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RITOMUNE - Ritonavir 100 mg Capsules
Optimizing Pl-based HAART
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Table
3: Established Drug Interactions: Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies
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Concomitant
Drug Class:
Drug Name |
Effect on Concentration
of Ritonavir or
Concomitant Drug |
Clinical Comment |
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HIV-Antiviral Agents |
HIV Protease
Inhibitor: indinavir |
When co-adminsitered 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 Protease Inhibitor:
saquinavir |
When co-adminsitered with
reduced doses of
saquinavir
and ritonavir
saquinavir
( « AUC,
¯ C max , C min ) |
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 hard gel
formulation (saquinavir mesylate) (400 mg b.i.d) and ritonavir (400 mg b.i.d.) are
similar to those achieved with soft gel saquinavir (400 mg b.i.d.) and ritonavir
(400 mg b.i.d.) |
Nucleoside
Reverse
Transcriptase
Inhibitor:
didanosine |
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Dosing of didanosine and ritonavir should be separated by 2.5 hours to avoid formulation incompatibility |
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Concomitant
Drug Class:
Drug Name |
Effect on Concentration
of Ritonavir or
Concomitant Drug |
Clinical Comment |
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Other Agents |
Anaesthetic:
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 |
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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) |
Anticoagulant:
warfarin |
¯ R-warfarin
¯ S-warfarin |
Initial frequent monitoring of the INR during ritonavir and warfarin co-administration is
indicated |
Antidepressant:
desipramine |
despiramine |
Dosage reduction and concentration monitoring of desipramine is recommended |
Antifungal:
ketoconazole |
ketoconazole |
High doses of ketoconazole (> 200 mg/day) are not recommended |
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 |
Antimycobacteial:
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 |
Bronchodilator:
theophylline |
¯ theophylline |
Increased dosage of theophylline may be required; therapeutic monitoring should
be considered |
Erectile Dysfunction:
sildenafil |
sildenafil |
Sildenafil should not exceed a maximum single dose of 25 mg in a 48-hour period in patients receiving concomitant ritonavir therapy (see WARNINGS ) |
Narcotic Analgesic:
methadone |
¯ methadone |
Dosage increase of methadone may be considered |
Oral Contraceptive:
ethinyl estradiol |
¯ ethinyl estradiol |
Dosage increase or alternate contraceptive measures should be considered |
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Table 4: Predicted Drug Interactions: Use with Caution, Dose Decrease of Coadministered Drug may be needed (see WARNINGS)
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| 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 |
| Antifungals |
Itraconazole |
| Antiparasitics |
Quinine |
| b -blockers |
Metoprolol, timolol |
| Calcium channel blockers |
Diltiazem, nifedipine, verapamil |
| Hypolipidemics, HMG CoA1 |
Atorvastatin2 |
| Immunosuppressants |
Cyclosporine, tacrolimus, sirolimus (rapamycin) |
| Neuroleptics |
Perphenazine, risperidone, thioridazine |
| Sedative/hypnotics |
Clorazepate, diazepam, estazolam, flurazepam, zolpidem |
| Steroids |
Dexamethasone, fluticasone, prednisone |
| Stimulants |
Methamphetamine |
1 Co-administration with lovastatin and simvastatin is not recommended (see WARNINGS, Drug Interactions )
2 Use lowest possible dose of atorvastatin with careful monitoring or consider HMG-CoA reductase inhibitor such as pravastatin or fluvastatin.
Table 5: Predicted Drug Interactions: Use with Caution, Dose Increase of
Co-administered Drug may be needed (see WARNINGS)
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Examples of drugs in which Plasma Concentrations may be decreased by
co-administration with Ritonavir |
| Drug Class |
Examples of Drugs |
| Anticonvulsants |
Phenytoin, divalproex, lamotrigine |
| Antiparasitics |
Atovaquone |
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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. 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.
Diabetes Mellitus/Hyperglycemia
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during pos-tmarketing 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.
General
Ritonavir is principally metabolized by the liver. Therefore, caution should be exercised when administering this drug to patients with impaired hepatic function.
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.
Haemophilia
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 Tables 2 and 4 for additional information on potential drug interactions with ritonavir and HMG CoA reductase inhibitors.
Laboratory Tests
Ritonavir has been shown to increase triglycerides, cholesterol, SGOT (AST), SGPT (ALT), GGT, CPK, and uric acid. Appropriate laboratory testing should be performed prior to initiating ritonavir therapy and at periodic intervals or if any clinical signs or symptoms occur during therapy. For comprehensive information concerning laboratory test alterations associated with nucleoside analogues, physicians should refer to the complete product information for each of these drugs.
