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FDA HIV/AIDS List Serve Archive 2008

On September 3, 2008, FDA granted tentative approval for the first generic combination formulation of abacavir sulfate and lamivudine tablets, 600 mg/300 mg, manufactured by Aurobindo Pharma Limited, Hyberdad, India. Abacavir sulfate and lamivudine are antivral agents in the Nucleoside Reverse Transcriptase Inhibitor (NRTI) class.  Combining two therapeutic agents in a single pill facilitates dosing, storage and distribution, and may contribute to improved patient adherence to drug regimens.

"Tentative approval" means that FDA has concluded that a drug product meets all required quality, safety and efficacy standards, but is not eligible for marketing in the U.S. because of existing patents and/or exclusivity rights. Tentative approval, however, does make the product eligible for consideration for purchase outside the United States under the President’s Emergency Plan for AIDS Relief (PEPFAR) .

The application was reviewed under expedited review provisions developed for the PEPFAR program

This tentative approval is a generic version of Epzicom Tablets, 600 mg/300 mg, a product of SmithKline Beecham Corporation. Epzicom is subject to existing patent protection. Effective patent dates can be found in the agency's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "Orange Book"

As with all generic applications, FDA conducts an on-site inspection of each manufacturing facility, and of the facilities performing the bioequivalence studies, to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application prior to granting approval or tentative approval to these applications.

A list of all Approved and Tentatively Approved Antiretrovirals in Association with the President's Emergency Plan is available on the FDA website.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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FDA approved, on August 29, 2008, changes to the product label for Norvir (ritonavir) Soft Gelatin Capsules, and Norvir Oral Solution reflecting new, post marketing information regarding QT/QTc interval and PR interval prolongation information from Study M06-80. 

The patient package insert has been updated, as well, with language related to electrocardiogram changes and cardiac arrhythmias.

The following information was added to the product label:
Under Clinical Pharmacology –
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.  See PRECAUTIONS –PR Interval Prolongation.

Under Precautions –
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.
NORVIR 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. See CLINICAL PHARMACOLOGY - Effects on Electrocardiogram.

Under Information for Patients -
Cardiovascular System
First –degree AV block, second-degree AV block, third-degree AV block, right bundle branch block have been reported (See PRECAUTIONS – PR Interval Prolongation).

Under Adverse Reactions –
Cardiovascular System
First –degree AV block, second-degree AV block, third-degree AV block, right bundle branch block have been reported (See PRECAUTIONS – PR Interval Prolongation).

In addition, the following information has been added to the Patient Product Insert, under the section What are the Possible Side Effects of Norvir? –
Changes in the electrocardiogram (EKG). Consult your physician if you experience dizziness, lightheadedness, fainting spells or abnormal heart beat, Patients with heart defects or conduction defects should avoid NORVIR.

The complete, revised label is available on the FDA website at Drugs@FDA  (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/)

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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The Reyataz (atazanavir) package insert has been updated to include important drug-drug interaction information regarding the administration of Reyataz with or without ritonavir and nevirapine, efavirenz, hormonal contraceptives, orally and parenterally administered midazolam, H₂-receptor antagonists and drugs that are substrates of cytochrome P450 2C8. Below is a summary of the changes.

Nevirapine:
Do not coadminister Reyataz with nevirapine because:

• nevirapine substantially decreases atazanavir exposures, and
• potential risk exists for nevirapine associated toxicity due to increased nevirapine exposures

Efavirenz:
Efavirenz decreases Reyataz exposure:

• For treatment-naïve patients the recommended dose is Reyataz 400 mg with ritonavir 100 mg and efavirenz 600 mg once daily. Efavirenz should be taken on an empty stomach preferably at bedtime
• For treatment-experienced patients: Do not coadminister Reyataz with efavirenz because efavirenz decreases atazanavir exposure

Hormonal Contraceptives:
Use with caution if co-administration of Reyataz or Reyataz/ritonavir with oral contraceptives is considered. If an oral contraceptive is administered with Reyataz/ritonavir, it is recommended the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If Reyataz is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol.

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

Coadministration of Reyataz or Reyataz/ritonavir with other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectible contraceptives) or oral contraceptives containing progestagens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of non-hormonal contraception are recommended.

Midazolam:
Coadministration of oral midazolam with Reyataz is contraindicated. Concomitant use of parenteral midazolam with Reyataz may increase plasma concentrations of midazolam. Coadministration 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.

H₂-receptor antagonists:
The packaged insert already contains the following dosing information for treatment naïve patients. Reyataz 300 mg with ritonavir100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H₂-receptor antagonist. H₂-receptor antagonist dose comparable to famotidine 40 mg twice daily can be used with Reyataz 300 mg with ritonavir 100 mg in treatment-naïve patients.

The label was updated to add the following:
For treatment-naïve patients unable to tolerate ritonavir, Reyataz 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H2-receptor antagonist. No single dose of the H₂-receptor antagonist should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg.

Substrates of CYP2C8:
Atazanavir is a weak inhibitor of CY2C8. Caution should be used when Reyataz without ritonavir is coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (e.g. paclitaxel, repaglinide). When Reyataz with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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The Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection have been revised. The new version includes updated information on:

• Recommended antiretroviral regimens for initial therapy
• Nelfinavir, which now meets FDA limits for ethyl methane sulfonate (EMS)

The changes in this revision are highlighted in yellow throughout the text and tables. 

The updated guidelines are available for download from the Pediatric Guidelines section of the AIDSinfo Web site. You can also request to receive them by mail or email from the AIDSinfo Order Publications section.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On July 18, 2008, FDA approved changes to the package insert for Ziagen (abacavir sulfate) highlighting information about the association of the HLA-B*5701 allele (a part of a gene) and hypersensitivity reactions (HSR) caused by abacavir-containing therapy.

Abacavir is associated with serious and sometimes fatal HSR. Abacavir HSR is a multi-organ syndrome characterized by 2 or more clinical signs or symptoms including fever, rash, gastrointestinal symptoms (nausea, vomiting, diarrhea or abdominal pain), respiratory symptoms (dyspnea, cough or pharyngitis) and constitutional symptoms (generalized malaise, fatigue or myalgia). Occurrence of abacavir HSR requires immediate and permanent discontinuation of abacavir therapy.

The label change recommends screening patients for the HLA-B*5701 allele prior to initiating or reinitiating abacavir-containing therapy. Prospective screening for HLA-B*5701 and selection of alternative therapy for subjects who carry this allele will reduce the incidence of abacavir hypersensitivity (HSR) reaction and improve the safety profile of this drug.

The product label for abacavir has been updated to include the following new information:

WARNING: Risk of hypersensitivity Reactions, Lactic Acidosis

Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir. Prior to initiating therapy with abacavir, screening for the HLA-B*5701 allele is recommended; this approach has been found to decrease the risk of hypersensitivity reaction. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. HLA-B*5701-negative patients may develop a suspected hypersensitivity reaction to abacavir; however, this occurs significantly less frequently than in HLA-B*5701-positive patients.
Regardless of HLA-B*5701 status, permanently discontinue ZIAGEN if hypersensitivity cannot be ruled out, even when other diagnoses are possible.

5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reaction

Serious and sometimes fatal hypersensitivity reactions have been associated with ZIAGEN and other abacavir-containing products. Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir. Prior to initiating therapy with abacavir, screening for the HLA-B*5701 allele is recommended; this approach has been found to decrease the risk of a hypersensitivity reaction. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. For HLA-B*5701-positive patients, treatment with an abacavir-containing regimen is not recommended and should be considered only with close medical supervision and under exceptional circumstances when the potential benefit outweighs the risk.

HLA-B*5701-negative patients may develop a hypersensitivity reaction to abacavir; however, this occurs significantly less frequently than in HLA-B*5701-positive patients. Regardless of HLA-B*5701 status, permanently discontinue ZIAGEN if hypersensitivity cannot be ruled out, even when other diagnoses are possible.

When therapy with ZIAGEN has been discontinued for reasons other than symptoms of a hypersensitivity reaction, and if reinitiation of ZIAGEN or any other abacavir-containing product is under consideration, carefully evaluate the reason for discontinuation of ZIAGEN to ensure that the patient did not have symptoms of a hypersensitivity reaction. If the patient is of unknown HLA-B*5701 status, screening for the allele is recommended prior to reinitiation of ZIAGEN.

If hypersensitivity cannot be ruled out, DO NOT reintroduce ZIAGEN or any other abacavir-containing product. Even in the absence of the HLA-B*5701 allele, it is important to permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction.

Risk Factor: HLA-B*5701 Allele: Studies have shown that carriage of the HLA-B*5701 allele is associated with a significantly increased risk of a hypersensitivity reaction to abacavir.

CNA106030 (PREDICT-1), a randomized, double-blind study, evaluated the clinical utility of prospective HLA-B*5701 screening on the incidence of abacavir hypersensitivity reaction in abacavir-naive HIV-1-infected adults (n = 1,650). In this study, use of pre-therapy screening for the HLA-B*5701 allele and exclusion of subjects with this allele reduced the incidence of clinically suspected abacavir hypersensitivity reactions from 7.8% (66/847) to 3.4% (27/803). Based on this study, it is estimated that 61% of patients with the HLA-B*5701 allele will develop a clinically suspected hypersensitivity reaction during the course of abacavir treatment compared with 4% of patients who do not have the HLA-B*5701 allele.

Screening for carriage of the HLA-B*5701 allele is recommended prior to initiating treatment with abacavir. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. For HLA-B*5701-positive patients, initiating or reinitiating treatment with an abacavir-containing regimen is not recommended and should be considered only with close medical supervision and under exceptional circumstances where potential benefit outweighs the risk.

Skin patch testing is used as a research tool and should not be used to aid in the clinical diagnosis of abacavir hypersensitivity.

In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision-making. Even in the absence of the HLA-B*5701 allele, it is important to permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction.

The following new information has been added to the Medication Guide:

Under What is the most important information I should know about ZIAGEN?
Serious Allergic Reaction to Abacavir. ZIAGEN contains abacavir (also contained in EPZICOM(R) and TRIZIVIR(R)). Patients taking ZIAGEN may have a serious allergic reaction (hypersensitivity reaction) that can cause death. Your risk of this allergic reaction is much higher if you have a gene variation called HLA-B*5701 than if you do not. Your doctor can determine with a blood test if you have this gene variation. If you get a symptom from 2 or more of the following groups while taking ZIAGEN, call your doctor right away to determine if you should stop taking this medicine.

Under Who should not take ZIAGEN?
Before starting ZIAGEN, tell your doctor about all of your medical conditions, including if you:
have been tested and know whether or not you have a particular gene variation called HLA-B*5701.

