FDA Notifications
EUA issued for treating novel 2009 H1N1 flu
On April 26, 2009, the Acting Secretary of Health and Human Services (HHS) declared a public health emergency related to the current outbreak of "swine flu" (now designated "novel 2009 H1N1").
In response to this public health emergency, the CDC requested Emergency Use Authorization (EUA) for the use of oseltamivir (Tamiflu®) and zanamivir (Relenza®) for treatment and prophylaxis of influenza for broader populations than are currently included in the product labeling, including pediatric populations, and others who fall outside of the indicated uses.
Influenza viruses cause serious, sometimes fatal, disease in immunocompromised patients, including HIV infected infants, toddlers, and young children.
Currently, zanamivir is approved to treat acute uncomplicated illnesses due to influenza in adults and children 7 years and older who have been symptomatic for less than two days, and for the prevention of influenza in adults and children 5 years and older. Oseltamivir is approved for the treatment and prevention of influenza in patients 1 year and older.
The EUAs allow for oseltamivir also to be used to treat and prevent influenza in children under 1 year, and to provide alternative dosing recommendations for children older than 1 year. In addition, under the EUAs, both medications may be distributed to large segments of the population without complying with the label requirements otherwise applicable to dispensed drugs, and accompanied by written information pertaining to the emergency use. They may also be distributed by a broader range of health care workers, including some public health officials and volunteers, in accordance with applicable state and local laws and/or public health emergency responses.
These temporary extensions of the indication, which will terminate when the emergency no longer exists, are summarized below:
1. Use of oseltamivir for treatment and prophylaxis of influenza in infants less than 1 year of age. Oseltamivir is currently approved for use in patients 1 year of age and older. New dosing recommendations in infants less than 1 year were based on expedited review of safety and pharmacokinetic data submitted by Roche and the Collaborative Antiviral Study Group of NIAID/NIH. In addition, age-based dose recommendations in older children were included in these new recommendations. These EUA recommendations are intended for use with Tamiflu for Oral Suspension and are shown here:
Expanded EUA Tamiflu Dose Recommendations for Treatment of Influenza in Pediatric Patients Body Weight (kg) Body Weight (lbs) Dose by Age Recommended Treatment Dose for 5 Days:
- Greater than 40 kg, greater than 88 lbs, and 10 years of age or older: 75 mg twice daily;
- Greater than 23 kg to 40 kg, greater than 51 lbs to 88 lbs, 6-9 years: 60 mg twice daily;
- Greater than 15 kg to 23 kg, greater than 33 lbs to 51 lbs, 3-5 years: 45 mg twice daily;
- 15 kg or less, 33 pounds or less, 1-2 years: 30 mg twice daily;
- Dosing for infants younger than 1 year is not based on weight: 6-11 months: 25 mg twice daily; 3-5 months: 20 mg twice daily; Less than 3 months: 12 mg twice daily.
The Tamiflu Oral Suspension bottle comes with a dispenser marked for 30, 45, or 60 mg. For children who weigh more than 40 kg (or 88 lbs) or adults who can't swallow capsules, you will need to measure out a dose of 30 mg plus another dose of 45 mg. For infants less than 1 year old, a different measuring device must be used that will dispense 2 mL (about 25 mg), 1.6 mL (about 20 mg) or 1 mL (12 mg).
Doses for prevention of the novel 2009 H1N1 are the same for each weight group, but doses are administered only once per day rather than twice. Prevention dosages should be taken for 10 days following close contact with an infected person or during a community outbreak.
2. Use of oseltamivir and zanamivir in patients not included in the current labeling. These drugs are currently indicated for use in patients with acute, uncomplicated influenza who have had symptoms for less than 48 hours. The EUA allows for use of Tamiflu and Relenza in patients who have more severe influenza disease or who have been ill for longer than 48 hours based on limited published data and the understanding that the novel 2009 H1N1 may have different presentations. Depending on available products and susceptibility data, clinicians may wish to make individual risk-benefit assessments regarding the appropriate use of the products.
