RITOMUNE Tablets (Ritonavir)

Table of Content

Black Box Warning: Drug-Drug Interactions Leading to Potentially Serious and/or Life Threatening Reactions

Co-administration of Ritomune with several classes of drugs including sedative hypnotics, antiarrhythmics, or ergot alkaloid preparations may result in potentially serious and/or life-threatening adverse events due to 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 .

Composition

Each tablet contains
Ritonavir ……..100 mg

Description

Ritonavir is an inhibitor of HIV protease with activity against the Human Immunodeficiency Virus (HIV).

Pharmacology

Pharmacodynamics

Ritonavir is a peptidomimetic inhibitor of the HIV-1protease. 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.

Pharmacokinetics

The pharmacokinetics of ritonavir has been studied in healthy volunteers and HIV-infected patients (CD 4 ≥ 50 cells/ μL). See Table 1 for ritonavir pharmacokinetic characteristics.

Absorption

The absolute bioavailability of ritonavir has not been determined. After a 600 mg dose of oral solution, peak concentrations of ritonavir were achieved approximately 2 hours and 4 hours after dosing under fasting and non-fasting conditions (514 Kcal; 9% fat, 12% protein, and 79% carbohydrate) conditions, respectively.

Ritonavir tablets are not bioequivalent to ritonavir capsules. 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 C max was increased by 26% (92.8% confidence intervals: ↑15 - ↑39%).

No information is available comparing ritonavir tablets to ritonavir capsules under fasting conditions.

Effect of Food on Oral Absorption

When the oral solution was given under non-fasting conditions, peak ritonavir concentrations decreased 23% and the extent of absorption decreased 7% relative to fasting conditions. Dilution of the oral solution, within one hour of administration, with 240 mL of chocolate milk did not significantly affect the extent and rate of ritonavir absorption. Administration of a single 600 mg dose oral solution under non-fasting conditions yielded mean ± SD areas under the plasma concentration-time curve (AUCs) of 129.0 ± 39.3 mg•h/mL.

A food effect is observed for ritonavir tablets. Food decreased the bioavailability of the ritonavir tablets when a single 100 mg dose of ritonavir was administered. Under high fat conditions (907 kcal; 52% fat, 15% protein, 33% carbohydrates), a 23% decrease in mean AUC (0-∞) , and a 23% decrease in mean C max ) was observed relative to fasting conditions. Under moderate fat conditions, a 21% decrease in mean AUC (0-∞) , and a 22% decrease in mean C max ) was observed relative to fasting conditions.

However, the type of meal administered did not change ritonavir tablet bioavailability when high fat was compared to moderate fat meals.

Metabolism

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

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 that 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.

 Table 1: Ritonavir pharmacokinetic characteristics

Parameter

N

Values (Mean ± SD)

V β/F

91

0.41 ± 0.25 L/kg

t ½

 

3 - 5 h

CL/F SS

10

8.8 ± 3.2 L/h

CL/F

91

4.6 ± 1.6 L/h

CL R

62

< 0.1 L/h

RBC/Plasma Ratio

 

0.14

Percent Bound *

 

98 to 99%

SS = steady state; patients taking ritonavir 600 mg q12h.

Single ritonavir 600 mg dose.

* Primarily bound to human serum albumin and alpha-1 acid glycoprotein over the ritonavir concentration range of 0.01 to 30 μg/mL.

Effects on Electrocardiogram

QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once-daily) controlled 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 .

Special Populations

Gender, Race and Age

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

A study of ritonavir pharmacokinetics in healthy males and females showed no statistically significant differences in the pharmacokinetics of ritonavir. Pharmacokinetic differences due to race have not been identified.

Renal Impairment

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.

Hepatic Impairment

Dose-normalized steady-state ritonavir concentrations in subjects with mild hepatic impairment (400 mg twice-daily, n = 6) were similar to those in control subjects dosed with 500 mg twice-daily. Dose-normalized steady-state ritonavir exposures in subjects with moderate hepatic impairment (400 mg twice-daily, n= 6) were about 40% lower than those in subjects with normal hepatic function (500 mg twice-daily, n = 6). Protein binding of ritonavir was not statistically significantly affected by mild or moderately impaired hepatic function. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. However, health care providers should be aware of the potential for lower ritonavir concentrations in patients with moderate hepatic impairment and should monitor patient response carefully. Ritonavir has not been studied in patients with severe hepatic impairment.

Indications

RITOMUNE Tablet is indicated in combination with other antiretroviral agents for the treatment of HIV-infection.

Dosage and Administration

RITOMUNE is administered orally. Ritonavir tablets should be swallowed whole, and not chewed, broken or crushed. Take ritonavir with meals.