Pregnancy
Category B. There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if clearly needed.
Lactation
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, it is advised that HIV-infected women do not breast-feed to avoid pos-tnatal transmission of HIV to a child who may not be infected.
Paediatric use
The safety and pharmacokinetic profile of ritonavir in paediatric patients below the age of 2 years have not been established. In HIV-infected patients aged 2 to 16 years, the adverse event profile appears to be similar to that for adult patients. |
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Side effects
Overall the most frequently reported clinical adverse events, other than asthenia, among patients receiving ritonavir were gastrointestinal and neurological disturbances including nausea, diarrhoea, vomiting, anorexia, abdominal pain, taste perversion, and circumoral and peripheral paraesthesias.
Adverse events occurring in less than 2% of patients receiving ritonavir in all phase II/phase III studies and considered at least possibly related and of at least moderate intensity are as follows:
Body as a Whole : Abdominal pain, asthenia, fever, headache, malaise, pain (unspecified)
Cardiovascular : Syncope, vasodilation
Digestive : Anorexia, constipation, diarrhea, dyspepsia, fecal, incontinence, flatulence, local throat irritation, nausea, vomiting
Metabolic and Nutritional : Weight loss
Musculoskeletal : Arthralgia, myalgia
Nervous : Anxiety, circumoral paraesthesia, confusion, depression, dizziness, insomnia, paresthesia, peripheral paresthesia, somnolence, thinking abnormal
Respiratory : Pharyngitis
Skin and Appendages : Rash, sweating
Special senses : Taste perversion
Urogenital : Nocturia
Laboratory Abnormalities: Elevations in cholesterol, triglycerides, SGOT and SGPT have been reported.
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Overdosage
Acute Overdosage
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 emesis or gastric lavage; usual precautions should be observed to maintain the airway. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Since ritonavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the drug.
Presentation
Ritomune-100 Bottle of 60 capsules |
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Chapter 7 |
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Place in Therapy |
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The boosted PI approach is rapidly becoming the standard of care with PI use. Two distinct strategies are being used:
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A combination of 2 PIs at a therapeutic dose (e.g. indinavir at 400 mg bid plus ritonavir at 400 mg bid).
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The combination of a PI with a low dose (100 mg) of ritonavir, which is a potent inhibitor of cytochrome P450 3A4 metabolism. This dose is not expected to be therapeutically active.
The first is regarded as 2-drug treatment, because both PIs contribute to the net activity. The second results in single PI-treatment, because a low dose of ritonavir does not contribute to the antiviral activity itself (e.g. saquinavir at 1000 mg plus ritonavir at 100 mg bid). Because of the poor tolerability of ritonavir at 400 mg bid, the second strategy is increasingly favoured.27
Regimens containing boosted PIs rank among the preferred first-line therapeutic options in antiretroviral therapy. 28,29,30 They also play an important role as part of second-line regimens, as well as components of salvage regimens for the treatment-experienced patient. Moreover, the ritonavir-saquinavir combination is a vital option for the management of the HIV and TB co-infected patient, when interactions with rifampin are a concern.
Current literature suggests that low-dose ritonavir-boosted regimens are potent and durable. It is to be expected that ritonavir will be increasingly used as a pharmacologic booster for other PIs, either as first-line or subsequent therapy, as part of once-daily or twice-daily PI regimens.
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BIBLIOGRAPHY |
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- Hsu A, Granneman R and Bertz RJ. Ritonavir. Clinical pharmacokinetics and interactions with other anti-HIV agents. Clin Pharmacokinet 1998; 35(4): 275-91
- Flexner C. Dual protease inhibitor therapy in HIV-infected patients: Pharmacologic rationale and clinical benefits. Annu Rev Pharmacol Toxicol 2000; 40: 649-74
- Kempf DJ, Marsh KC, Kumar G et al. Pharmacokinetic enhancement of inhibitors of the HIV protease by co-administration with ritonavir. Antimicrob Agents Chemother 1997; 41(3): 654-60
- Moyle G. Use of HIV protease inhibitors as pharmacoenhancers. AIDS Reader 2001; 11(2): 87-98
- Gerber JG. Using pharmacokinetics to optimize antiretroviral drug-drug interactions in the treatment of HIV infection. Clin Infect Dis 2003; 30 (suppl 2): S123-9
- Phanuphak P. Advances in the clinical pharmacology of antiretroviral therapy. www.medscape.com/viewprogram/2592_pnt Accessed 17 th November 2003
- Veldkamp Al, Hoetelmans RMW, Beijnen JH et al. Ritonavir enables combined therapy with rifampin and saquinavir. Clin Infect Dis 1999; 29: 1586
- Notice to readers: Updated guidelines for the use of rifabutin or rifampin for the treatment and prevention of tuberculosis among HIV-infected patients taking protease inhibitors or non-nucleoside reverse transcriptase inhibitors. MMWR Weekly 2000; 49(9): 185-9
- Rockstroh JK, Bergmann F, Wiesel W et al. Efficacy and safety of twice daily first-line ritonavir/indinavir plus double nucleoside combination therapy in HIV-infected individuals. AIDS 2000; 14: 1181-85
- Boyd M, Duncombe C, Ruxrungtham K et al. HIV-NAT 005: Results of 112 weeks follow-up. Poster G30e. http://63.126.3.84/2002/posters/13001.pdf. Accessed 16th December 2003 .