You can find the complete revised label on the FDA web site at Drugs@FDA, entering "Ziagen," clicking on the NDA number, and following the link to the product label.

Labeling for the abacavir-containing combination products marketed as Trizivir and Epzicom will be updated through labeling supplements in the near future.

The labeling changes described here are predicated on data from two studies. CNA106030 (PREDICT-1), a prospective, randomized, double-blind study, evaluated the clinical utility of pre-therapy HLA-B*5701 screening compared to no screening on the incidence of abacavir hypersensitivity reaction in abacavir-naive, HIV-1 infected subjects. ABC107442 (SHAPE), a retrospective, case-control study was designed to evaluate the sensitivity and specificity of the HLA-B*5701 allele with respect to abacavir HSR within the racial groups of black and white subjects in the United States. These studies support the recommendation for pre-therapy screening for patients carrying the HLA-B*5701 allele and selection of alternative therapy in positive subjects. Avoidance of abacavir therapy in HLA-B*5701 positive patients will significantly decrease the risk of developing clinical abacavir hypersensitivity.

Abacavir HSR generally develops within the first 6 weeks of initiation of therapy (median 11 days) in the majority of subjects who are affected. However, due to the wide range of clinical signs and symptoms that may signify the development of abacavir HSR, and confounding multiple antiretroviral and prophylactic medications, definitive diagnosis can sometimes be difficult. Earlier studies suggested a genetic basis relating to the development of abacavir HSR.

The Medication Guide and Warning Card that provide information about signs and symptoms of hypersensitivity reactions is dispensed with every new prescription and refill, and an Abacavir Hypersensitivity Registry has been established to encourage providers to register patients by calling a "1-800" number listed in the product label to allow FDA to monitor post marketing cases of abacavir hypersensitivity.

Abacavir is a nucleoside reverse transcriptase inhibitor (NRTI) antiretroviral indicated in combination with other antiretroviral agents for treatment of HIV-1 infection in adult and pediatric patients, manufactured by Glaxo SmithKline.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On June 26, 2008, FDA granted approval for a generic Zidovudine Oral Solution USP, 50 mg/5 mL formulation manufactured by Cipla Limited of of Mumbai, India.  The is a full approval, meaning that this generic zidovudine formulation can be marketed in the United States. The application was reviewed under the expedited review provisions of the President's Emergency Plan for AIDS Relief (PEPFAR).

Other oral solution and tablet dosage forms of generic zidovudine were approved for sale in the United States following expiration of patents for GlaxoSmithKline's Retrovir brand product.

A list of FDA approved generic antiretroviral drugs for the treatment of HIV is available on the web at http://www.fda.gov/oashi/aids/viralsgeneric.html

Zidovudine is in the class of drugs called nucleoside reverse transcriptase inhibitors (NRTIs), which help keep the AIDS virus from reproducing.  This anti-retroviral drug is intended to be used with other anti-retroviral agents for the treatment of HIV-1 infection.

The approval of generic zidovudine means that there are no existing patents and/or exclusivity preventing the approval of generic versions of this product to prevent marketing in the United States. 

As with all FDA-approved generics, this product must meet all of FDA's manufacturing quality, and clinical safety and effectiveness standards for U.S. marketing. 

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On June  24, 2008, FDA approved labeling changes to the Viramune (nevirapine) oral solution and tablets to reflect various updates, including:

• Dosing recommendations for pediatric patients 15 days to 2 months of age.
• Dose recommendations for all pediatric age groups are now based on body surface area (BSA) instead of weight-based dosing.  Studies were conducted comparing weight-based dosing and BSA-based dosing.  While comparable drug concentrations are achieved with either method, BSA dosing allows for smoother dose transitions between pediatric age groups and is therefore preferred.
• Addition of data from a pharmacokinetic hepatic impairment study
• Revision of the recommendation that nevirapine not be administered to patients with severe hepatic impairment to a recommendation that nevirapine not be administered to patients with moderate (Childs Pugh B) or severe (Childs Pugh C) hepatic impairment.
• Revision of recommendations for the occurrence of rash during the once daily lead-in phase of dosing. The label now states that lead-in dosing should not be extended beyond 28 days of dosing.

Important changes made to the product label include the following: 

Under Dosage and Administrations (2.0)

Pediatric Patients (2.2)

The recommended oral dose for pediatric patients 15 days and older is 150 mg/m² once daily for 14 days followed by 150 mg/m² twice daily thereafter.  The total daily dose should not exceed 400 mg for any patient.

Table 1  Calculation of the Volume of VIRAMUNE Oral Suspension (50 mg/5 mL) Required for Pediatric Dosing Based on Body Surface and a Dose of 150 mg/m²

BSA range (m²)       Volume (mL)

0.06 – 0.12                1.25

0.12 – 0.25                2.5

0.25 – 0.42                5

0.42 – 0.58                7.5

0.58 – 0.75                10

0.75 – 0.92                12.5

0.92 – 1.08                15

1.08 – 1.25                17.5

1.25+                         20

Dosage Adjustment (2.4)

Patients with Rash

VIRAMUNE should be discontinued if a patient experiences severe rash or any rash accompanied by constitutional findings [see Boxed Warning, Warnings and Precautions (5.2), and Patient Counseling Information (17.1)]. A patient experiencing mild to moderate rash without constitutional symptoms during the 14-day lead-in period of 200 mg/day (150 mg/m²/day in pediatric patients) should not have their VIRAMUNE dose increased until the rash has resolved [see Warnings and Precautions (5.2) and Patient Counseling Information (17.1)].  The total duration of the once daily lead-in dosing period should not exceed 28 days at which point an alternative regimen should be sought.

Under Use in Specific Populations (8.0)

Hepatic Impairment (8.7)

Because increased nevirapine levels and nevirapine accumulation may be observed in patients with serious liver disease, do not administer VIRAMUNE to patients with moderate or severe (Child Pugh Class B or C, respectively) hepatic impairment  [see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

Under Pharmacokinetics (12.3)

Hepatic Impairment 

In a steady state study comparing 46 patients with mild (n=17; expansion of some portal areas; Ishak Score 1-2), moderate (n=20; expansion of most portal areas with occasional portal-to-portal and portal-to-central bridging; Ishak Score 3-4), or severe (n=9;  marked bridging with occasional cirrhosis without decompensation indicating Child-Pugh A; Ishak Score 5-6) fibrosis as a measure of hepatic impairment, the multiple dose pharmacokinetic disposition of nevirapine and its five oxidative metabolites were not altered. However, approximately 15% of these patients with hepatic fibrosis had nevirapine trough concentrations above 9,000 ug/mL (2-fold the usual mean trough). Therefore, patients with hepatic impairment should be monitored carefully for evidence of drug induced toxicity [see Warnings and Precautions (5.1)]. The patients studied were receiving antiretroviral therapy containing Viramune 200 mg twice-daily for at least 6 weeks prior to pharmacokinetic sampling, with a median duration of therapy of 3.4 years.

Pediatric Patients

Pharmacokinetic data for nevirapine have been derived from two sources: a 48 week pediatric trial in South Africa (BI Trial 1100.1368) involving 123 HIV-1 positive, antiretroviral naïve patients aged 3 months to 16 years; and a consolidated analysis of five Pediatric AIDS Clinical Trials Group (PACTG) protocols comprising 495 patients aged 14 days to 19 years.

BI Trial 1100.1368 studied the safety, efficacy, and pharmacokinetics of a weight-based and a body surface area (BSA)-based dosing regimen of nevirapine. In the weight-based regimen, pediatric patients up to 8 years of age received a dose of 4 mg/kg once daily for two weeks followed by 7 mg/kg twice daily thereafter.  Patients 8 years and older were dosed 4 mg/kg once daily for two weeks followed by 4 mg/kg twice daily thereafter.  In the BSA regimen all pediatric patients received 150 mg/m² once daily for two weeks followed by 150 mg/m² twice daily thereafter [see Use in Specific Populations (8.4) and Adverse Reactions (6.2)].  Dosing of nevirapine at 150 mg/m² BID (after a two-week lead in of 150 mg/m² QD) produced geometric mean or mean trough nevirapine concentrations between 4-6 µg/mL (as targeted from adult data). In addition, the observed trough nevirapine concentrations were comparable between the two dosing regimens studied (BSA and weight-based methods).

The consolidated analysis of Pediatric AIDS Clinical Trials Group (PACTG) protocols 245, 356, 366, 377, and 403 allowed for the evaluation of pediatric patients less than 3 months of age (n=17).  The plasma nevirapine concentrations observed were within the range observed in adults and the remainder of the pediatric population, but were more variable between patients, particularly in the second month of age.  For dose recommendations for pediatric patients see Dosage and Administration (2.2).

Under Clinical Studies (14.0)

Clinical Studies in Pediatric Patients (14.2)

The pediatric safety and efficacy of VIRAMUNE was examined in BI Trial 1100.1368, an open-label, randomized clinical study performed in South Africa in which 123 HIV-1 infected treatment naïve patients between 3 months and 16 years of age received VIRAMUNE oral solution for 48 weeks. Patients were divided into 4 age groups (3 months to <2 years, 2 to <7 years, 7 to <12 years, and 12 to ≤16 years) and randomized to receive one of two VIRAMUNE doses, determined by 2 different dosing methods [body surface area (150mg/m²) and weight-based dosing (4 or 7mg/kg)] in combination with zidovudine and lamivudine [see Adverse Reactions (6.2),Use in Specific Population (8.4), and Clinical Pharmacology (12.3)]. The total daily dose of VIRAMUNE did not exceed 400 mg in either regimen. There were 66 patients in the body surface area (BSA) dosing group and 57 patients in the weight-based (BW) dosing group. 

Baseline demographics included: 49% male; 81% Black and 19% Caucasian; 4% had previous exposure to ARVs.  Patients had a median baseline HIV RNA of 5.45 log10 copies/mL and a median baseline CD4 cell count of 527 cells/mm³ (range 37-2279). One hundred and five (85%) completed the 48 weeks period while  18 (15%) discontinued prematurely. Of the patients who discontinued prematurely, 9 (7%) discontinued due to adverse reactions and 3 (2%) discontinued due to virologic failure. Overall the proportion of patients who achieved and maintained an HIV RNA <400 copies/mL at 48 weeks was 47% (58/123).  For dose recommendations for pediatric patients see Dosage and Administration (2.2).

You can view the complete, updated labeling using this link to Drugs@FDA , clicking on the appropriate dosage form, and folloing links for “Labeling Information.”

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On June 23, 2008, FDA approved a new Aptivus (tipranavir) oral solution (100 mg/mL). The product label has been updated to include dosing recommendations for pediatric patients 2-18 years of age.  

