RITONAVIR
WARNING
CO-ADMINISTRATION OF RITONAVIR WITH CERTAIN NONSEDATING ANTIHISTAMINES, 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. SEE CONTRAINDICATIONS AND PRECAUTIONS SECTIONS.
DESCRIPTION
Ritonavir is an inhibitor of HIV protease with activity against the Human Immunodeficiency Virus (HIV).
Ritonavir is chemically designated as 10-Hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3, 6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)]. Its molecular formula is C 37 H 48 N 6 O 5 S 2 , and its molecular weight is 720.95.
Ritonavir is a white-to-light-tan powder. Ritonavir has a bitter metallic taste. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water.
RITONAVIR soft gelatin capsules are available for oral administration in a strength of 100 mg ritonavir with the following inactive ingredients: Butylated hydroxytoluene, ethanol, gelatin, iron oxide, oleic acid, polyoxyl 35 castor oil, and titanium dioxide.
RITONAVIR oral solution is available for oral administration as 80 mg/mL of ritonavir in a peppermint and caramel flavored vehicle. Each 8-ounce bottle contains 19.2 grams of ritonavir. RITONAVIR oral solution also contains ethanol, water, polyoxyl 35 castor oil, propylene glycol, anhydrous citric acid to adjust pH, saccharin sodium, peppermint oil, creamy caramel flavoring, and FD&C Yellow No. 6.
CLINICAL PHARMACOLOGY
Microbiology
Mechanism of action : Ritonavir is a peptidomimetic inhibitor of both the HIV-1 and HIV-2 proteases. 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.
Antiviral activity in vitro : The activity of ritonavir was assessed in vitro in acutely infected lymphoblastoid cell lines and in peripheral blood lymphocytes. The concentration of drug that inhibits 50% (EC 50 ) of viral replication ranged from 3.8 to 153 nM depending upon the HIV-1 isolate and the cells employed. The average EC 50 for low passage clinical isolates was 22 nM (n=13). In MT 4 cells, ritonavir demonstrated additive effects against HIV-1 in combination with either zidovudine (ZDV) or didanosine (ddI). Studies which measured cytotoxicity of ritonavir on several cell lines showed that >20 µM was required to inhibit cellular growth by 50% resulting in an in vitro therapeutic index of at least 1000.
Resistance : HIV-1 isolates with reduced susceptibility to ritonavir have been selected in vitro . Genotypic analysis of these isolates showed mutations in the HIV protease gene at amino acid positions 84 (Ile to Val), 82 (Val to Phe), 71 (Ala to Val), and 46 (Met to Ile). Phenotypic (n=18) and genotypic (n=44) changes in HIV isolates from selected patients treated with ritonavir were monitored in phase I/II trials over a period of 3 to 32 weeks. Mutations associated with the HIV viral protease in isolates obtained from 41 patients appeared to occur in a stepwise and ordered fashion; in sequence, these mutations were position 82 (Val to Ala/Phe), 54 (Ile to Val), 71 (Ala to Val/Thr), and 36 (Ile to Leu), followed by combinations of mutations at an additional 5 specific amino acid positions. Of 18 patients for which both phenotypic and genotypic analysis were performed on free virus isolated from plasma, 12 showed reduced susceptibility to ritonavir in vitro . All 18 patients possessed one or more mutations in the viral protease gene. The 82 mutation appeared to be necessary but not sufficient to confer phenotypic resistance. Phenotypic resistance was defined as a >/=5-fold decrease in viral sensitivity in vitro from baseline. The clinical relevance of phenotypic and genotypic changes associated with ritonavir therapy has not been established.
Cross-resistance to other antiretrovirals : Among protease inhibitors variable cross-resistance has been recognized. Serial HIV isolates obtained from six patients during ritonavir therapy showed a decrease in ritonavir susceptibility in vitro but did not demonstrate a concordant decrease in susceptibility to saquinavir in vitro when compared to matched baseline isolates. However, isolates from two of these patients demonstrated decreased susceptibility to indinavir in vitro (8-fold). Isolates from 5 patients were also tested for cross-resistance to amprenavir and nelfinavir; isolates from 2 patients had a decrease in susceptibility to nelfinavir (12- to 14-fold), and none to amprenavir. Cross-resistance between ritonavir and reverse transcriptase inhibitors is unlikely because of the different enzyme targets involved. One ZDV-resistant HIV isolate tested in vitro retained full susceptibility to ritonavir.
