New Norvir Tablet Application Submitted to FDA by Abbott
January 21, 2009
Abbott is pleased to announce that it has submitted applications seeking registration for a new tablet formulation of our protease inhibitor (PI) Norvir (ritonavir) with U.S. and E.U. regulatory authorities. This new formulation will not require refrigeration, which will make its use more convenient, particularly in developing countries where the majority of people with HIV live.
Abbott's development of the Norvir tablet is the result of the efforts of our scientists to address the needs of people living with HIV. Abbott scientists tested multiple formulations before developing and submitting the final formulation for regulatory consideration. The Norvir tablet was developed using Meltrex technology, which is also used in Abbott's Kaletra (lopinavir/ritonavir) tablets. Even with the use of Meltrex technology, ritonavir had unique formulation requirements to ensure stability and absorption. Abbott first presented data from a pivotal bioavailability study of the tablet, which compared the new formulation to the current Norvir soft gel capsule, at the XVII International AIDS conference in Mexico City (AIDS 2008) in August 2008.
Norvir is indicated in combination with other antiretroviral agents for the treatment of HIV infection. Kaletra is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
Abbott intends to register the new Norvir tablet formulation broadly worldwide. We look forward to continuing to work with the HIV community to improve the lives of individuals with HIV.
If I can provide further information or address any questions you may have, please do not hesitate to contact me.
Director, Advocacy and Policy, Abbott
Please see below for the Indication and Important Safety Information about Norvir and Kaletra in combination therapy.
Please click here for Norvir full Prescribing Information
Please click here for Kaletra full Prescribing Information
NORVIR INDICATION AND IMPORTANT SAFETY INFORMATION
NORVIR (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 NORVIR either alone or in combination with nucleoside analogues. Median duration of follow-up in this study was 13.5 months.
Important Safety Information1
CO-ADMINISTRATION OF NORVIR WITH CERTAIN NONSEDATING ANTIHISTAMINES, SEDATIVE HYPNOTICS, ANTIARRYTHMICS, OR ERGOT ALKALOID PREPERATIONS MAY RESULT IN POTENTIALLY SERIOUS AND/OR LIFE=THREATENING ADVERSE EVENTS DUE TO POSSIBLE EFFECTS OF NORVIR ON THE HEPATIC METABOLISM OF CERTAIN DRUGS.
NORVIR should not be given to patients with known hypersensitivity to ritonavir or any of its ingredients.
NORVIR is contraindicated with alfuzosin, amiodarone, astemizole, bepridil, cisapride, dihydroergotamine, ergonovine, ergotamine, flecainide, methylergonovine, midazolam, pimozide, propafenone, quinidine, terfenadine, triazolam, and voriconazole.
NORVIR is an inhibitor of CYP3A and CYP2D6. Co-administration of ritonavir and drugs primarily metabolized by CYP3A and CYP2D6 may result in increased plasma concentrations of other drugs that could increase or prolong its therapeutic and adverse effects.
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.
Particular caution should be used with co-administration of NORVIR with PDE5 inhibitors (sildenafil, tadalafil, or vardenafil) as NORVIR is expected to substantially increase PDE5 inhibitor concentrations and may result in an increase in sildenafil-associated adverse events, including hypotension, syncope, visual changes and prolonged erection.
NORVIR should not be co-administered with St. John's wort (Hypericum perforatum), lovastatin, or simvastatin. Caution should be exercised if used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway such as atorvastatin, cerivastatin, and rosuvastatin. Co-administration of fluticasone propionate and NORVIR is not recommended.
Tipranavir co-administered with 200 mg of ritonavir has been associated with reports of clinical hepatitis and hepatic decompensation including some fatalities. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of hepatotoxicity.
Allergic reactions ranging from mild to severe have been reported.
Caution should be exercised when administering NORVIR to patients with preexisting liver diseases, liver enzyme abnormalities, or hepatitis. Increased AST/ALT monitoring should be considered in these patients, especially during the first three months of NORVIR 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, including some fatalities, has been observed in patients receiving NORVIR therapy.
New onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy.
Varying degrees of cross-resistance among protease inhibitors have been observed.
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.