In addition, information regarding oral and parenterally administered midazolam was updated in the Contraindication and Drug Interactions section.

The changes are described below:

Pediatric Patient Information:

The dose selection for children ages 2-18 years of age including possible dose reduction was based on the following information. This information is also contained in section 14.2 Pediatric Studies

• A greater proportion of patients receiving APTIVUS/ritonavir 375 mg/m2/150 mg/m2 compared to 290 mg/m2/115 mg/m² achieved HIV-1 RNA < 400 and < 50 copies/mL.
• A greater proportion of patients 6 to18 years of age with multiple baseline protease inhibitor resistance-associated substitutions receiving APTIVUS/ritonavir 375 mg/m2/150 mg/m2 achieved HIV-1 RNA <400 copies/mL at 48 weeks compared to patients receiving APTIVUS/ritonavir 290 mg/m²/115 mg/m².
• No clinically significant increase in adverse event rates observed with 375 mg/m²/150 mg/m² compared to 290 mg/m²/115 mg/m²
• Overall, 6 (5%) patients ages 6 to18 had AIDS defining illness during the treatment period and all received the 290 mg/m²/115 mg/m² dose.

The guidance for possible dose reduction for patients who develop intolerance or toxicity and cannot continue with APTIVUS/ritonavir 14 mg/kg/6 mg/kg (or 375 mg/m²/150 mg/m² ) is based on the following:

• The 290 mg/m²/115 mg/m² twice daily regimen provided tipranavir plasma concentrations similar to those obtained in adults receiving 500/200 mg twice-daily. The 375 mg/m2/150 mg/m² twice daily regimen provided tipranavir plasma concentrations 37% higher than those obtained in adults receiving 500/200 mg twice-daily.
• The observed response rates for APTIVUS/ritonavir dose of 290 mg/m2/115 mg/m²

Dose reduction is not appropriate for patients whose virus is resistant to more than one protease inhibitor.

Dosing in children (2 – 18 years of age) is based on body weight or body surface area (size). The Dosage and Administration section 2.2 Pediatric Patients was updated to include the following.

APTIVUS must be co-administered with ritonavir and can be taken with or without food

APTIVUS may be administered as either capsules or oral solution to either pediatric or adult patients.

2.2 Pediatric Patients (age 2 to 18 years)
Healthcare professionals should pay special attention to accurate calculation of the dose of APTIVUS, transcription of the medication order, dispensing information and dosing instruction to minimize risk for medication errors, overdose, and underdose.

Prescribers should calculate the appropriate dose of APTIVUS for each individual child based on body weight (kg) or body surface area (BSA, m2) and should not exceed the recommended adult dose.

Before prescribing APTIVUS 250 mg capsules, children should be assessed for the ability to swallow capsules. If a child is unable to reliably swallow an APTIVUS capsule, the APTIVUS oral solution formulation should be prescribed.

The recommended pediatric dose of APTIVUS is 14 mg/kg with 6 mg/kg ritonavir (or 375 mg/m2 co-administered with ritonavir 150 mg/m2) taken twice daily not to exceed a maximum dose of APTIVUS 500 mg co-administered with ritonavir 200 mg twice daily. For children who develop intolerance or toxicity and cannot continue with APTIVUS 14 mg/kg with 6 mg/kg ritonavir, physicians may consider decreasing the dose to APTIVUS 12 mg/kg with 5 mg/kg ritonavir (or APTIVUS 290 mg/m² co-administered with 115 mg/m² ritonavir) taken twice daily provided their virus is not resistant to multiple protease inhibitors. [See Adverse Reactions (6.2), Use in Specific Populations (8.4) and Clinical Studies (14.2)].

Body surface area (BSA) can be calculated as follows:

Section 5 Warnings and Precautions subsection 5.4 Effects on Platelet Aggregation and Coagulation was updated as follows:

In rats, tipranavir treatment alone induced dose-dependent changes in coagulation parameters, bleeding events and death. Co-administration with vitamin E significantly increased these effects. However, analyses of stored plasma from adult patients treated with APTIVUS capsules and pediatric patients treated with APTIVUS oral solution (which contains a vitamin E derivative) showed no effect of APTIVUS/ritonavir on vitamin K-dependent coagulation factors (Factor II and Factor VII), Factor V, or on prothrombin or activated partial thromboplastin times.

In in vitro experiments, tipranavir was observed to inhibit human platelet aggregation at levels consistent with exposures observed in patients receiving APTIVUS/ritonavir

A new Warning and Precaution was added for patients receiving the oral solution formulation.

5.5 Vitamin E Intake
Patients taking APTIVUS oral solution should be advised not to take supplemental vitamin E greater than a standard multivitamin as APTIVUS oral solution contains 116 IU/mL of vitamin E which is higher than the Reference Daily Intake (adults 30 IU, pediatrics approximately 10 IU).

Subsection 5.6 Rash was revised to include rash information in children

In the pediatric clinical trial, the frequency of rash (all grades, all causality) through 48 weeks of treatment was 21%. Overall, most of the pediatric patients had mild rash and 5 (5%) had moderate rash. Overall 3% of pediatric patients interrupted APTIVUS treatment due to rash and the discontinuation rate for rash in pediatric patients was 0.9%.

The following information was added to section 6 Adverse Reactions subsection 6.2 Pediatric Patients - Clinical Trials Experience

6.2 Clinical Trials in Pediatric Patients
APTIVUS, co-administered with ritonavir, has been studied in a total of 135 HIV-1 infected pediatric patients age 2 through 18 years as combination therapy. This study enrolled HIV-1 infected, treatment-experienced pediatric patients (with the exception of 3 treatment naïve patients), with baseline HIV-1 RNA of at least 1500 copies/mL. One hundred and ten (110) patients were enrolled in a randomized, open-label 48-week clinical trial (Study 1182.14) and 25 patients were enrolled in other clinical studies including Expanded Access and Emergency Use Programs.

The adverse reactions profile seen in Study 1182.14 was similar to adults. Pyrexia (6.4%), vomiting (5.5%), cough (5.5%), rash (5.5%), nausea (4.5%), and diarrhea (3.6%) were the most frequently reported adverse reactions (Grade 2-4, all causes) in pediatric patients. Rash was reported more frequently in pediatric patients than in adults.

The most common Grade 3-4 laboratory abnormalities were increase in CPK (11%), ALT (6.5%), and amylase (7.5%).

Due to previous reports of both fatal and non-fatal intracranial hemorrhage (ICH), an analysis of bleeding events was performed. At 48 weeks of treatment, the frequency of pediatric patients with any bleeding adverse reactions was 7.5%. No drug related serious bleeding adverse reaction was reported. The most frequent bleeding adverse reaction was epistaxis (3.7%). No other bleeding adverse reaction was reported in frequency of >1%. Additional trial follow-up through 100 weeks showed a cumulative 12% frequency of any bleeding adverse reaction.

The following information was added to Section 8 Use in Specific Populations subsection 8.4 Pediatric Use

The safety, pharmacokinetic profile, and virologic and immunologic responses of APTIVUS oral solution and capsules were evaluated in HIV-1 infected pediatric patients age 2 to 18 years.

The most frequent adverse reactions (grades 2-4) were similar to those described in adults. However, rash was reported more frequently in pediatric patients than in adults

The risk-benefit has not been established in pediatric patients <2 years of age.

Section 12.3 Pharmacokinetics was updated as follows

Among pediatric patients in clinical trial 1182.14, steady-state plasma tipranavir trough concentrations were obtained 10 to 14 hours following study drug administration.

Pharmacokinetic parameters by age group are presented in Table 6.

^a Population pharmacokinetic parameters reported as mean ± standard deviation

Section 12.4 Microbiology was updated to include statements regarding the similar resistance profile in adults and pediatric patients. Also substitution at position I54V/A/M was included in the list of other substitutions that developed in 10-20% of Aptivus/ritonavir virologic failure isolates.

Section 14 Clinical Studies subsection 14.4 Pediatric Studies was also updated with the following study results.

The pharmacokinetic profile, safety and activity of APTIVUS/ritonavir was evaluated in a randomized, open-label, multicenter study. This study enrolled HIV-1 infected, treatment-experienced pediatric patients (with the exception of 3 treatment naïve patients), with baseline HIV-1 RNA of at least 1500 copies/mL. The age ranged from 2 through 18 years and patients were stratified by age (2 to < 6 years, 6 to < 12 years and 12 to 18 years). One hundred and ten (110) patients were randomized to receive one of two APTIVUS/ritonavir dose regimens: 375 mg/m²/150 mg/m² dose (N=55) or 290 mg/m²/115 mg/m² dose (N=55), plus background therapy of at least two non-protease inhibitor antiretroviral drugs, optimized using baseline genotypic resistance testing. All patients initially received APTIVUS oral solution. Pediatric patients who were 12 years or older and received the maximum dose of 500/200 mg BID could subsequently change to APTIVUS capsules at day.

Demographics and baseline characteristics were balanced between the APTIVUS/ritonavir dose groups. The 110 randomized pediatric patients had a median age of 11.7 years (range 2 to18), and were 57.2% male, 68.1% white, 30% black, and 1.8% Asian. The median baseline plasma HIV-1 RNA was 4.7 (range 3.0 to 6.8) log10 copies/mL and median baseline CD4+ cell count was 379 (range 2 to 2578) cells/mm³. Overall, 37.4% of patients had a baseline HIV-1 RNA of >100,000 copies/mL; 28.7% had a baseline CD4+ cell count ≤ 200 cells/mm³, and 48% had experienced a prior AIDS defining Class C event at baseline. Patients had prior exposure to a median of 4 NRTIs, 1 NNRTI, and 2 PIs.

Eighty three (75%) completed the 48 week period while 25% discontinued prematurely. Of the patients who discontinued prematurely, 9 (8%) discontinued due to virologic failure, and 9 (8%) discontinued due to adverse reactions.

At 48 weeks, 40% of patients had viral load <400 copies/mL. The proportion of patients with viral load <400 copies/mL tended to be greater (70%) in the youngest group of patients, who had less baseline viral resistance, compared to the older groups (37% and 31%). The HIV-1 RNA results are presented in Table 13.