Pharmacokinetics
The pharmacokinetics of ritonavir have been studied in healthy volunteers and HIV-infected patients (CD 4 >/= 50 cells/µL). See Table 1 for ritonavir pharmacokinetic characteristics.
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 (514 KCal; 9% fat, 12% protein, and 79% carbohydrate) conditions, respectively. 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, Advera® or Ensure® did not significantly affect the extent and rate of ritonavir absorption. After a single 600 mg dose under non-fasting conditions, in two separate studies, the soft gelatin capsule (n=57) and oral solution (n=18) formulations yielded mean ± SD areas under the plasma concentration-time curve (AUCs) of 121.7 ± 53.8 and 129.0 ± 39.3 µg·h/mL, respectively. Relative to fasting conditions, the extent of absorption of ritonavir from the soft gelatin capsule formulation was 13% higher when administered with a meal (615 KCal; 14.5% fat, 9% protein, and 76% carbohydrate).
Nearly all of the plasma radioactivity after a single oral 600 mg dose of 14 C-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.
In a study of five subjects receiving a 600 mg dose of 14 C-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)
C max SS ** 10 11.2 ± 3.6 µg/mL
C trough SS ** 10 3.7 ± 2.6 µg/mL
V beta /F *** 91 0.41 ± 0.25 L/kg
t 1/2 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.
The pharmacokinetic profile of ritonavir in pediatric patients below the age of 2 years has not been established. Steady-state pharmacokinetics were evaluated in 37 HIV-infected patients ages 2 to 14 years receiving doses ranging from 250 mg/m 2 b.i.d. to 400 mg/m 2 b.i.d. Across dose groups, ritonavir steady-state oral clearance (CL/F/m 2 ) was approximately 1.5 times faster in pediatric patients than in adult subjects. Ritonavir concentrations obtained after 350 to 400 mg/m 2 twice daily in pediatric patients were comparable to those obtained in adults receiving 600 mg (approximately 330 mg/m 2 ) twice daily.
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 Insufficiency : Ritonavir pharmacokinetics have not been studied in patients with renal insufficiency; however, since renal clearance is negligible, a decrease in total body clearance is not expected in patients with renal insufficiency.
Hepatic Insufficiency : Ritonavir pharmacokinetics have not been studied in subjects with hepatic insufficiency (see PRECAUTIONS ).
Drug-Drug Interactions : Table 2 summarizes the effects on AUC and C max , with 95% confidence intervals (95% CI), of co-administration of ritonavir with a variety of drugs. For information about clinical recommendations see PRECAUTIONS -- Drug Interactions .
Table 2
Effects of Co-administered Drug on Ritonavir Plasma AUC and C max Effect on Ritonavir
Co-administered Dose of Co-administered Dose of Ritonavir
Drug Drug (mg) (mg) n AUC % (95% CI) C max % (95% CI)
Clarithromycin 500 mg q12h 4 d 200 mg q8h 4 d 22 up 12% (2, 23%) up 15% (2, 28%)
Didanosine 200 mg q12h 4 d 600 mg q12h 4 d 12 <-> <->
Fluconazole 400 mg day 1, 200 mg daily 4 d 200 mg q6h 4 d 8 up 12% (5, 20%) up 15% (7, 22%)
Fluoxetine 30 mg q12h 8 d 600 mg single d 16 up 19% (7, 34%) <->
Ketoconazole 200 mg daily 7 d 500 mg q12h 10 d 12 up 18% (-3, 52%) up 10% (-11, 36%)
Rifampin 600 mg or 300 mg daily 10 d 500 mg q12h 20 d 7,9 * down 35% (7, 55%) down 25% (-5, 46%)
Zidovudine 200 mg q8h 4 d 300 mg q6h 4 d 10 <-> <->
Effects of Ritonavir on Co-administered Drug Plasma AUC and C max
Co-administered Dose of Co-administered Dose of Ritonavir
Drug Drug (mg) (mg) n AUC % (95% CI) C max % (95% CI)
Alprazolam 1 mg single dose 500 mg q12h 10 d 12 down 12% (-5, 30%) down 16% (5, 27%)
Clarithromycin 500 mg q12h 4 d 200 mg q8h 4 d 22 up 77% (56, 103%) up 31% (15, 51%)
14-OH clarithromycin metabolite down 100% down 99%
Desipramine 100 mg single dose 500 mg q12h 12 d 14 up 145% (103, 211%) up 22% (12, 35%)
2-OH desipramine metabolite down 15% (3, 26%) down 67% (62, 72%)
Didanosine 200 mg q12h 4 d 600 mg q12h 4 d 12 down 13% (0, 23%) down 16% (5, 26%)