More detailed information about Influenza Antiviral Drugs is available on the FDA web site at http://www.fda.gov/cder/drug/antivirals/influenza/default.htm. The TAMIFLU® FACT SHEET FOR HEALTH CARE PROVIDERS contains information specific to the expanded pediatric dosing recommendations for Tamiflu.
Tenofovir in India receives tentative approval
On April 29, 2009, the Food and Drug Administration granted tentative approval for tenofovir disoproxil fumarate tablets, 300 mg, manufactured by Cipla, Limited, of Mumbai, India, indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults. 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 patent protections. Tentative approval does, however, make the product eligible for consideration for purchase outside the United States under the PEPFAR program.
This product is a generic version of Viread Tablets, 300 mg, a Nucleoside Reverse Transcriptase Inhibitor (NRTI), made by Gilead Sciences Inc. Patent information is available in the FDA Orange Book.
As with all generic applications, the 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.
Kaletra product label changed
The FDA approved, on April 20, 2009, changes to the product label for lopinavir/ritonavir (Kaletra®) Tablets and Oral Solution, to include results from Study 730 comparing treatment with lopinavir/ritonavir 800/200 mg once-daily plus tenofovir DF and emtricitabine versus lopinavir/ritonavir 400/100 mg twice-daily plus tenofovir DF and emtricitabine in antiretroviral treatment-naïve patients.
Results from this study were included in section 6, "Adverse Reactions," and section 14, "Clinical Studies," as follows.
The statement about diarrhea comparing once daily and twice daily dosing of lopinavir/ritonavir capsules was removed from the label because capsule formulation is no longer marketed. Information regarding incidence of diarrhea in Study 730 is included in section 6, "Adverse Reactions." Study 730 provides the more relevant longer term data for once daily and twice daily dosing with lopinavir/ritonavir tablets.
It reads as follows:
"6.1 Adults - Clinical Trials Experience
The most common adverse reaction was diarrhea, which was generally of mild to moderate severity. In study 730, the incidence of diarrhea of any severity during 48 weeks of therapy was 60% in patients receiving KALETRA tablets once daily compared to 57% in patients receiving KALETRA tablets twice daily. More patients receiving KALETRA tablets once-daily (14, 4.2%) had ongoing diarrhea at the time of discontinuation as compared to patients receiving KALETRA tablets twice-daily (6, 1.8%). In study 730, discontinuations due to any adverse reaction were 4.8% in patients receiving KALETRA tablets once-daily as compared to 3% in patients receiving KALETRA tablets twice-daily."
Also, the FDA approved, on April 6, 2009, changes to the product label for lopinavir/ritonavir (Kaletra) Tablets and Oral Solution, reflecting new warnings and precautions regarding QT/QTC interval and PR interval prolongation information.
QT/QTC interval and PR interval prolongation refer to changes in electrical activity and rhythm of the heart.
The following information was added to the product label:
"5 WARNINGS AND PRECAUTIONS
"5.5 PR Interval Prolongation: Lopinavir/ritonavir prolongs the PR interval in some patients. Cases of second or third degree atrioventricular block have been reported. KALETRA should be used with caution in patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease or cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities.
"The impact on the PR interval of co-administration of KALETRA 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 KALETRA with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended.
"5.6 QT Interval Prolongation
"Postmarketing cases of QT interval prolongation and torsade de pointes have been reported although causality of KALETRA could not be established. Avoid use in patients with congenital long QT syndrome, those with hypokalemia, and with other drugs that prolong the QT interval."
In addition to these label changes, a new Medication Guide is now available for Kaletra.
Medication Guides are paper handouts that are dispensed with some prescription medicines. These handouts are required by FDA for certain drugs, but are created by the drug manufacturer. They are different from the routine information handouts provided by some pharmacies. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.
On April 26, 2009, the Acting Secretary of Health and Human Services (HHS) declared a public health emergency related to the current outbreak of "swine flu" (now designated "novel 2009 H1N1").Subscribe Now for Access
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