*The number of baseline tipranavir resistance-associated substitutions were fewer in the 2 to <6 year old patients than the 6 to 18 year old patients enrolled in study 1182.14

The dose selection for all age groups was based on the following:

• A greater proportion of patients receiving APTIVUS/ritonavir 375 mg/m²/150 mg/m² compared to 290 mg/m²/115 mg/m2 achieved HIV-1 RNA < 400 and < 50 copies/mL.
• A greater proportion of patients 6 to18 years of age with multiple baseline protease inhibitor resistance-associated substitutions receiving APTIVUS/ritonavir 375 mg/m²/150 mg/m² achieved HIV-1 RNA <400 copies/mL at 48 weeks compared to patients receiving APTIVUS/ritonavir 290 mg/m²/115 mg/m².
• No clinically significant increase in adverse event rates observed with 375 mg/m²/150 mg/m² compared to 290 mg/m²/115 mg/m²
• Overall, 6 (5%) patients ages 6 to18 had AIDS defining illness during the treatment period and all received the 290 mg/m²/115 mg/m² dose.

The guidance for possible dose reduction for patients who develop intolerance or toxicity and cannot continue with APTIVUS/ritonavir 14 mg/kg/6 mg/kg (or 375 mg/m²/150 mg/m² ) is based on the following:

• The 290 mg/m2/115 mg/m² twice daily regimen provided tipranavir plasma concentrations similar to those obtained in adults receiving 500/200 mg twice-daily. The 375 mg/m²/150 mg/m² twice daily regimen provided tipranavir plasma concentrations 37% higher than those obtained in adults receiving 500/200 mg twice-daily.
• The observed response rates for APTIVUS/ritonavir dose of 290 mg/m²/115 mg/m² as shown in Table 13.

Dose reduction is not appropriate for patients whose virus is resistant to more than one protease inhibitor.

When body surface area (BSA) dosing is converted to mg/kg dosing, the APTIVUS/ritonavir 375 mg/m²/150 mg/m² twice daily regimen is similar to 14 mg/kg/6 mg/kg and APTIVUS/ritonavir 290 mg/m²/115 mg/m² twice daily regimen is similar to 12 mg/kg/5 mg/kg twice daily .

Section 16 How Supplied/Storage and Handling was updated to provide information for the oral solution formulation as follows:

APTIVUS oral solution is a clear yellow viscous buttermint-butter toffee flavored liquid containing 100 mg tipranavir in each mL. The solution is supplied in a unit-of-use amber glass bottle providing 95 mL of solution with a child resistant closure. A 5 mL plastic oral dispensing syringe is also provided. (NDC 0597-0002-01)

Storage

APTIVUS oral solution should be stored at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Do not refrigerate or freeze. The solution must be used within 60 days after first opening the bottle.

Midazolam Information:

Orally administered midazolam is contraindicated for use with Aptivus. This change is reflected in section 4 Contraindications.

Section 7 Drug Interactions Table 4 Established and Other Potentially Significant Drug Interactions was updated to include information on parenterally administered midazolam and includes the following statement.

Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, Aptivus should not be given with orally administered midazolam. If Aptivus is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.

The Kaletra (lopinavir/ritonavir) Tablet and Oral Solution labels were updated to include dosing recommendations for pediatric patients 14 days to 6 months of age and from 12 to 18 years of age.

 In addition, information regarding oral and parenterally administered midazolam was updated in the Contraindication and Drug Interactions section.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration 

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The Kaletra (lopinavir/ritonavir) Tablet and Oral Solution labels were updated to include dosing recommendations for pediatric patients 14 days to 6 months of age and from 12 to 18 years of age. In addition, information regarding oral and parenterally administered midazolam was updated in the Contraindication and Drug Interactions section.

Pediatric Patient Information:

Dose selection in pediatric patients was based on the following. This information is also contained in section 14.4 Pediatric Studies

• Among patients 14 days to 6 months of age receiving 300/75 mg/m2 twice daily without nevirapine, plasma concentrations were lower than those observed in adults or in older children. This dose resulted in HIV-1 RNA < 400 copies/mL in 55% of patients (70% in those initiating treatment at <6 weeks of age).
• Among patients 6 months to 12 years of age, the 230/57.5 mg/m² oral solution twice daily regimen without nevirapine and the 300/75 mg/m2 oral solution twice daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice daily regimen (without nevirapine). These doses resulted in treatment benefit (proportion of patients with HIV-1 RNA < 400 copies/mL) similar to that seen in the adult clinical trials.
• Among patients 12 to 18 years of age receiving 400/100 mg/m² or 480/120 mg/m² (with efavirenz) twice daily, plasma concentrations were 60-100% higher than among 6 to 12 year old patients receiving 230/57.5 mg/m2. Mean apparent clearance was similar to that observed in adult patients receiving standard dose and in patients 6 to 12 years of age. Although changes in HIV-1 RNA in patients with prior treatment failure were less than anticipated, the pharmacokinetic data supports use of similar dosing as in patients 6 to 12 years of age, not to exceed the recommended adult dose.
• For all age groups, the body surface area dosing was converted to body weight dosing using the actual patient dose

Dosing in children (14 days – 18 years of age) is based on body weight or body surface area (size). The Dosage and Administration section 2.2 Pediatric Patients was updated to include the following.

2.2 Pediatric Patients

KALETRA tablets and oral solution should not be administered once-daily in pediatric patients < 18 years of age.

Healthcare professionals should pay special 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.

Prescribers should calculate the appropriate dose of KALETRA for each individual child based on body weight (kg) or body surface area (BSA) and should not exceed the recommended adult dose.

Body surface area (BSA) can be calculated as follows:

The KALETRA dose can be calculated based on weight or BSA:
Based on Weight:
Patient Weight (kg) × Prescribed lopinavir dose (mg/kg) = Administered lopinavir dose (mg)
Based on BSA:
Patient BSA (m²) × Prescribed lopinavir dose (mg/m²) = Administered lopinavir dose (mg)

If KALETRA oral solution is used, the volume (mL) of KALETRA solution can be determined as follows:

Volume of KALETRA solution (mL) = Administered lopinavir dose (mg) ÷ 80 (mg/mL)

The dose of the oral solution should be administered using a calibrated dosing syringe.

Before prescribing KALETRA 100/25 mg tablets, children should be assessed for the ability to swallow intact tablets. If a child is unable to reliably swallow a KALETRA tablet, the KALETRA oral solution formulation should be prescribed.

14 Days to 6 Months:

In pediatric patients 14 days to 6 months of age, the recommended dosage of lopinavir/ritonavir using KALETRA oral solution is 16/4 mg/kg or 300/75 mg/m² twice daily. Prescribers should calculate the appropriate dose based on body weight or body surface area.

Because no data exists for dosage when administered with efavirenz, nevirapine, (fos)amprenavir, or nelfinavir, it is recommended that KALETRA not be administered in combination with these drugs in patients < 6 months of age.

6 Months to 18 Years:
Without Concomitant Efavirenz, Nevirapine, (Fos)amprenavir or Nelfinavir

In children 6 months to 18 years of age, the recommended dosage of lopinavir/ritonavir using KALETRA oral solution without concomitant efavirenz, nevirapine, (fos)amprenavir or nelfinavir is 230/57.5 mg/m2 given twice daily, not to exceed the recommended adult dose. If weight-based dosing is preferred, the recommended dosage of lopinavir/ritonavir for patients < 15 kg is 12/3 mg/kg given twice daily and the dosage for patients > 15 kg to 40 kg is 10/2.5 mg/kg given twice daily.

Table 1 provides the dosing recommendations for pediatric patients 6 months to 18 years of age based on body weight or body surface area for KALETRA tablets.

*KALETRA oral solution is available for children with a BSA less than 0.6 m² or those who are unable to reliably swallow a tablet.

Concomitant Therapy: Efavirenz, Nevirapine, (Fos)amprenavir, or Nelfinavir

A dose increase of KALETRA to 300/75 mg/m2 is needed when co-administered with efavirenz, nevirapine, (fos)amprenavir, or nelfinavir in children (both treatment-naïve and treatment-experienced) 6 months to 18 years of age, not to exceed the recommended adult dose. If weight-based dosing is preferred, the recommended dosage for patients <15 kg is 13/3.25 mg/kg given twice daily and the dosage for patients >15 kg to 45 kg is 11/2.75 mg/kg given twice daily.

Table 2 provides the dosing recommendations for pediatric patients 6 months to 18 years of age based on body weight or body surface area for KALETRA tablets when given in combination with efavirenz, nevirapine, (fos)amprenavir, or nelfinavir.

*KALETRA oral solution is available for children with a BSA less than 0.6 m2 or those who are unable to reliably swallow a tablet.
† Please refer to the individual product labels for appropriate dosing in children

The following information was added to section 6 Adverse Reactions subsection 6.2 Pediatric Patients - Clinical Trials Experience

KALETRA oral solution dosed at 300/75 mg/m2 has been studied in 31 pediatric patients 14 days to 6 months of age. The adverse reaction profile in Study 1030 was similar to that observed in older children and adults. No adverse reaction was reported in greater than 10% of subjects. Adverse drug reactions of moderate to severe intensity occurring in 2 or more subjects included decreased neutrophil count (N=3,) anemia (N=2), high potassium (N=2), and low sodium (N=2).

KALETRA oral solution and soft gelatin capsules dosed at higher than recommended doses including 400/100 mg/m2 (without concomitant NNRTI) and 480/120 mg/m2 (with concomitant NNRTI) have been studied in 26 pediatric patients 7 to 18 years of age in Study 1038. Patients also had saquinavir mesylate added to their regimen at Week 4. Rash (12%), blood cholesterol abnormal (12%) and blood triglycerides abnormal (12%) were the only adverse reactions reported in greater than 10% of subjects. Adverse drug reactions of moderate to severe intensity occurring in 2 or more subjects included rash (N=3), blood triglycerides abnormal (N=3), and electrocardiogram QT prolonged (N=2). Both subjects with QT prolongation had additional predisposing conditions such as electrolyte abnormalities, concomitant medications, or pre-existing cardiac abnormalities.

The following information was added to Section 8 Use in Specific Populations subsection 8.4 Pediatric Use

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.
An open-label, multi-center, dose-finding trial was performed to evaluate the pharmacokinetic profile, tolerability, safety and efficacy of KALETRA oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL at a dose of with 300/75 mg/m2 twice daily plus two NRTIs in HIV-infected infants ≥14 days and < 6 months of age. Results revealed that infants younger than 6 months of age generally had lower lopinavir AUC12 than older children (6 months to 12 years of age), however, despite the lower lopinavir drug exposure observed, antiviral activity was demonstrated as reflected in the proportion of subjects who achieved HIV-RNA <400 copies/mL at Week 24.

Safety and efficacy in pediatric patients > 6 months of age was demonstrated in a clinical trial in 100 patients. The clinical trial was an open-label, multicenter trial evaluating the pharmacokinetic profile, tolerability, safety, and efficacy of KALETRA oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL in 100 antiretroviral naïve and experienced pediatric patients ages 6 months to 12 years. Dose selection for patients 6 months to 12 years of age was based on the following results. The 230/57.5 mg/m2 oral solution twice-daily regimen without nevirapine and the 300/75 mg/m2 oral solution twice-daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice-daily regimen (without nevirapine).