Ethinyl estradiol 50 µg single dose 500 mg q12h 16 d 23 down 40% (31, 49%) down 32% (24, 39%)
Indinavir 400 mg q12h 15 Day 400 mg q12h 15 d 10 up 6% (-14, 29%) down 51% (40, 61%)
Indinavir 400 mg q12h Day 15 1 400 mg q12h 15 d 10 down 7% (-25, 16%) down 62% (52, 70%)
Ketoconazole 200 mg daily 7 d 500 mg q12h 10 d 12 up 3.4-fold (2.8, 4.3X) up 55% (40, 72%)
Meperidine 50 mg oral single dose 500 mg q12h 10 d 8 down 62% (59, 65%) down 59% (42, 72%)
Normeperidine metabolite 6 up 47% (-24, 345%) up 87% (42, 147%)
Methadone 5 mg single dose 2 500 mg q12h 15 d 11 down 36% (16, 52%) down 38% (28, 46%)
Rifabutin 150 mg daily 16 d 500 mg q12h 10 d 5,11 * up 4-fold (2.8, 6.1X) up 2.5-fold (1.9, 3.4X)
25-O-desacetyl rifabutin metabolite up 35-fold (25, 78X) up 16-fold (14, 20X)
Saquinavir 400 mg bid steady-state 3 400 mg bid steady-state 7 up 17-fold (9, 31X) up 14-fold (7, 28X)
Sildenafil 100 mg single dose 500 mg bid 8 d 28 up 11-fold up 4-fold
Sulfamethoxazole 800 mg single dose 4 500 mg q12h 12 d 15 down 20% (16, 23%) <->
Theophylline 3 mg/kg q8h 15 d 500 mg q12h 10 d 13,11 * down 43% (42, 45%) down 32% (29, 34%)
Trimethoprim 160 mg single dose 4 500 mg q12h 12 d 15 up 20% (3, 43%) <->
Zidovudine 200 mg q8h 4 d 300 mg q6h 4 d 9 down 25% (15, 34%) down 27% (4, 45%)
1 Ritonavir and indinavir were coadministered for 15 days; Day 14 doses were administered after a 15%-fat breakfast (757 Kcal) and 9%-fat evening snack (236 Kcal), and Day 15 doses were administered after a 15%-fat breakfast (757 Kcal) and 32%-fat dinner (815 Kcal). Indinavir C min was also increased 4-fold. Effects were assessed relative to an indinavir 800 mg q8h regimen under fasting conditions.
2 Effects were assessed on a dose-normalized comparison to a methadone 20 mg single dose.
3 Comparison to a standard saquinavir HGC 600 mg t.i.d. regimen (n=114).
4 Sulfamethoxazole and trimethoprim taken as single combination tablet.
up Indicates increase.
down Indicates decrease.
<-> Indicates no change.
* Parallel group design; entries are subjects receiving combination and control regimens, respectively.
INDICATIONS AND USAGE
RITONAVIR is indicated in combination with other antiretroviral agents for the treatment of HIV-infection. This indication is based on the results from a study in patients with advanced HIV disease that showed a reduction in both mortality and AIDS-defining clinical events for patients who received RITONAVIR either alone or in combination with nucleoside analogues. Median duration of follow-up in this study was 13.5 months.
Description of Clinical Studies
The activity of RITONAVIR as monotherapy or in combination with nucleoside analogues has been evaluated in 1446 patients enrolled in two double-blind, randomized trials.
Advanced Patients with Prior Antiretroviral Therapy
Study 247 was a randomized, double-blind trial (with open-label follow-up) conducted in HIV-infected patients with at least nine months of prior antiretroviral therapy and baseline CD 4 cell counts = 100 cells/µL. RITONAVIR 600 mg b.i.d. or placebo was added to each patient' baseline antiretroviral therapy regimen, which could have consisted of up to two approved antiretroviral agents. The study accrued 1090 patients, with mean baseline CD 4 cell count at study entry of 32 cells/µL. After the clinical benefit of RITONAVIR therapy was demonstrated, all patients were eligible to switch to open-label RITONAVIR for the duration of the follow-up period. Median duration of double-blind therapy with RITONAVIR and placebo was 6 months. The median duration of follow-up through the end of the open-label phase was 13.5 months for patients randomized to RITONAVIR and 14 months for patients randomized to placebo.
The cumulative incidence of clinical disease progression or death during the double-blind phase of Study 247 was 26% for patients initially randomized to RITONAVIR compared to 42% for patients initially randomized to placebo. This difference in rates was statistically significant (see Figure 1).