General Dosing Guidelines

Patients who take the 600 mg twice daily soft gel capsule ritonavir dose may experience more gastrointestinal side effects such as nausea, vomiting, abdominal pain or diarrhea when switching from the soft gel capsule to the tablet formulation because of greater maximum plasma concentration (C max) achieved with the tablet formulation relative to the soft gel capsule. Patients should also be aware that these adverse events (gastrointestinal or paresthesias) may diminish as therapy is continued.

Dose Modification for Ritonavir

Dose reduction of ritonavir is necessary when used with other protease inhibitors: atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir.

Prescribers should consult the full prescribing information and clinical study information of these protease inhibitors if they are coadministered with a reduced dose of ritonavir .

Adults

Recommended Dosage for Treatment of HIV-1

The recommended dosage of ritonavir is 600 mg twice daily by mouth to be taken with meals. Use of a dose titration schedule may help to reduce treatment-emergent adverse events while maintaining appropriate ritonavir plasma levels. Ritonavir should be started at no less than 300 mg twice daily and increased at 2 to 3 day intervals by 100 mg twice daily. The maximum dose of 600 mg twice daily should not be exceeded upon completion of the titration.

Contraindications

  • When co-administering ritonavir with other protease inhibitors, see the full prescribing information for that protease inhibitor including contraindication information.
  • Ritonavir is contraindicated in patients with known hypersensitivity (e.g. toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome) to ritonavir or any of its ingredients.
  • Co-administration of ritonavir with several classes of drugs (including sedative hypnotics, antiarrhythmics, or ergot alkaloid preparations) is contraindicated and may result in potentially serious and/or life-threatening adverse events due to possible effects of ritonavir on the hepatic metabolism of these drugs (see Table 2). Voriconazole and St. John’s Wort are exceptions in that co-administration of ritonavir and voriconazole results in a significant decrease in plasma concentrations of voriconazole, and co-administration of ritonavir with St. John’s Wort may result in decreased ritonavir plasma concentrations.

Table 2: Drugs that are contraindicated with Ritonavir

Drug Class

Drugs Within Class That Are Contraindicated With Ritonavir **

Clinical Comments

Alpha 1­adrenoreceptor antagonist

Alfuzosin HCL

Potential for hypotension.

Antiarrhythmics

Amiodarone, flecainide, propafenone, quinidine

Potential for cardiac arrhythmias.

Antifungal

Voriconazole

Coadministration of voriconazole with ritonavir 400 mg every 12 hours significantly decreases voriconazole plasma concentrations and may lead to loss of antifungal response. Voriconazole is contraindicated with ritonavir doses of 400 mg every 12 hours or greater .

Ergot Derivatives

Dihydroergotamine, ergotamine, methylergonovine

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

GI Motility Agent

Cisapride

Potential for cardiac arrhythmias.

Herbal Products

St. John's Wort (hypericum perforatum)

Co-administration of ritonavir with St. John’s Wort may result in decreased ritonavir plasma concentrations and may lead to loss of virologic response and possible resistance to ritonavir or to the class of protease inhibitors.

HMG-CoA Reductase Inhibitors:

Lovastatin, simvastatin

Potential for myopathy including rhabdomyolysis.

Neuroleptic

Pimozide

Potential for cardiac arrhythmias.

PDE5 enzyme inhibitor

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

A safe and effective dose has not been established when used with ritonavir. There is an increased potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope .

Sedative/hypnotics

Oral midazolam, triazolam

Prolonged or increased sedation or respiratory depression .

* see WARNINGS AND PRECAUTIONS - Drug Interactions for co-administration of sildenafil in patients with erectile dysfunction.

** For additional information for these contraindicated drugs, see also WARNINGS AND PRECAUTIONS - Drug Interactions

Warnings and Precautions

Drug Interactions

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 (greater than 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 4.

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 3 provides a list of established or potentially clinically significant drug interactions. Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction.

Table 3. Established and oher potentially significant drug interactions

Concomitant Drug Class: Drug Name

Effect on Concentration of Ritonavir or Concomitant Drug

Clinical Comment

HIV-Antiviral Agents

HIV-1 Protease Inhibitor: atazanavir

When co-administered with reduced doses of atazanavir and ritonavir

↑ atazanavir (↑ AUC, ↑ C max, ↑ C min)

Atazanavir plasma concentrations achieved with atazanavir 300 mg once daily and ritonavir 100 mg once daily are higher than those achieved with atazanavir 400 mg once daily. See the complete prescribing information for atazanavir for details on co­administration of atazanavir 300 mg once daily with ritonavir 100 mg once daily.