A prospective multicenter, open-label trial evaluated the pharmacokinetic profile, tolerability, safety and efficacy of high-dose KALETRA with or without concurrent NNRTI therapy (Group 1: 400/100 mg/m2 twice daily + ≥ 2 NRTIs; Group 2: 480/120 mg/m2 twice daily + ≥ 1 NRTI + 1 NNRTI) in children and adolescents ≥ 2 years to < 18 years of age who had failed prior therapy. Patients also had saquinavir mesylate added to their regimen. This strategy was intended to assess whether higher than approved doses of KALETRA could overcome protease inhibitor cross-resistance. High doses of KALETRA exhibited a safety profile similar to those observed in previous trials; changes in HIV-1 RNA were less than anticipated; three patients had HIV-1 RNA <400 copies/mL at Week 48. CD4+ cell count increases were noted in the eight patients who remained on treatment for 48 weeks.

Section 12.3 Pharmacokinetics was updated as follows

The pharmacokinetics of KALETRA oral solution at approximately 300/75 mg/m2 twice-daily have also been evaluated in infants at approximately 6 weeks of age (n = 9) and between 6 weeks and 6 months of age (n = 18) in Study 1030. The mean steady-state lopinavir AUC, 12Cmax, and C12 were 43.4 ± 14.8 μg• h/mL, 5.2 ± 1.8 μg/mL and 1.9 ± 1.1 μg/mL, respectively, in infants at approximately 6 weeks of age, and 74.5 ± 37.9 μg• h/mL, 9.4 ± 4.9 and 3.1 ± 1.8 μg/mL, respectively, in infants between 6 weeks and 6 months of age after KALETRA oral solution was administered at approximately 300/75 mg/m2 twice-daily without concomitant NNRTI therapy.

The pharmacokinetics of KALETRA soft gelatin capsule and oral solution (Group 1: 400/100 mg/m2 twice daily + 2 NRTIs; Group 2: 480/120 mg/m2 twice daily + ≥ 1 NRTI + 1 NNRTI) have been evaluated in children and adolescents age ≥ 2 years to < 18 years of age who had failed prior therapy (n=26) in Study 1038. KALETRA doses of 400/100 and 480/120 mg/m2 resulted in high lopinavir exposure, as almost all subjects had lopinavir AUC12 above 100 μg•h/mL. Both groups of subjects also achieved relatively high average minimum lopinavir concentrations.

KALETRA once-daily has not been evaluated in pediatric patients.

Section 14 Clinical Studies subsection 14.4 Pediatric Studies was also updated with the following study results.

Study 1030 was an open-label, multicenter, dose-finding trial evaluating the pharmacokinetic profile, tolerability, safety and efficacy of KALETRA oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL at a dose of 300/75 mg/m2 twice daily plus 2 NRTIs in HIV-1 infected infants ≥14 days and <6 months of age.

Ten infants, ≥14 days and <6 wks of age, were enrolled at a median (range) age of 5.7 (3.6-6.0) weeks and all completed 24 weeks. At entry, median (range) HIV-1 RNA was 6.0 (4.7-7.2) log10 copies/mL. Seven of 10 infants had HIV-1 RNA <400 copies/mL at Week 24. At entry, median (range) CD4+ percentage was 41 (16-59) with a median decrease of 1% (95% CI: -10, 18) from baseline to week 24 in 6 infants with available data.

Twenty-one infants, between 6 weeks and 6 months of age, were enrolled at a median (range) age of 14.7 (6.9-25.7) weeks and 19 of 21 infants completed 24 weeks. At entry, median (range) HIV RNA level was 5.8 (3.7-6.9) log10 copies/mL. Ten of 21 infants had HIV RNA <400 copies/mL at Week 24. At entry, the median (range) CD4+ percentage was 32 (11-54) with a median increase of 4% (95% CI: -1, 9) from baseline to week 24 in 19 infants with available data.

Midazolam Information:

Orally administered midazolam is contraindicated for use with Kaletra. This change is reflected in section 4 Contraindications.

Section 7 Drug Interactions Table 9 Established and Other Potentially Significant Drug Interactions was updated to include information on parenterally administered midazolam and includes the following statement.

Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On June 19, 2008, FDA granted tentative approval to fixed dose combination lamivudine/stavudine tablets, 30mg/6mg & 60mg/12mg for oral suspension for pediatric use, manufactured by Cipla Limited of Mumbai, India. The application was reviewed under expedited review provisions for the President’s Emergency Plan for AIDS Relief (PEPFAR),

Lamivudine and stavudine are anti-viral drugs indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. Combination products such as this one can decrease pill burden and could result in improved dosing compliance for HIV infected individuals.

FDA's tentative approval of this product means that although existing patents and/or exclusivity prevent marketing of this product in the United States, the product has been shown to meet all of FDA's safety, efficacy, and manufacturing quality standards required for marketing in the U.S., and thus qualifies for consideration for purchase under PEPFAR.

As with all generic applications, FDA conducts an on-site inspection of each manufacturing facility and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to these applications to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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The CDC is publishing important information in the Mortality and Morbidity Weekly Report (MMWR) about false-positive oral fluid rapid tests for HIV, reported in New York City between 2005 and 2008.  The information highlights the importance of confirmatory testing, as required by product labeling, to confirm both oral fluid and whole-blood reactive rapid HIV tests.

Before testing, all patients should be informed that reactive rapid HIV test results are preliminary and require confirmation. In general, testing with blood or serum specimens is more accurate than testing with oral fluid and is preferred when feasible, especially in settings where blood specimens already are obtained routinely.

The complete article is available on the CDC web site at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm57e618a1.htm?s_cid=mm57e618a1_e

A list of the FDA-approved rapid HIV antibody screening tests is available at http://www.cdc.gov/hiv/topics/testing/rapid/rt-comparison.htm

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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Roche Laboratories, Inc. has updated their package insert for their protease inhibitor, Invirase (saquinavir) to include the following drug interaction information and include new warnings regarding coadministration of Invirase/ritonavir and digoxin (used in the treatment of various cardiac conditions).

Updated drug interaction information has been added on five products in the product package insert revision:

1. Digoxin (see Warnings; see also Clinical Pharmacology Table 2, Precautions, Drug Interactions, Table 6) A new Warning has been added. Caution should be exercised when Invirase and digoxin are coadministered.  Coadministration results in a significant increase in serum concentration of digoxin; therefore, the serum concentration of digoxin should be monitored and the dose of digoxin may need to be reduced.

2. Garlic capsules (see Warnings; see also Precautions, Drug Interactions) No data are available for the coadministration of Invirase/ritonavir with garlic capsules.  A Warning has been added that the coadministration of garlic capsules and saquinavir is not recommended due to the potential for garlic capsules to induce the metabolism of saquinavir, which may result in subtherapeutic saquinavir concentrations.

3. Methadone (see Precautions, Drug Interactions; see also Clinical pharmacology, Table 2) Methadone levels are decreased and the dosage of methadone may need to be increased when coadministered with Invirase/ritonavir.

4. Tipranavir/ritonavir (see Precautions, Drug Interactions) Combining saquinavir with tipranavir/ritonavir is not recommended due to a decrease in saquinavir levels with coadministration.

5. Omeprazole (see Precautions, Drug Interactions) When Invirase/ritonavir is coadministered with omeprazole, saquinavir concentrations are increased significantly.  If omeprazole or another proton pump inhibitor is taken concomitantly with Invirase/ritonavir, caution is advised and monitoring for potential saquinavir toxicities is recommended, particularly gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On May 9, 2008, FDA granted tentative approval for a generic formulation of emtricitabine capsules, 200 mg, manufactured by Aurobindo Pharma Limited, Hyberdad, India, for use in combination with other antiretrovirals in the treatment of HIV infection.  The application was reviewed under expedited review provisions for the President’s Emergency Plan for AIDS Relief (PEPFAR), and represents the first tentative approval of a generic formulation of emtricitabine.

 "Tentative approval" means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards, but is not eligible for marketing in the U.S. because of existing patent protections and/or exclusivity rights. Tentative approval does, however, make the product eligible for consideration for purchase outside the United States under the PEPFAR program.

As with all generic applications, FDA conducts an on-site inspection of each manufacturing facility, and of the facilities performing the bioequivalence studies, to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application prior to granting approval or tentative approval to these applications.

This tentative approval is for a generic version of Emtriva Capsules, 200 mg, marketed by Gilead Sciences Inc., a Nucleoside Reverse Transcriptase Inhibitor (NRTI).  Emtriva is subject to existing patent protections and pediatric exclusivity extensions. Effective patent dates can be found in the agency's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "Orange Book"

A list of all Approved and Tentatively Approved Antiretrovirals in Association with the President's Emergency Plan (PEPFAR) is available on the FDA website.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On May 15, 2008, FDA granted tentative approval for a generic formulation of nevirapine tablets, 200 mg, manufactured by Matrix Laboratories Limited, Hyberdad, India, for use in combination with other antiretrovirals in the treatment of HIV infection.  The application was reviewed under expedited review provisions for the President’s Emergency Plan for AIDS Relief (PEPFAR)

 "Tentative approval" means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards, but is not eligible for marketing in the U.S. because of existing patents and/or exclusivity rights. Tentative approval, however, does make the product eligible for consideration for purchase outside the United States under the PEPFAR program.

This tentative approval is a generic version of Viramune Tablets, 200 mg, a Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI), which is a product  of Boehringer Ingelheim Pharmaceuticals Inc. Viramune is subject to existing patent protection. Effective patent dates can be found in the agency's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "Orange Book"

As with all generic applications, FDA conducts an on-site inspection of each manufacturing facility, and of the facilities performing the bioequivalence studies, to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application prior to granting approval or tentative approval to these applications.

A list of all Approved and Tentatively Approved Antiretrovirals in Association with the President's Emergency Plan (PEPFAR) is available on the FDA website.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On March 27, 2008, FDA approved a new HIV diagnostic test, the VITROS Anti-HIV 1+2 Reagent Pack and VITROS Anti-HIV 1+2 Calibrator, manufactured by Ortho-Clinical Diagnostics. The VITROS Anti-HIV 1+2 Reagent Pack and VITROS Anti-HIV 1+2 Calibrator is an in vitro chemiluminescent immunoassay intended for the in vitro qualitative detection of antibodies to human immunodeficiency virus types 1 and 2 in human serum and plasma using the VITROS ECi/ECiQ Immunodiagnostic System.