The cumulative mortality through the end of the open-label follow-up phase for patients enrolled in Study 247 was 18% for patients initially randomized to RITONAVIR compared to 26% for patients initially randomized to placebo. This difference in rates was statistically significant (see Figure 2). Since the analysis at the end of the open-label phase includes patients in the placebo arm who were switched from placebo to RITONAVIR therapy, the survival benefit of RITONAVIR cannot be precisely estimated.
Figures 3 and 4 summarize the mean change from baseline for CD 4 cell count and plasma HIV RNA (copies/mL), respectively, during the first 24 weeks for the double-blind phase of Study 247.
Patients Without Prior Antiretroviral Therapy
In Study 245, 356 antiretroviral-naive HIV-infected patients (mean baseline CD 4 = 364 cells/µL) were randomized to receive either RITONAVIR 600 mg b.i.d., zidovudine 200 mg t.i.d., or a combination of these drugs. Figures 5 and 6 summarize the mean change from baseline for CD 4 cell count and plasma HIV RNA (copies/mL), respectively, during the first 24 weeks for the double-blind phase of Study 245.
CONTRAINDICATIONS
RITONAVIR is contraindicated in patients with known hypersensitivity to ritonavir or any of its ingredients.
RITONAVIR should not be administered concurrently with the drugs listed in Table 3 (also see PRECAUTIONS Table 4: Contraindicated Drugs) because competition for primarily CYP3A by ritonavir could result in inhibition of the metabolism of these drugs and create the potential for serious and/or life-threatening reactions such as cardiac arrhythmias, prolonged or increased sedation, and respiratory depression.
Postmarketing reports indicate that co-administration of ritonavir with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities.
Table 3
DRUGS THAT ARE CONTRAINDICATED WITH RITONAVIR USE
Drug Class Drugs Within Class That Are
CONTRAINDICATED With RITONAVIR
Antiarrhythmics amiodarone, bepridil, flecainide, propafenone, quinidine
Antihistamines astemizole, terfenadine
Antimigraine dihydroergotamine, ergotamine
Sedative/hypnotics midazolam, triazolam
GI motility agent cisapride
Neuroleptic pimozide
WARNINGS
Drug Interactions
The magnitude of the interactions and therapeutic consequences between ritonavir and the drugs listed in Table 4 Predicted Drug Interactions: Use With Caution cannot be predicted with any certainty. When co-administering ritonavir with any agent listed in Table 4 Predicted Drug Interactions: Use With Caution , special attention is warranted.
Cardiac and neurologic events have been reported with ritonavir when co-administered with disopyramide, mexiletine, nefazodone, fluoxetine and beta blockers. The possibility of drug interaction cannot be excluded.
Particular caution should be used when prescribing sildenafil in patients receiving RITONAVIR. Co-administration of RITONAVIR with sildenafil is expected to substantially increase sildenafil concentrations (11-fold increase in AUC) and may result in an increase in sildenafil-associated adverse events, including hypotension, syncope, visual changes, and prolonged erection (see PRECAUTIONS : Drug Interactions , Table 4 Established Drug Interactions: Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies and the complete prescribing information for sildenafil).
Concomitant use of RITONAVIR with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including RITONAVIR, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (e.g., atorvastatin or cerivastatin). The risk of myopathy including rhabdomyolysis may be increased when HIV protease inhibitors, including RITONAVIR, are used in combination with these drugs.
Concomitant use of RITONAVIR, and St. John's wort (hypericum perforatum) or products containing St. John's wort is not recommended. Coadministration of protease inhibitors, including RITONAVIR, with St. John's wort is expected to substantially decrease protease inhibitor concentrations and may result in sub-optimal levels of RITONAVIR and lead to loss of virologic response and possible resistance to RITONAVIR or to the class of protease inhibitors.
Allergic Reactions
Allergic reactions including urticaria, mild skin eruptions, bronchospasm, and angioedema have been reported. Rare cases of anaphylaxis and Stevens-Johnson syndrome have also been reported.
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 (see Table 6). 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.
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.
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.
PRECAUTIONS
General
Ritonavir is principally metabolized by the liver. Therefore, caution should be exercised when administering this drug to patients with impaired hepatic function (see WARNINGS ).
Resistance/Cross-resistance
Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of ritonavir therapy following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors (see MICROBIOLOGY ).
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 has not been established.
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.