HIV-1 Protease Inhibitor: darunavir

When co-administered with reduced doses of ritonavir

↑ darunavir (↑ AUC, ↑ C max, ↑ C min)

See the complete prescribing information for darunavir for details on co-administration of darunavir 600 mg twice daily with ritonavir 100 mg twice daily or darunavir 800 mg once daily with ritonavir 100 mg once daily.

HIV-1 Protease Inhibitor: fosamprenavir

When co-administered with reduced doses of ritonavir

↑ amprenavir (↑ AUC, ↑ C max, ↑ C min)

See the complete prescribing information for fosamprenavir for details on co-administration of fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily, fosamprenavir 1400 mg once daily with ritonavir 200 mg once daily or fosamprenavir 1400 mg once daily with ritonavir 100 mg once daily.

HIV-1 Protease Inhibitor: indinavir

When co-administered with reduced doses of indinavir and ritonavir

↑ indinavir (↔ AUC, ↓ C max, ↑ C min)

Alterations in concentrations are noted when reduced doses of indinavir are co-administered with ritonavir.

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

HIV-1 Protease Inhibitor: saquinavir

When co-administered with reduced doses of ritonavir

↑ saquinavir (↑ AUC, ↑ C max, ↑ C min)

See the complete prescribing information for saquinavir for details on co-administration of saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily.

Saquinavir/ritonavir should not be given together with rifampin, due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together.

HIV-1 Protease Inhibitor: tipranavir

When co-administered with reduced doses of ritonavir

↑ tipranavir (↑ AUC, ↑ C max, ↑ C min)

See the complete prescribing information for tipranavir for details on co-administration of tipranavir 500 mg twice daily with ritonavir 200 mg twice daily. There have been reports of clinical hepatitis and hepatic decompensation including some fatalities. All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co­-infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed prior to initiating therapy with tipranavir/ritonavir, and frequently throughout the duration of treatment.

Non-Nucleoside Reverse Transcriptase Inhibitor: delavirdine

↑ ritonavir (↑ AUC, ↑ C max, ↑ C min)

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

HIV-1 CCR5 – antagonist: maraviroc

↑ maraviroc

Concurrent administration of maraviroc with ritonavir will increase plasma levels of maraviroc. For specific dosage adjustment recommendations, please refer to the complete prescribing information for maraviroc.

Integrase 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

 

A dose decrease may be needed for these drugs when co-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

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

Concentrations of these drugs may be increased when co­-administered with ritonavir resulting in the potential for increased adverse events usually associated with these 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

↓ R-warfarin

↓↑ S-warfarin

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

Anticoagulant:

rivaroxaban

↑ rivaroxaban

Avoid concomitant use of rivaroxaban and ritonavir. Co-administration of ritonavir and rivaroxaban is expected to result in increased exposure of rivaroxaban which may lead to risk of increased bleeding.

Anticonvulsants: carbamazepine, clonazepam, ethosuximide

↑ anticonvulsants

Use with caution. 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

Use with caution. 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

Concurrent administration of bupropion with ritonavir may decrease plasma levels of both bupropion and its 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

Concomitant use of trazodone and ritonavir increases plasma concentrations of trazodone. Adverse events of 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 ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.

Antiemetic: dronabinol

↑ dronabinol

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

Antifungal: ketoconazole itraconazole voriconazole

↑ ketoconazole

↑ itraconazole

↓ voriconazole

High doses of ketoconazole or itraconazole (greater than 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

Patients with renal or hepatic impairment should not be given colchicine with ritonavir.

 

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

0.6 mg (one tablet) for one dose, followed by 0.3 mg (half tablet) one hour later. Dose to be repeated no earlier than three 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 the following dosage adjustments should be considered:

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

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

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 (see Antimycobacterial: rifabutin, for dose reduction recommendations).

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:

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-Protease Inhibitor: simeprevir

↑ simeprevir

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

HMG-CoA Reductase Inhibitor: atorvastatin rosuvastatin

↑ atorvastatin

↑ rosuvastatin

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.

Inhaled or Intranasal Steroid e.g.: fluticasone

budesonide

↑ glucocorticoids

Concomitant use of ritonavir and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid side effects. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations.

Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when ritonavir has been coadministered with fluticasone propionate or budesonide.

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.

Narcotic Analgesic: methadone

fentanyl

↓ methadone

↑ fentanyl

Dosage increase of methadone may be considered. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with ritonavir.

Neuroleptics: perphenazine, risperidone, thioridazine

↑ neuroleptics

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

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

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 when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with ritonavir .

 

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

Co-administration of oral midazolam with ritonavir is CONTRAINDICATED. Concomitant use of parenteral midazolam with ritonavir 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.

Steroids (systemic) e.g.: budesonide, dexamethasone, prednisone

↑ glucocorticoids

Concomitant use of glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. This may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.