The results of the VITROS Anti-HIV 1+2 assay, in conjunction with other serological evidence and clinical information may be used as an aid in the diagnosis of infection with HIV-1 and/or HIV-2 in persons with signs or symptoms of, or at risk for, HIV infection.

The assay is highly sensitive and specific for the detection of anti-HIV types 1 and 2 antibody. The VITROS ECi/ECiQ Immunodiagnostic System is fully automated, reducing the potential for operator errors, with redundant checks to ensure integrity of the system. This automation allows for increased efficiency and convenience.

FDA-approved assays for diagnosis and donor screening for HIV are listed at http://www.fda.gov/cber/products/testkits.htm.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

Return to Index

FDA has been made aware of recent, preliminary findings from analyses of data collected from "The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study," a large observational study of 33,347 HIV-1 infected patients living in North America, Europe and Australia. Patients in this study are being followed to evaluate the short- and long-term adverse effects of treatment with anti-HIV drugs.

Analyses of data collected through February 1, 2007 examined the risk of myocardial infarction (heart attack) in patients taking selected HIV drugs from the class of drugs known as nucleoside reverse transcriptase inhibitors (NRTIs).  The NRTIs included in the analyses were zidovudine, stavudine, abacavir, didanosine, and lamivudine. No analyses were conducted evaluating the risk of heart attack when patients take tenofovir or emtricitabine, two other drugs in the class. The analyses, specifically, describe the relative risk of heart attack among cumulative use, recent use (currently using or use within the past 6 months), and past use (last use greater than 6 months ago) of these drugs.

These analyses showed that recent use of abacavir or didanosine was associated with an increased risk of heart attack. Patients taking either of these drugs had a greater chance of developing a heart attack than patients taking other medications. The risk did not appear to increase over time, but remained stable and appeared to be reversible after abacavir or didanosine were stopped.

In late 2007, GlaxoSmithKline (GSK), the manufacturer of abacavir, received the preliminary findings from the D:A:D Study analyses and conducted a search of their own clinical study databases. The results of the GSK analysis are inconclusive, but did not show an increased risk.

Bristol Myers Squibb (BMS), the manufacturer of didanosine, conducted an analysis of their clinical databases, and similarly, found no increased risk for heart attack with didanosine use. The results of the BMS analysis are also inconclusive.

Key findings from the D:A:D Study are as follows:

• The excess risk of heart attack in patients taking at least some NRTIs appears to be greater in patients with other risk factors for heart disease. Risk factors include a history of heart disease, high cholesterol, high blood pressure, diabetes, smoking, and age.
• Certain analyses found the risk of heart attack increased by 49% in patients taking didanosine and increased by 90% in patients taking abacavir.
• The increased risk for heart attack remained stable over the course of treatment and the effect was not seen 6 months after stopping the drugs.

FDA currently believes analyses conducted with D:A:D Study data are incomplete; no analyses were conducted evaluating the risk of heart attack when patients take tenofovir or emtricitabine, two other drugs in the class of NRTIs. However, FDA continues to evaluate the overall risks and benefits of abacavir and didanosine. This evaluation may result in the need to revise labeling for the products. Until this evaluation is complete, healthcare providers should evaluate the potential risks and benefits of each HIV-1 antiretroviral drug their patients are taking, including abacavir and didanosine.

This early communication is in keeping with FDA's commitment to inform the public about ongoing safety reviews of drugs. FDA will work with the manufacturers of abacavir and didanosine to fully evaluate the risks and benefits associated with the use of these products as part of an HIV treatment regimen. As soon as this process is complete, FDA will communicate the conclusions and recommendations to the public.

The FDA urges healthcare professionals to promptly report serious and unexpected adverse reactions associated with abacavir and didanosine to the FDA MedWatch reporting program, as described below.

• online at www.fda.gov/medwatch/report.htm
• by returning the postage-paid FDA form 3500 (available in PDF format at www.fda.gov/medwatch/getforms.htm) to 5600 Fishers Lane, Rockville, MD 20852-9787
• faxing the form to 1-800-FDA-0178
• by phone at 1-800-332-1088

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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The Reyataz (atazanavir) Capsule label has been updated to include the dosing recommendations for pediatric patients 6 to 18 years of age.

REYATAZ should not be administered to pediatric patients below the age of 3 months due to the risk of kernicterus (a type of brain damage caused by  excessive levels of bilirubin).

Important changes made to the product label include the following: 

Section 2.2 Recommended Pediatric Dosage was added to the label.

The recommended dosage of REYATAZ for pediatric patients (6 to less than 18 years of age) is based on body weight and should not exceed the recommended adult dosage.  REYATAZ Capsules must be taken with food. The data are insufficient to recommend dosing of REYATAZ for any of the following: (1) patients less than 6 years of age, (2) without ritonavir in patients less than 13 years of age, and (3) treatment-experienced pediatric patients with body weight less than 25 kg.

Therapy-Naive Pediatric Patients

The recommended dosage of REYATAZ with ritonavir in treatment-naive patients at least 6 years of age is shown in Table 1.

For treatment-naive patients at least 13 years of age and at least 39 kg, who are unable to tolerate ritonavir, the recommended dose is REYATAZ 400 mg (without ritonavir) once daily with food.

Table 1: Dosage for Treatment-Naive Pediatric Patients (6 to less than 18 years of age) for REYATAZ Capsules with ritonavir

Therapy-Experienced Pediatric Patients
The recommended dosage of REYATAZ with ritonavir in treatment-experienced patients at least 6 years of age is shown in Table 2.

Table 2: Dosage for Treatment-Experienced Pediatric Patients (6 to less than 18 years of age) for REYATAZ Capsules with ritonavir

In section 6 Adverse Reactions subsection 6.2 Clinical Trial Experience in Pediatric Patients was added and includes the following information:

The safety profile of REYATAZ in pediatric patients (6 to less than 18 years of age) was comparable to that observed in clinical studies of REYATAZ in adults. The most common Grade 2–4 adverse events (³5%, regardless of causality) reported in pediatric patients were cough (21%), fever (19%), rash (14%), jaundice/scleral icterus (13%), diarrhea (8%), vomiting (8%), headache (7%), and rhinorrhea (6%). Asymptomatic second-degree atrioventricular block was reported in 2% of patients. The most common Grade 3–4 laboratory abnormality was elevation of total bilirubin (³3.2 mg/dL) which occurred in 49% of pediatric patients. All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%.

In section 14 Clinical Studies, subsection 14.3 Pediatric Patients was added and includes the following:

Assessment of the pharmacokinetics, safety, tolerability, and efficacy of REYATAZ is based on data from the open-label, multicenter clinical trial PACTG 1020A conducted in patients from 3 months to 21 years of age.  In this study, 182 patients (83 antiretroviral-naive and 99 antiretroviral-experienced) received once daily REYATAZ, with or without ritonavir, in combination with two NRTIs.

Ninety-nine patients (6 to less than 18 years of age) treated with the REYATAZ capsule formulation, with or without ritonavir, were evaluated. In this cohort, the overall proportions of antiretroviral-naive and -experienced patients with HIV RNA <400 copies/mL at week 24 were 68% (28/41) and 33% (19/58), respectively. The overall proportions of antiretroviral-naive and ‑experienced patients with HIV RNA <50 copies/mL at week 24 were 59% (24/41) and 24% (14/58), respectively. The median increase from baseline in absolute CD4 count at 20 weeks of therapy was 171 cells/mm3 in antiretroviral-naive patients and 116 cells/mm3 in antiretroviral-experienced patients.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On March 20, 2008, the Food and Drug Administration (FDA) granted tentative approval to two fixed-dose combination products containing generic versions of stavudine/lamivudine/nevirapine 30mg/150mg/200mg Tablets, and stavudine/lamivudine/nevirapine 40mg/150mg/200mg Tablets, under expedited procedures for the President's Emergency Plan for AIDS Relief (PEPFAR) program. Both fixed dose combinations are manufactured by Strides Arcolab Limited of Bangalore, India, and indicated for the treatment of HIV-1 infection.

Each ingredient of this generic tablet is currently approved to treat HIV-1 in combination with other antiretroviral agents. The safety and effectiveness of the combination of stavudine/lamivudine/nevirapine in lowering viral load and increasing CD4+ cells has been demonstrated in previously conducted controlled studies of the individual ingredients used together.

Combination products such as these can significantly reduce pill burden. potentially resulting in improved therapeutic compliance with complex dosing regimens, as well as facilitating the storage and distribution of these HIV medications.

FDA's tentative approval means that although a product meets all of the safety, efficacy, and manufacturing quality standards required for marketing in the U.S., existing patents and/or proprietary issues currently prevent marketing of the product in the United States.  Tentative approval, however, does qualify the product for consideration for purchase under the PEPFAR program.

As with all generic applications, FDA conducts an on-site inspection of each manufacturing facility and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to these applications to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application.

These products were reviewed under the FDA guidance titled Fixed Dose Combinations, Co-Packaged Drug Products, and Single-Entity Versions of Previously approved Antiretrovirals for the Treatment of HIV developed to clarify what regulatory requirements apply to such applications, what issues might be of concern, and how these issues should be addressed.  The guidance is intended to encourage sponsors to submit applications for combination and co-packaged products, and to facilitate submission of such applications to FDA.

A list of all approvals and tentative approvals under these provisions can be found at http://www.fda.gov/oia/pepfar.htm

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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Tibotec Therapeutics, in cooperation with the U.S. Food and Drug Administration, issued a Dear Healthcare Professional letter to relay important, updated prescribing information for PREZISTA  (darunavir) tablets, that includes a warning about Hepatotoxicity.

The letter provides, in addition to other information, the following, which has been added to the WARNINGS section of the Prezista label:

"Hepatotoxicity

Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA/rtv. During the clinical development program (N=3063), hepatitis has been reported in 0.5% of patients receiving combination therapy with PREZISTA/rtv. Patients with preexisting liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse events.

Postmarketing cases of liver injury, including some fatalities, have been reported. These have generally occurred in patients with advanced HIV1 disease taking multiple concomitant medications, having comorbidities including hepatitis B or C coinfection, and/or developing immune reconstitution syndrome. A causal relationship with PREZISTA/rtv therapy has not been established.

Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA/rtv and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pretreatment elevations of transaminases, especially during the first several months of PREZISTA/rtv treatment.

If there is evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on PREZISTA/rtv, interruption or discontinuation of treatment must be considered."

In addition, the Adverse Reaction section of the PREZISTA label and the Patient Package Insert have been updated to include this new information.

The letter, and the new label are available on line in pdf format..