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. 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. See PRECAUTIONS Table 4 for additional information on potential drug interactions with RITONAVIR and HMG CoA reductase inhibitors.
Information For Patients
Patients should be informed that RITONAVIR is not a cure for HIV infection and that they may continue to acquire illnesses associated with advanced HIV infection, including opportunistic infections.
Patients should be told that the long-term effects of RITONAVIR are unknown at this time. They should be informed that RITONAVIR therapy has not been shown to reduce the risk of transmitting HIV to others through sexual contact or blood contamination.
Patients should be advised to take RITONAVIR with food, if possible.
Patients should be informed to take RITONAVIR every day as prescribed. Patients should not alter the dose or discontinue RITONAVIR without consulting their doctor. If a dose is missed, patients should take the next dose as soon as possible. However, if a dose is skipped, the patient should not double the next dose.
Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time.
RITONAVIR may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John's wort.
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. For comprehensive information concerning laboratory test alterations associated with nucleoside analogues, physicians should refer to the complete product information for each of these drugs.
Drug Interactions
Ritonavir has been found to be an inhibitor of cytochrome P450 3A (CYP3A) both in vitro and in vivo (Table 2). 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. 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 as well as other enzymes, including glucuronosyl transferase, CYP1A2, and possibly CYP2C9.
Drugs that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse events are listed both in CONTRAINDICATIONS Table 3 and under Contraindicated Drugs in Table 4.
Those drug interactions that have been established based on drug interaction studies are listed with the pharmacokinetic results in CLINICAL PHARMACOLOGY , Table 2. The clinical recommendations based on the results of these studies are listed in Table 4 Established Drug Interactions: Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies.
A systematic review of over 200 medications prescribed to HIV-infected patients was performed to identify potential drug interactions with ritonavir. 2 There are a number of agents in which CYP3A or CYP2D6 partially contribute to the metabolism of the agent. In these cases, the magnitude of the interaction and therapeutic consequences cannot be predicted with any certainty.
When co-administering ritonavir with calcium channel blockers, immunosuppressants, some HMG-CoA reductase inhibitors (see WARNINGS , Drug Interactions ), some steroids, or other substrates of CYP3A, or most antidepressants, certain antiarrhythmics, and some narcotic analgesics which are partially mediated by CYP2D6 metabolism, it is possible that substantial increases in concentrations of these other agents may occur, possibly requiring a dosage reduction (>50%); examples are listed in Table 4 Predicted Drug Interactions: Use With Caution, Dose Decrease May be Needed.
When co-administering ritonavir with any agent having a narrow therapeutic margin, such as anticoagulants, anticonvulsants, and antiarrhythmics, special attention is warranted. With some agents, the metabolism may be induced, resulting in decreased concentrations (see Table 4 Predicted Drug Interactions: Use With Caution, Dose Increase May be Needed).
Table 4
Drug Interactions With RITONAVIR
CONTRAINDICATED DRUGS
(Same as Table 3) DRUGS THAT ARE CONTRAINDICATED WITH RITONAVIR USE
Drug Class Drugs Within Class That Are
CONTRAINDICATED With RITONAVIR
Antiarrhythmics amiodarone, bepridil, flecainide, propafenone, quinidine
Antihistamines astemizole, terfenadine
Antimigraine dihydroergotamine, ergotamine
Sedative/hypnotics midazolam, triazolam
GI motility agent cisapride
Neuroleptic pimozide
Established Drug Interactions: Alteration in Dose or
Regimen Recommended Based on Drug Interaction Studies
(see CLINICAL PHARMACOLOGY , Table 2 for Magnitude or Interaction) Drug Name Effect Clinical Comment
Clarithromycin up clarithromycin
concentration 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.
Desipramine up desipramine concentration Dosage reduction and concentration monitoring of desipramine is recommended
Didanosine Dosing of didanosine and ritonavir should be separated by 2.5 hours to avoid formulation incompatibility
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)
Indinavir up indinavir concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established
Ketoconazoleup ketoconazole concentration High doses of ketoconazole (>200 mg/day) are not recommended
Meperidine down meperidine concentration/
up normeperidine
concentration (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)
Methadone down methadone concentration Dosage increase of methadone may be considered
Oral Contraceptives down ethinyl estradiol
concentration Dosage increase or alternate contraceptive measures should be considered
Rifabutin up rifabutin and rifabutin
metabolite concentration 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
Rifampindown ritonavir concentration Alternate antimycobacterial agents such as rifabutin should be considered (see Rifabutin, for dose reduction recommendations)
Saquinavir up saquinavir concentration When used in combination therapy for up to 24 weeks, doses of 400 mg b.i.d. of ritonavir and saquinavir were better tolerated than the higher doses of the combination. Saquinavir plasma concentrations achieved with Invirase® (saquinavir mesylate) (400 mg b.i.d.) and ritonavir (400 mg b.i.d.) are similar to those achieved with Fortovase™ (saquinavir) (400 mg b.i.d.) and ritonavir (400 mg b.i.d.)