Ritonavir prolongs the PR interval in some patients. Postmarketing cases of second and third degree atrioventricular block have been reported. Use with caution in patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease, cardiomyopathies, or when administering with other drugs that prolong the PR interval, particularly those drugs metabolized by CYP3A. Clinical monitoring is recommended.
Redistribution/accumulation of body fat has been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Treatment with NORVIR has resulted in substantial increases in the concentration of total triglycerides and cholesterol, which should be monitored before and during therapy.
Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy including NORVIR.
In NORVIR clinical trials, the most common adverse events of moderate to severe intensity reported in ≥2% of adult patients included diarrhea, nausea, vomiting, asthenia, taste perversion, abdominal pain, anorexia, peripheral paresthesia and circumoral paresthesia, headache and dizziness. Vomiting, diarrhea, and skin rash/allergy were reported in ≥2% of pediatric patients.
__KALETRA INDICATION AND IMPORTANT SAFETY INFORMATION
__Indication2 __KALETRA (lopinavir/ritonavir) is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. The following points should be considered when initiating therapy with KALETRA:
- The use of other active agents with KALETRA is associated with a greater likelihood of treatment response.
- Genotypic or phenotypic testing and/or treatment history should guide the use of KALETRA. The number of baseline primary protease inhibitor mutations affects the virologic response to KALETRA.
- Once-daily administration of KALETRA is not recommended for adult therapy-experienced patients or any pediatric patients <18 years of age.
Important Safety Information2
KALETRA is contraindicated in patients with hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme) to any of its ingredients, including ritonavir.
Co-administration of KALETRA is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions, and with potent CYP3A inducers where significantly reduced lopinavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance. These contraindicated drugs include: cisapride, dihydroergotamine, ergonovine, ergotamine, methylergonovine, midazolam (oral), pimozide, triazolam, rifampin, St. John's wort(Hypericum perforatum), lovastatin, and simvastatin.
Consider drug-drug interaction potential to reduce the risk of serious or life-threatening adverse reactions. Alteration in dose or regimen, drug level monitoring, and increased observations for adverse events or clinical response may be recommended during co-administration of KALETRA with other CYP3A inducers, inhibitors or substrates. Please see full Prescribing Information for a listing of established or other potentially significant drug interactions.
KALETRA should not be administered once-daily in combination with efavirenz, nevirapine, (fos)amprenavir, nelfinavir, carbamazepine, phenobarbital, or phenytoin.
Pancreatitis, including some fatalities, has been observed in patients receiving KALETRA; suspend therapy as clinically appropriate.
Hepatotoxicity, including some fatalities, has been observed in patients receiving KALETRA. Monitor liver function before and during therapy, especially in patients with underlying hepatic disease including hepatitis B and hepatitis C, or marked transaminase elevations.
Patients receiving protease inhibitor therapy may develop new onset or exacerbations of diabetes mellitus or hyperglycemia.
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including KALETRA.
Redistribution/accumulation of body fat have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown.
Treatment with KALETRA has resulted in large increases in concentrations of total cholesterol and triglycerides. Monitor lipids prior to therapy and periodically thereafter.
There have been reports of increased bleeding in patients with hemophilia treated with protease inhibitors.
Various degrees of cross-resistance among protease inhibitors have been observed.
The safety, efficacy and pharmacokinetic profiles of KALETRA in pediatric patients below the age of 14 days have not been established. KALETRA once-daily has not been evaluated in pediatric patients.
Healthcare professionals should pay close attention to accurate calculation of the dose of KALETRA, transcription of the medication order, dispensing information, and dosing instructions to minimize the risk for medication errors, overdose, and underdose. The appropriate dose must be carefully calculated for each pediatric patient, based on the body weight or body surface area recommendations in the full Prescribing Information, and should not exceed the recommended adult dose.
In KALETRA clinical trials, the most common adverse reactions of moderate to severe intensity reported in ≥5% of adult patients were diarrhea, nausea, abdominal pain, asthenia, vomiting, headache, and dyspepsia. In children receiving KALETRA oral solution, the most common adverse reactions of any severity were taste aversion, vomiting, and diarrhea.
1 NORVIR [prescribing information]. North Chicago, IL: Abbott Laboratories
2 KALETRA [prescribing information]. North Chicago, IL: Abbott Laboratories
2009 Abbott Laboratories Abbott Park, IL 60064 036-217704 January 2009