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

Return to Index

Updates have been made to Prezista (darunavir) tablets labeling to reflect significant new risk information. Changes have been made to the CLINICAL PHARMACOLOGY section to include data from 6 pharmacokinetic, drug interaction Phase 1 trials, and to the WARNINGS, PRECAUTIONS AND ADVERSE REACTIONS sections of the package insert to include hepatotoxicity information. Other updates include those made to PRECAUTIONS, updates to DOSAGE AND ADMINISTRATION, and changes to Table 11 to include information regarding a potential drug-drug interaction with rosuvastatin.

In the WARNINGS section, the following has been added:

"Hepatotoxicity
Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA/rtv. During the clinical development program (N=3063), hepatitis has been reported in 0.5% of patients receiving combination therapy with PREZISTA/rtv. Patients with preexisting liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse events.

Post-marketing cases of liver injury, including some fatalities, have been reported. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with PREZISTA/rtv therapy has not been established.

Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA/rtv and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of PREZISTA/rtv treatment.

If there is evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on PREZISTA/rtv, interruption or discontinuation of treatment must be considered."

The PRECAUTIONS section has been changed to read as follows:

"Patients with co-existing conditions
Hepatic Impairment: No dose adjustment of PREZISTA/rtv is necessary for patients with either mild or moderate hepatic impairment. There are no pharmacokinetic or safety data available for subjects with severe hepatic impairment, therefore, PREZISTA/rtv is not recommended for use in patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Adults, Special Populations, Hepatic Impairment and DOSAGE AND ADMINISTRATION)."

Table 11, Established and Other Potentially Significant Drug Interactions, has been modified, under HMG-CoA Reductase Inhibitors, to include rosuvastatin, indicating increased concentration of rosuvastatin, with the following clinical comment: "Use the lowest possible dose of atorvastatin, pravastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin in combination with PREZISTA/rtv."

The following sentence has been added to the CLINICAL PHARMACOLOGY section, under Absorption and Bioavailabilty: "In vivo data suggests that darunavir/ritonavir is an inhibitor of the p-glycoprotein (p-gp) transporters."

The following has been added under: Special Populations
"Hepatic Impairment: Darunavir is primarily metabolized by the liver. The steady-state pharmacokinetic parameters of darunavir were similar after multiple dose co-administration of PREZISTA/rtv 600/100 mg b.i.d. to subjects with normal hepatic function (n=16), mild hepatic impairment (Child-Pugh Class A, n=8), and moderate hepatic impairment (Child-Pugh Class B, n=8). The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been evaluated (see PRECAUTIONS, Patients with co-existing conditions, Hepatic Impairment and DOSAGE AND ADMINISTRATION)."

In addition, there are updates to Table 4: Drug Interactions Pharmacokinetic Parameters for Darunavir in the Presence of Co-administered Drugs, and Table 5: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Darunavir/Ritonavir.

The last paragraph of the ADVERSE REACTIONS section now reads: "Patients co-infected with hepatitis B and/or hepatitis C virus: In subjects co-infected with hepatitis B or C virus receiving PREZISTA/rtv, the incidence of adverse events and clinical chemistry abnormalities was not higher than in subjects receiving PREZISTA/rtv who were not co-infected, except for increased hepatic enzymes (see WARNINGS, Hepatotoxicity). The pharmacokinetic exposure in co-infected subjects was comparable to that in subjects without co-infection."

In addition, the following has been added:

"Additional adverse reactions identified in clinical studies, occurring in less than 1% of the patients, are listed below by body system:

Hepatobiliary System: acute hepatitis, cytolytic hepatitis, hepatotoxicity, hyperbilirubinemia

Skin and Appendages: erythema multiforme, Stevens-Johnson Syndrome
[this duplicate information was deleted from the Skin and Appendages section under the treatment-emergent adverse events occurring in less than 2% of de novo subjects]"

Changes were also made to DOSAGE AND ADMINISTRATION, to include the following: "Hepatic Impairment: No dose adjustment is required in patients with mild or moderate hepatic impairment. There are no data regarding the use of PREZISTA/rtv when co-administered to subjects with severe hepatic impairment; therefore, PREZISTA/rtv is not recommended for use in patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Adults, Special Populations, Hepatic Impairment and PRECAUTIONS, Patients with co-existing conditions, Hepatic Impairment)."

The new label is available at Drugs@fda.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

Return to Index

On February 29, 2008, FDA granted tentative approval for a generic formulation of efavirenz tablets, 600 mg, manufactured by Hetero Drugs Limited, Hyberdad, India, for use in combination with other antiretrovirals in the treatment of HIV infection.  The application was reviewed under expedited review provisions for the President’s Emergency Plan for AIDS Relief (PEPFAR)

"Tentative approval" means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards, but is not eligible for marketing in the U.S. because of existing patents and/or exclusivity rights. Tentative approval, however, does make the product eligible for consideration for purchase under the PEPFAR program.

Effective patent dates for efavirenz can be found in the agency's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "Orange Book"

This tentative approval is a generic version of Sustiva (efavirenz) tablets, a Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI), 600 mg. Sustiva is a products of Bristol Myers Squibb.

As with all generic applications, FDA conducts an on-site inspection of each manufacturing facility and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to these applications to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application.

A list of all Approved and Tentatively Approved Antiretrovirals in Association with the President's Emergency Plan (PEPFAR) is available on the FDA website.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

Return to Index

On February 29, 2008, FDA granted tentative approval for a generic formulation of stavudine capsules, 15 mg, 20 mg, 30 mg, and 40 mg, manufactured by Hetero Drugs Limited, Hyberdad, India, for use in combination with other antiretrovirals in the treatment of HIV infection.  The application was reviewed under expedited review provisions for the President’s Emergency Plan for AIDS Relief (PEPFAR)

"Tentative approval" means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards, but is not eligible for marketing in the U.S. because of existing patents and/or exclusivity rights. Tentative approval, however, does make the product eligible for consideration for purchase under the PEPFAR program.

Effective patent dates can be found in the agency's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "Orange Book"

This tentative approval is a generic version of Zerit (stavudine) capsules, a Nucleoside Reverse Transcriptase Inhibitor (NRTI), 15 mg, 20 mg, 30 mg, and 40 mg, Zerit which is a product of Bristol Myers Squibb.

As with all generic applications, FDA conducts an on-site inspection of each manufacturing facility and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to these applications to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application.

A list of all Approved and Tentatively Approved Antiretrovirals in Association with the President's Emergency Plan (PEPFAR) is available on the FDA website.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

Return to Index

The  Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection have been revised. The new version includes updated information on:

• When to initiate therapy, including
  - Change in treatment recommendations for when to initiate therapy in HIV-infected children <12 months of age
  - Reduction from 4 to 3 age bands for recommendations on when to initiate therapy (<12 months, 1 to <5 years, and 5 years and older) 
  - Changes in immunologic thresholds for when to start in children 1 year or older
• Timing of diagnostic testing in HIV-exposed infants 
• The pediatric drug appendix and hyperlink on drug preparations, new dosage formulations, and pediatric studies 
• Recently approved antiretrovirals: maraviroc (including a new coreceptor tropism assay section), raltegravir, and etravirine 
• Revised antiretroviral toxicity hyperlink with new tables detailing toxicity management

Changes are highlighted in yellow throughout the text and tables. 

The updated guidelines are available for download from the Pediatric Guidelines section of the AIDSinfo Web site. You can also request to receive them by mail or email from the AIDSinfo Order Publications section.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On February 25, 2008, FDA approved a new 600 mg tablet strength for Prezista (darunavir), manufactured by Tibotec, Inc., Yardley, PA. The new 600 mg tablet facilitates dosing by reducing pill burden.

The recommended oral dose of Prezista tablets is 600 mg (two 300 mg tablets or one 600 mg tablet) twice daily taken with ritonavir 100 mg twice daily and with food.

The 600 mg formulation will be available in bottles of 60 tablets.

The 300 mg tablet will continue to be available.

Darunavir is a protease inhibitor, which inhibits the formation of mature virus in HIV infected cells.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On February 14, 2008, FDA granted approval for a generic formulation of Zidovudine Tablets, 300 mg, manufactured by Matrix Laboratories, Inc. of Hyderabad, India. The application was reviewed under the expedited review provisions of the President’s Emergency Plan for AIDS Relief (PEPFAR).  However, because patent protections for the reference product, Retrovir Tablets,300 mg, made by GlaxoSmithKline have expired, this generic product can be marketed in the United States, as well as being available for purchase under the PEPFAR program.

A list of all FDA approved generic antiretroviral drugs for the treatment of HIV is available on the web at http://www.fda.gov/oashi/aids/viralsgeneric.html

Zidovudine is a Nucleoside Reverse Transcriptase Inhibitors (NRTI) indicated for the treatment of HIV in combination with other antiviral medications.

As with all FDA-approved generics, this product must meet all of FDA's manufacturing quality, and clinical safety and effectiveness standards.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On February 4, 2008, FDA granted tentative approval for a generic formulation of atazanavir sulfate capsules, 100 mg, 150 mg, and 200 mg, manufactured by Emcure Pharmaceuticals of Pune, India. The application was reviewed under expedited review provisions for the President’s Emergency Plan for AIDS Relief (PEPFAR).

Indicated for the treatment of HIV infection in combination with other antiviral medications, atazanavir is a member of the protease inhibitor class of antiretroviral drugs.

As with all generic applications, FDA conducts an on-site inspection of each manufacturing facility and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to these applications to evaluate the ability of the manufacturer to produce a quality product, and to assess the quality of the bioequivalence data supporting the application.

While tentatively approved generic products meet FDA-required standards, they cannot yet be fully approved for sale in the U.S. because of existing patent protections. However, tentative approval does make the product eligible for purchase under the PEPFAR program for treatment use in nations where PEPFAR is active.

This product is a generic formulation of Reyataz Capsules, 100 mg, 150 mg, and 200 mg, made by Bristol Myers Squibb Co. which remains subject to existing patents as listed in the agency's publication titled "Approved Drug Products with Therapeutic Equivalence Evaluations," also known as the "orange book ." 

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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FDA has approved a new formulation of Epivir (lamivudine) designed to facilitate dosing in appropriate pediatric patients who can reliably swallow tablets. Epivir is now available as 150 mg scored tablets. The scored tablets allow for dosing recommendations in pediatric patients. The DOSING AND ADMINISTRATION section of the Epivir label was revised as follows:

Pediatric Patients

The recommended oral dose of EPIVIR Oral Solution in HIV-1-infected pediatric patients 3 months to 16 years of age is 4 mg/kg twice daily (up to a maximum of 150 mg twice a day), administered in combination with other antiretroviral agents.