Sildenafil up sildenafil concentration Sildenafil should not exceed a maximum single dose of
25 mg in a 48-hour period in patients receiving concomitant ritonavir therapy (see WARNINGS )
Theophyllinedown theophylline concentration Increased dosage of theophylline may be required; therapeutic monitoring should be considered
Predicted Drug Interactions: Use With Caution, Dose
Decrease of Coadministered Drug May Be Needed
(see WARNINGS )
Examples of Drugs in Which Plasma Concentrations May Be Increased
By Co-Administration With RITONAVIR
Drug Class Examples of Drugs
Analgesics, narcotic tramadol, propoxyphene
Antiarrhythmics disopyramide, lidocaine, mexilitine
Anticonvulsants carbamazepine, clonazepam, ethosuximide
Antidepressants bupropion, nefazodone, selective serotonin reuptake inhibitors (SSRIs), tricyclics
Antiemetics dronabinol
Antiparasitics quinine
(beta)-blockers metoprolol, timolol
Calcium channel blockers diltiazem, nifedipine, verapamil
Hypolipidemics, HMG CoA reductase inhibitors 1 atorvastatin, cerivastatin, lovastatin, simvastatin
Immunosuppressants cyclosporine, tacrolimus
Neuroleptics perphenazine, risperidone, thioridazine
Sedative/hypnotics clorazepate, diazepam, estazolam, flurazepam, zolpidem
Steroids dexamethasone, prednisone
Stimulants methamphetamine
1 Coadministration with lovastatin and simvastatin is not recommended (see WARNINGS , Drug Interactions ).
Predicted Drug Interactions: Use With Caution, Dose Increase of Coadministered Drug May Be Needed (see WARNINGS )
Examples of Drugs in Which Plasma Concentrations
May Be Decreased By Co-Administration
With RITONAVIR
Anticoagulants warfarin
Anticonvulsants phenytoin, divalproex, lamotrigine
Antiparasitics atovaquone
Post-Marketing Experience with Drugs Listed in Table 4
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.
Carcinogenesis and Mutagenesis
Long-term carcinogenicity studies of ritonavir in animal systems have not been completed. However, ritonavir was not mutagenic or clastogenic in a battery of in vitro and in vivo assays including bacterial reverse mutation (Ames) using S. typhimurium and E. coli , mouse lymphoma, mouse micronucleus, and chromosome aberrations in human lymphocytes.
Pregnancy, Fertility, and Reproduction
Pregnancy Category B: Ritonavir produced no effects on fertility in rats at drug exposures approximately 40% (male) and 60% (female) of that achieved with the proposed therapeutic dose. Higher dosages were not feasible due to hepatic toxicity.
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.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ritonavir is administered to a nursing woman. However, the U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid postnatal transmission of HIV to a child who may not be infected.
Pediatric Use
The safety and pharmacokinetic profile of ritonavir in pediatric patients below the age of 2 years have not been established. In HIV-infected patients age 2 to 16 years, the adverse event profile seen during a clinical trial and postmarketing experience was similar to that for adult patients. The evaluation of the antiviral activity of ritonavir in pediatric patients in clinical trials is ongoing.
ADVERSE REACTIONS
The safety of RITONAVIR alone and in combination with nucleoside analogues was studied in 1270 patients. Table 5 lists treatment-emergent adverse events (at least possibly related and of at least moderate intensity) that occurred in 2% or greater of patients receiving RITONAVIR alone or in combination with nucleosides in Study 245 or Study 247 and in combination with saquinavir in ongoing Study 462. In that study, 141 protease inhibitor-naive, HIV-infected patients with mean baseline CD 4 of 300 cells/µL were randomized to one of four regimens of RITONAVIR + saquinavir, including RITONAVIR 400 mg b.i.d. + saquinavir 400 mg b.i.d. Overall the most frequently reported clinical adverse events, other than asthenia, among patients receiving RITONAVIR were gastrointestinal and neurological disturbances including nausea, diarrhea, vomiting, anorexia, abdominal pain, taste perversion, and circumoral and peripheral paresthesias. Similar adverse event profiles were reported in patients receiving ritonavir in other trials.