Stimulant: methamphetamine

↑ methamphetamine

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

Risk of Serious Adverse Reactions Due to Drug Interactions

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

See Table 5 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during ritonavir therapy; review concomitant medications during ritonavir therapy, and monitor for the adverse reactions associated with the concomitant medications .

Hepatic Reactions

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 transaminases 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 post-marketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients taking multiple concomitant medications and/or with advanced AIDS.

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.

Allergic Reactions/Hypersensitivity

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

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, preexisting 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. .

Lipid Disorders

Treatment with ritonavir therapy alone or in combination with saquinavir has resulted in substantial increases in the concentration of total cholesterol and triglycerides . Triglyceride 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 .

Diabetes Mellitus/Hyperglycaemia

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during post-marketing 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.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including ritonavir. 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.

Fat Redistribution

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

Patients with 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

Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of ritonavir 600 mg twice daily following loss of viral suppression may increase the likelihood of cross-resistance to other protease 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.

Pregnancy

Pregnancy Category B:

Human Data

There are no adequate and well-controlled studies in pregnant women. Ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk of the fetus.

Animal Data

No treatment related malformations were observed when ritonavir was administered to pregnant rats or rabbits. Developmental toxicity observed in rats (early resorptions, decreased fetal body weight and ossification delays and developmental variations) occurred at a maternally toxic dosage at an exposure equivalent to approximately 30% of that achieved with the proposed therapeutic dose. A slight increase in the incidence of cryptorchidism was also noted in rats at an exposure approximately 22% of that achieved with the proposed therapeutic dose.

Developmental toxicity observed in rabbits (resorptions decreased litter size and decreased fetal weights) also occurred at a maternally toxic dosage equivalent to 1.8 times the proposed therapeutic dose based on a body surface area conversion factor.

Lactation

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. It is not known whether ritonavir is secreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving ritonavir.

Pediatric Use

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.

Geriatric Use

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.

Hepatic Impairment

No dose adjustment of ritonavir is necessary for patients with either mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding the use of ritonavir in subjects with severe hepatic impairment (Child-Pugh class C), therefore, ritonavir is not recommended for use in patients with severe hepatic impairment .

Undesirable Effects

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 4 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 4. 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

 

 

Hypersensivity including urticatria 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

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

Laboratory Abnormalities in Adults

Table 5 shows the percentage of adult patients who developed marked laboratory abnormalities.

Table 5. Percentage of adult patients, by study and treatment group, with chemistry and hematology abnormalities occurring in greater than 3% of patients receiving ritonavir

 

 

Study 245 Naive Patients

Study 247 Advanced Patients

Study 462 PI-Naive Patients

Variable

Limit

Ritonavir plus ZDV

Ritonavir

ZDV

Ritonavir

Placebo

Ritonavir plus Saquinavir

Chemistry

High

 

 

 

 

 

 

Cholesterol

> 240 mg/dL

30.7

44.8

9.3

36.5

8.0

65.2

CPK

> 1000 IU/L

9.6

12.1

11.0

9.1

6.3

9.9

GGT

> 300 IU/L

1.8

5.2

1.7

19.6

11.3

9.2

SGOT (AST)

> 180 IU/L

5.3

9.5

2.5

6.4

7.0

7.8

SGPT (ALT)

> 215 IU/L

5.3

7.8

3.4

8.5

4.4

9.2

Triglycerides

> 800 mg/dL

9.6

17.2

3.4

33.6

9.4

23.4

Triglycerides

> 1500 mg/dL

1.8

2.6

-

12.6

0.4

11.3

Triglycerides Fasting

> 1500 mg/dL

1.5

1.3

-

9.9

0.3

-

Uric Acid

> 12 mg/dL

-

-

-

3.8

0.2

1.4

Hematology

Low

 

 

 

 

 

 

Hematocrit

< 30%

2.6

-

0.8

17.3

22.0

0.7

Hemoglobin

< 8.0 g/dL

0.9

-

-

3.8

3.9

-

Neutrophils

≤ 0.5 x 10 9/L

-

-

-

6.0

8.3

-

RBC

< 3.0 x 10 12/L

1.8

-

5.9

18.6

24.4

-

WBC

< 2.5 x 10 9/L

-

0.9

6.8

36.9

59.4

3.5

- Indicates no events reported.

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 co­administered 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.

Overdosage

Acute Overdosage - Human Overdose Experience

Human experience of acute overdose with ritonavir is limited. One patient in clinical trials took ritonavir 1500 mg/day for two 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 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. A Certified Poison Control Center should be consulted for up-to-date information on the management of overdose with ritonavir.

Packaging Information

RITOMUNE Tablets……Bottle of 60 tablets

Last Updated: Mar 2015
Last Reviewed: Jun  2015