EPIVIR is also available as a scored tablet for HIV-1-infected pediatric patients who weigh ≥14 kg for whom a solid dosage form is appropriate. Before prescribing EPIVIR Tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow EPIVIR Tablets, the oral solution formulation should be prescribed. The recommended oral dosage of EPIVIR Tablets for HIV-1-infected pediatric patients is presented in Table 1.

Epivir is a Nucleoside Reverse Transcriptase Inhibitor (NRTI) manufactured by GlaxoSmithKline.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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On January 29, 2008, FDA granted tentative approval for a generic version of lamivudine tablets, 150 mg and 300 mg, manufactured by Hetero Drugs Limited,  Hyderabad, India, for use in combination with other antiretrovirals in the treatment of HIV infection.

"Tentative Approval" means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards, even though it is not yet eligible to be marketed in the U.S. because of existing patents and/or exclusivity rights. However, this tentative approval does make the product eligible for consideration for purchase under the PEPFAR program.

This is a generic version of Epivir, manufactured by GlaxoSmithKline, which is subject to existing patent protection.

Effective patent dates can be found in the agency's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "Orange Book"

As with all generic applications, FDA conducts an on-site inspection of each manufacturing facility and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to these applications to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

Return to Index

On January 29, 2008, t he following changes were made to several sections of the December 1, 2007 version of the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents:

What to Start: Initial Combination Regimens for the Antiretroviral-Naïve Patient?

The Panel revised its recommendations for several "preferred" and "alternative" antiretroviral components for treatment-naïve patients:

• "Abacavir + lamivudine" has been changed from "alternative" to "preferred" 2-NRTI component in patients who have tested negative for HLA-B*5701 (AII).
• Zidovudine + lamivudine" has been changed from "preferred" to "alternative" 2-NRTI component (BII).
• "Ritonavir-boosted saquinavir" has been changed from a PI-option that was considered as "Acceptable as initial antiretroviral components but inferior to preferred or alternative components" to an "alternative" PI component (BII).
• The following options are no longer recommended as components for initial therapy in treatment-naïve patients:
  • Nelfinavir as PI component
  • Stavudine + lamivudine as 2-NRTI components
  • Abacavir + zidovudine + lamivudine as a triple-NRTI combination regimen

A new topic entitled "Other Treatment Options Under Investigation: Insufficient Data to Recommend" has been added, which includes a review of recent clinical trial data in treatment-naïve patients for ritonavir-boosted darunavir­based regimens, maraviroc-based regimens, and raltegravir-based regimens.

Treatment Interruption

This section has been updated with recent data on short-term and long-term treatment interruption. The Panel reaffirms our recommendation that aside from unplanned or planned short-term interruption due to illnesses precluding oral therapy or toxicities, long-term treatment interruption is not recommended unless in the context of a clinical trial (DI).

Acute HIV Infection

• A new table on "Identifying, diagnosing, and managing acute HIV- 1 infection" has replaced the table on "Associated signs and symptoms of acute retroviral syndrome and percentage of expected frequency".
• The Panel also recommends that since clinically significant resistance to PIs is less common than resistance to NNRTIs in antiretroviral-naïve persons who harbor drug resistant virus, if therapy is initiated before drug resistance test results are available, consideration should be given to using a PI-based regimen (BIII).

Mycobacterium Tuberculosis Disease or Latent Tuberculosis Infection with HIV Coinfection
This section has been updated with the following information:

• Discussions and recommendations on the timing of initiation of antiretroviral therapy in patients with active tuberculosis (TB), with emphasis on the risks and benefits of concomitant therapy related to overlapping toxicities, drug interactions, CD4 cell counts, and potential for immune reconstitution inflammatory syndrome.
• Recommendation for repeat testing to detect latent TB infection in persons who had CD4 count <200 cells/mm3 and have tested negative prior to antiretroviral therapy and have improved CD4 count to >200 cells/mm3 (BII).

Table Updates:

• Various tables have been updated to include information regarding etravirine, updates on various antiretroviral drugs, as well as new atazanavir dosing recommendations when used in combination with proton pump inhibitors or H2 receptor antagonists.
• The following tables have been removed from the document:
  • Antiretroviral components that are acceptable as initial antiretroviral components but are inferior to preferred or alternative components"; and
  • Treatment outcome of selected clinical trials of combination antiretroviral regimens in treatment-naïve patients with 48-week follow-up data".

The complete January 29, 2008 version of the adult treatment guidelines is available on the aidsinfo web site at http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.  Changes will display highlighted in yellow.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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The Food and Drug Administration (FDA), on January 18, 2007, granted accelerated approval for etravirine 100 mg tablets, a non-nucleoside reverse transcriptase inhibitor (NNRTI), an antiviral drug that helps to block reverse transcriptase, an enzyme necessary for HIV virus replication.  It is the first NNRTI to demonstrate antiviral activity in patients with NNRTI-resistant virus. Etravirine will be sold under the trade name Intelence.

Etravirine is indicated for use in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV -1) infection in antiretroviral treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to a non-nucleoside reverse transcriptase inhibitor (NNRTI) and other antiretroviral agents.

Accelerated approval is a regulatory mechanism that allows earlier approval of drugs used to treat serious or life-threatening conditions, based on surrogate endpoints that demonstrate meaningful therapeutic advantage over existing treatment.  Accelerated approval is based on evidence of a drug's effect on a surrogate endpoint that reasonably suggests clinical benefit.  Accelerated approval requires any necessary studies to establish and define the degree of clinical benefit to patients be completed before traditional approval can be granted.

FDA granted this accelerated approval based on 24 week viral load and CD4 data from 1,203 adults in two randomized, double-blind, placebo-controlled trials (DUET-1 and -2 studies) conducted in clinically advanced, antiretroviral treatment-experienced adults with evidence of resistance to NNRTI(s) and protease inhibitors (PIs). The studies compared 599 patients receiving etravirine 200 mg twice daily plus optimized background regimen with 604 patients receiving optimized background regimen plus placebo.  All patients received darunavir/rtv (DRV/rtv) as part of their optimized background regimen.

The 24 week pooled analysis of the DUET studies showed significantly more patients in the etravirine arm as compared to the placebo arm achieved undetectable viral load (less than 50 copies/mL); 59.8 percent vs. 40.2 percent (p<0.0001), and significantly greater mean increase in CD4+ cell count from baseline of 81 vs. 64 cells/mm3 (p<0.0022).

The most common adverse events reported were rash (16.9 percent) and nausea (13.9 percent).

In general, rash was mild to moderate, occurred primarily in the second week of therapy, and was infrequent after Week 4. Rash generally resolved within 1-2 weeks on continued therapy. Patients developing a rash while taking etravirine should contact their doctor.

Rare cases of serious skin reactions such as Stevens-Johnson syndrome and erythema multiforme have been reported. Treatment with etravirine should be discontinued if severe rash develops.

Elevations in total cholesterol and low density lipoprotein (LDL) and initiation of lipid lowering therapy were more common in etravirine-treated subjects compared with those in the placebo arm.

Etravirine should be used with caution in patients with severe hepatic impairment (Child-Pugh class C) as pharmacokinetics of etravirine have not been studied in these patients.

To avoid drug interactions, patients starting etravirine treatment should tell their doctors about all the medications they take. Information about drug interactions is contained in the etravirine package insert.

The long-term effects of etravirine are not known, and its safety and effectiveness in children ages 16 years and younger has not been studied.

Etravirine also has not been studied in pregnant women. Women who are taking HIV medications when they get pregnant are advised to consult their physician or other health care professional about use of etravirine during pregnancy and about registering with the Antiviral Pregnancy Registry.

Etravirine is distributed by Tibotec Therapeutics, Bridgewater, N.J., a division of Ortho Biotech Products, L.P.

Richard Klein
HIV/AIDS Program Director
Food and Drug Administration

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The Reyataz (atazanavir) package insert was revised to include information regarding the administration of atazanavir and/or atazanavir/ritonavir with food, proton pump inhibitors, H2 receptor antagonists, acetaminophen, and fluconazole. Additionally, dosing information in patients with renal impairment was included.

Please refer to http://www.fda.gov/cder/foi/label/2007/021567s014lbl.pdf for complete labeling. Below are highlight of the major recent changes.

The Dosage and Administration section and Precautions: Drug Interaction Table 11 were updated to include drug interaction information regarding the use of Reyataz and proton pump inhibitors and H2-Receptor antagonists.

The dose recommendations for therapy-naïve patients receiving H2-receptor antagonists or proton pump inhibitors are the following:

• H2-receptor antagonist: The H2-receptor antagonist dose should not exceed a 40 mg dose equivalent of famotidine twice daily. Reyataz 300 mg and ritonavir 100 mg should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2-receptor antagonist.
• proton-pump inhibitors: The proton-pump inhibitor dose should not exceed a 20 mg dose equivalent of omeprazole and must be taken approximately 12 hours prior to the Reyataz 300 mg and ritonavir 100 mg dose.

The dose recommendations for therapy-experienced patients receiving H2-receptor antagonists or proton pump inhibitors are the following:

• Whenever an H2-receptor antagonist is given to a patient receiving Reyataz with ritonavir, the H2-receptor antagonist dose should not exceed a dose equivalent to famotidine 20 mg twice daily, and the Reyataz and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2-receptor antagonist.
  • Reyataz 300 mg (one 300-mg capsule or two 150-mg capsules) with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2-receptor antagonist.
  • Reyataz 400 mg (two 200-mg capsules) with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir and an H2-receptor antagonist.
• Proton-pump inhibitors should not be used in treatment-experienced patients receiving Reyataz.

In addition, the Dosage and Administration section was updated to provide dosing information in patients with renal impairment as follows:

• For patients with renal impairment, including those with severe renal impairment who are not managed with hemodialysis, no dose adjustment is required for Reyataz. Treatment-naive patients with end stage renal disease managed with hemodialysis should receive Reyataz 300 mg with ritonavir 100 mg. Reyataz should not be administered to HIV-treatment experienced patients with end stage renal disease managed with hemodialysis.

No dose adjustments are needed when Reyataz is co-administered with acetaminophen or fluconazole.

The Clinical Pharmacology section was updated to include the following information:

• results of a food effect study with Reyataz 300 mg with ritonavir 100 mg with a light meal and high fat meal (see Clinical Pharmacology: Food Effect).
• results of a study in adult subjects with severe renal impairment, including those on hemodialysis is presented (see Clinical Pharmacology: Special Populations: Impaired Renal Function).
• results of drug-drug interaction studies with acetaminophen famotidine, fluconazole, and omperazole (See Clinical Pharmacology: Table 4: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of C administered Drugs and Table 5: : Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Reyataz.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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