Table 5
Percentage of Patients with Treatment-Emergent Adverse Events 1 of Moderate or
Severe Intensity Occurring in >/=2% of Patients Receiving RITONAVIR Study 245
Naive Patients 2 Study 247
Advanced Patients 3 Study 462
PI-Naive
Patients 4 Adverse
Events RITONAVIR + ZDV RITONAVIR ZDV RITONAVIR Placebo RITONAVIR + Saquinavir
n=116 n=116 n=119 n=541 n=545 n=141
Body as a Whole
Abdominal Pain 5.2 6.0 5.9 8.3 5.1 2.1
Asthenia 28.4 10.3 11.8 15.3 6.4 16.3
Fever 1.7 0.9 1.7 5.0 2.4 0.7
Headache 7.8 6.0 6.7 6.5 5.7 4.3
Malaise 5.2 1.7 3.4 0.7 0.2 2.8
Pain (unspecified) 0.9 1.7 0.8 2.2 1.8 4.3
Cardiovascular
Syncope 0.9 1.7 0.8 0.6 0.0 2.1
Vasodilation 3.4 1.7 0.8 1.7 0.0 3.5
Digestive
Anorexia 8.6 1.7 4.2 7.8 4.2 4.3
Constipation 3.4 0.0 0.8 0.2 0.4 1.4
Diarrhea 25.0 15.4 2.5 23.3 7.9 22.7
Dyspepsia 2.6 0.0 1.7 5.9 1.5 0.7
Fecal
Incontinence 0.0 0.0 0.0 0.0 0.0 2.8
Flatulence 2.6 0.9 1.7 1.7 0.7 3.5
Local Throat Irritation 0.9 1.7 0.8 2.8 0.4 1.4
Nausea 46.6 25.6 26.1 29.8 8.4 18.4
Vomiting 23.3 13.7 12.6 17.4 4.4 7.1
Metabolic and Nutritional
Weight Loss 0.0 0.0 0.0 2.4 1.7 0.0
Musculoskeletal
Arthralgia 0.0 0.0 0.0 1.7 0.7 2.1
Myalgia 1.7 1.7 0.8 2.4 1.1 2.1
Nervous
Anxiety 0.9 0.0 0.8 1.7 0.9 2.1
Circumoral Paresthesia 5.2 3.4 0.0 6.7 0.4 6.4
Confusion 0.0 0.9 0.0 0.6 0.6 2.1
Depression 1.7 1.7 2.5 1.7 0.7 7.1
Dizziness 5.2 2.6 3.4 3.9 1.1 8.5
Insomnia 3.4 2.6 0.8 2.0 1.8 2.8
Paresthesia 5.2 2.6 0.0 3.0 0.4 2.1
Peripheral Paresthesia 0.0 6.0 0.8 5.0 1.1 5.7
Somnolence 2.6 2.6 0.0 2.4 0.2 0.0
Thinking Abnormal 2.6 0.0 0.8 0.9 0.4 0.7
Respiratory
Pharyngitis 0.9 2.6 0.0 0.4 0.4 1.4
Skin and Appendages
Rash 0.9 0.0 0.8 3.5 1.5 0.7
Sweating 3.4 2.6 1.7 1.7 1.1 2.8
Special Senses
Taste Perversion 17.2 11.1 8.4 7.0 2.2 5.0
Urogenital
Nocturia 0.0 0.0 0.0 0.2 0.0 2.8
1 Includes those adverse events at least possibly related to study drug or of unknown relationship and excludes concurrent HIV conditions.
2 The median duration of treatment for patients randomized to regimens containing RITONAVIR in Study 245 was 9.1 months.
3 The median duration of treatment for patients randomized to regimens containing RITONAVIR in Study 247 was 9.4 months.
4 The median duration of treatment for patients in ongoing Study 462 was 48 weeks.
Adverse events occurring in less than 2% of patients receiving RITONAVIR in all phase II/phase III studies and considered at least possibly related or of unknown relationship to treatment and of at least moderate intensity are listed below by body system.
Body as a Whole: Abdomen enlarged, accidental injury, allergic reaction, back pain, cachexia, chest pain, chills, facial edema, facial pain, flu syndrome, hormone level altered, hypothermia, kidney pain, neck pain, neck rigidity, pelvic pain, photosensitivity reaction, and substernal chest pain.
