration Site Conditions: asthenia

The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

Ritonavir

The following adverse reactions are discussed in greater detail in other sections of the labeling.

  • Drug Interactions
  • Hepatotoxicity
  • Pancreatitis
  • Allergic Reactions/Hypersensitivity

When co-administering ritonavir with other protease inhibitors, see the full prescribing information for that protease inhibitor including adverse reactions.

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions 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.

Adverse Reactions in Adults

The safety of ritonavir alone and in combination with other antiretroviral agents was studied in 1,755 adult patients. Table 19 lists treatment-emergent Adverse Reactions (with possible or probable relationship to study drug) occurring in greater than or equal to 1% of adult patients receiving ritonavir in combined Phase II/IV studies.

The most frequently reported adverse drug reactions among patients receiving ritonavir alone or in combination with other antiretroviral drugs were gastrointestinal (including diarrhea, nausea, vomiting, abdominal pain (upper and lower)), neurological disturbances (including paresthesia and oral paresthesia), rash, and fatigue/asthenia.

Table 19: Treatment-Emergent Adverse Reactions (With Possible or Probable Relationship to Study Drug) Occurring in greater than or equal to 1% of Adult Patients Receiving ritonavir in Combined Phase II/IV Studies (N = 1,755)

Adverse Reactions

n

%

Eye disorders

 

 

Blurred vision

113

6.4

Gastrointestinal disorders

 

 

Abdominal Pain (upper and lower)*

464

26.4

Diarrhea including severe with electrolyte imbalance*

1,192

67.9

Dyspepsia

201

11.5

Flatulence

142

8.1

Gastrointestinal hemorrhage*

41

2.3

Gastroesophageal reflux disease (GERD)

19

1.1

Nausea

1,007

57.4

Vomiting*

559

31.9

General disorders and administration site conditions

 

 

Fatigue including asthenia*

811

46.2

 

 

 

Hepatobiliary disorders

 

 

Blood bilirubin increased (including jaundice)*

25

1.4

Hepatitis (including increased AST, ALT, GGT)*

153

8.7

Immune system disorders

 

 

Hypersensitivity including urticaria and face edema*

114

8.2

Metabolism and nutrition disorders

 

 

Edema and peripheral edema*

110

6.3

Gout*

24

1.4

Hypercholesterolemia*

52

3.0

Hypertriglyceridemia*

158

9.0

Lipodystrophy acquired*

51

2.9

Edema and peripheral edema*

110

6.3

Musculoskeletal and connective tissue disorders

 

 

Arthralgia and back pain*

326

18.6

Myopathy/creatine phosphokinase increased*

66

3.8

Myalgia

156

8.9

Nervous system disorders

 

 

Dizziness*

274

15.6

Dysgeusia*

285

16.2

Paresthesia (including oral paresthesia)*

889

50.7

Peripheral neuropathy

178

10.1

Syncope*

58

3.3

Psychiatric disorders

 

 

Confusion*

52

3.0

Disturbance in attention

44

2.5

Renal and urinary disorders

 

 

Increased urination*

74

4.2

Respiratory, thoracic and mediastinal disorders

 

 

Coughing*

380

21.7

Oropharyngeal Pain*

279

15.9

Skin and subcutaneous tissue disorders

 

 

Acne*

67

3.8

Pruritus*

214

12.2

Rash (includes erythematous and maculopapular)*

475

27.1

Vascular disorders

 

 

Flushing, feeling hot*

232

13.2

Hypertension*

58

3.3

Hypotension including orthostatic hypotension*

30

1.7

Peripheral coldness*

21

1.2

 

 

 

* Represents a medical concept including several similar MedDRA PTs

Postmarketing Experience

The following adverse events (not previously mentioned in the labeling) have been reported during post-marketing use of ritonavir. Because these reactions are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to ritonavir exposure.

Body as a Whole

Dehydration, usually associated with gastrointestinal symptoms, and sometimes resulting in hypotension, syncope, or renal insufficiency has been reported. Syncope, orthostatic hypotension, and renal insufficiency have also been reported without known dehydration.

Co-administration of ritonavir with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system.

Cardiovascular System

First-degree AV block, second-degree AV block, third-degree AV block, right bundle branch block have been reported .

Cardiac and neurologic events have been reported when ritonavir has been co-administered with disopyramide, mexiletine, nefazodone, fluoxetine, and beta blockers. The possibility of drug interaction cannot be excluded.

Endocrine System

Cushing's syndrome and adrenal suppression have been reported when ritonavir has been co-administered with fluticasone propionate or budesonide.

Nervous System

There have been postmarketing reports of seizure. Also, see Cardiovascular System.

Skin and subcutaneous tissue disorders

Toxic epidermal necrolysis (TEN) has been reported.

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024.  

By reporting side effects you can help provide more information on the safety of this product

Overdosage

If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.

Atazanavir

Human experience of acute overdose with atazanavir is limited. Single doses up to 1200 mg have been taken by healthy volunteers without symptomatic untoward effects. A single self-administered overdose of 29.2 g of atazanavir in an HIV-infected patient (73 times the 400 mg recommended dose) was associated with asymptomatic bifascicular block and PR interval prolongation. These events resolved spontaneously. At atazanavir doses resulting in high drug exposures, jaundice due to indirect (unconjugated) hyperbilirubinemia (without associated liver function test changes) or PR interval prolongation may be observed (see WARNINGS and PRECAUTIONS; PHARMACOLOGY, Pharmacodynamics, Effects on Electrocardiogram).

Treatment of overdosage with atazanavir should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patient’s clinical status. If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of the unabsorbed drug. There is no specific antidote for overdose with atazanavir.  Since atazanavir is extensively metabolized by the liver and is highly protein-bound, dialysis is unlikely to be beneficial in significant removal of this medicine.

Ritonavir (Full dose)

Acute overdosage – Human Overdose Experience

Human experience of acute overdose with ritonavir is limited. in clinical trials, 1 patient took ritonavir 1500 mg/day for 2 days.The patient reported paresthesias, which resolved after the dose was decreased. A post-marketing case of renal failure with eosinophilia has been reported with ritonavir overdose.The approximate lethal dose was found to be greater than 20 times the related human dose in rats and 10 times the related human dose in mice.

Management of overdosage

Treatment of overdose with ritonavir consists of general supportive measures, including monitoring of vital signs and observation of the clinical status of the patient.  There is no specific antidote for overdose with ritonavir.  If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway.  Administration of activated charcoal may also be used to aid in removal of unabsorbed drug.  Since ritonavir is extensively metabolized by the liver and is highly protein-bound, dialysis is unlikely to be beneficial in significant removal of the drug.

TDF/FTC

If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.

Emtricitabine

Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis.

Tenofovir DF

Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of tenofovir DF, a 4-hour haemodialysis session removed approximately 10% of the administered tenofovir dose.

Packaging Information

QVIR Kit ……….Carton containing 10 kits

Last Updated: Dec 2018

Last Reviewed: Dec 2018