- Workman C, Whittaker W, Dyer W et al. Combining ritonavir and indinavir decreases indinavir-associated nephrolithiasis. 6 th CROI 1999 Abstract 677
- Ghosn J, Lamotte C, Ait-Mohand H et al. Efficacy of a twice-daily antiretroviral regimen containing 100 mg ritonavir/400 mg indinavir in HIV-infected patients. AIDS 2003; 17: 209-14
- Antela A, Iribarren JA, Santos I et al. Interim analysis of the Amadeus O1 study. 43 rd ICAAC 2003, Abstract H-841
- Bush L, Novak R, Ma L et al. Protocol 112. 42 nd ICAAC 2002, Poster H-174
- van Praag RME, Weverling GJ, Portegies P et al. Enhanced penetration of indinavir in cerebrospinal fluid and semen after the addition of low-dose ritonavir. AIDS 2000; 14: 1187-94
- O'Brien WA, Rojo D, Acosta E et al. Switch of saquinavir 400 mg/ritonavir 400 mg to saquinavir 1000 mg/ritonavir 100 mg during bid 4 drug antiretroviral therapy in patients with viral load less than 200 copies/ml. 14 th International AIDS Conference 2002 Abstract WeOrB1263
- Dragsted UB, Gerstoft J, Pedersen C et al. Randomized trial to evaluate indinavir/ritonavir versus saquinavir/ritonavir in HIV type 1-infected patients: The
MaxCmin l trial. J Infect Dis 2003; 188: 635-42
- Dragsted UB, Gerstoft J, Youle M et al. Interim analysis of a phase IV, randomized, open-label, multicentre trial to evaluate safety and efficacy of lopinavir/ritonavir (400/100 mg bid) vs. saquinavir/ritonavir (1000/100 mg bid) in adult HIV-1 infection. The MaxCmin2 trial. 6 th International Congress on Drug Therapy in HIV infection 2002 Poster PL14.5
- Hall CS, Raines CP, Barnett SH et al. Efficacy of salvage therapy containing ritonavir and saquinavir after failure of single protease inhibitor-containing regimens. AIDS 1999; 13: 1207-12
- Montaner JSG, Saag MS, Barylski C et al. FOCUS study: Saquinavir QD regimen versus efavirenz QD regimen week 48 analysis in HIV-infected patients. 42 nd ICAAC 2002, Poster H-167
- www.who.int/medicines Application for inclusion of saquinavir/low dose ritonavir combination on WHO model list of essential medicines. Accessed 3 rd October 2003
- Inpharma 2003 20 th Sep. No. 1405
- www.fda.gov/cder/approval/index.htm
- Collier AC and Squires KE. Saquinavir. In: AIDS therapy Dolin R, Masur H and Saag, MS Eds. Churchill Livingstone 2003, p157-173
- www.who.int/medicines Application for inclusion of indinavir/low dose ritonavir combination on WHO Model list of Essential Medicines. Accessed 3 rd October 2003
- Gulick R. Indinavir. In: AIDS therapy Dolin R, Masur H and Saag, MS Eds. Churchill Livingstone 2003, p190-211
- Cooper CL, Van Heeswijk RPG, Gallicano K et al. A review of low-dose ritonavir in protease inhibitor combination therapy. Clin Infect Dis 2003; 36: 1585-92
- British HIV Association Guidelines 2003
- Department of Health and Human Services Guidelines, USA , 2003
- WHO Guidelines for scaling up antiretroviral therapy in resource-poor settings, 2003
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