Cardiovascular System: Cardiovascular disorder, cerebral ischemia, cerebral venous thrombosis, hypertension, hypotension, migraine, myocardial infarct, palpitation, peripheral vascular disorder, phlebitis, postural hypotension, tachycardia and vasospasm.
Digestive System: Abnormal stools, bloody diarrhea, cheilitis, cholestatic jaundice, colitis, dry mouth, dysphagia, eructation, esophageal ulcer, esophagitis, gastritis, gastroenteritis, gastrointestinal disorder, gastrointestinal hemorrhage, gingivitis, hepatic coma, hepatitis, hepatomegaly, hepatosplenomegaly, ileus, liver damage, melena, mouth ulcer, pancreatitis, pseudomembranous colitis, rectal disorder, rectal hemorrhage, sialadenitis, stomatitis, tenesmus, thirst, tongue edema, and ulcerative colitis.
Endocrine System: Adrenal cortex insufficiency and diabetes mellitus.
Hemic and Lymphatic System: Acute myeloblastic leukemia, anemia, ecchymosis, leukopenia, lymphadenopathy, lymphocytosis, myeloproliferative disorder, and thrombocytopenia.
Metabolic and Nutritional Disorders: Albuminuria, alcohol intolerance, avitaminosis, BUN increased, dehydration, edema, enzymatic abnormality, glycosuria, gout, hypercholesteremia, peripheral edema, and xanthomatosis.
Musculoskeletal System: Arthritis, arthrosis, bone disorder, bone pain, extraocular palsy, joint disorder, leg cramps, muscle cramps, muscle weakness, myositis, and twitching.
Nervous System: Abnormal dreams, abnormal gait, agitation, amnesia, aphasia, ataxia, coma, convulsion, dementia, depersonalization, diplopia, emotional lability, euphoria, grand mal convulsion, hallucinations, hyperesthesia, hyperkinesia, hypesthesia, incoordination, libido decreased, manic reaction, nervousness, neuralgia, neuropathy, paralysis, peripheral neuropathic pain, peripheral neuropathy, peripheral sensory neuropathy, personality disorder, sleep disorder, speech disorder, stupor, subdural hematoma, tremor, urinary retention, vertigo, and vestibular disorder.
Respiratory System: Asthma, bronchitis, dyspnea, epistaxis, hiccup, hypoventilation, increased cough, interstitial pneumonia, larynx edema, lung disorder, rhinitis, and sinusitis.
Skin and Appendages: Acne, contact dermatitis, dry skin, eczema, erythema multiforme, exfoliative dermatitis, folliculitis, fungal dermatitis, furunculosis, maculopapular rash, molluscum contagiosum, onychomycosis, pruritus, psoriasis, pustular rash, seborrhea, skin discoloration, skin disorder, skin hypertrophy, skin melanoma, urticaria, and vesiculobullous rash.
Special Senses: Abnormal electro-oculogram, abnormal electroretinogram, abnormal vision, amblyopia/blurred vision, blepharitis, conjunctivitis, ear pain, eye disorder, eye pain, hearing impairment, increased cerumen, iritis, parosmia, photophobia, taste loss, tinnitus, uveitis, visual field defect, and vitreous disorder.
Urogenital System: Acute kidney failure, breast pain, cystitis, dysuria, hematuria, impotence, kidney calculus, kidney failure, kidney function abnormal, kidney pain, menorrhagia, penis disorder, polyuria, urethritis, urinary frequency, urinary tract infection, and vaginitis.
Post-Marketing Experience:
There have been postmarketing reports of seizure. Cause and effect relationship has not been established.
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.
Redistribution/accumulation of body fat has been reported (see PRECAUTIONS , Fat Redistribution ). There have been reports of increased bleeding in patients with hemophilia A or B (see PRECAUTIONS , Hemophilia ).
Laboratory Abnormalities
Table 6 shows the percentage of patients who developed marked laboratory abnormalities.
Table 6
Percentage of Patients, by Study and Treatment Group, with Chemistry and
Hematology Abnormalities Occurring in > 3% of Patients Receiving RITONAVIR Study 245
Naive Patients Study 247
Advanced Patients Study 462
PI-Naive
Patients
Variable Limit
RITONAVIR + ZDV RITONAVIR ZDV RITONAVIR Placebo RITONAVIR + 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 × 10 9 /L -- -- -- 6.0 8.3 --
RBC <3.0 × 10 12 /L 1.8 -- 5.9 18.6 24.4 --
WBC <2.5 × 10 9 /L -- 0.9 6.8 36.9 59.4 3.5
1 ULN = upper limit of the normal range.
- Indicates no events reported.