FDA safety updates to antiretroviral labels

The following summaries cover revisions to the US drug labels that were recently approved by the FDA in the US. Please check the full update for details.

Revised label are posted to the FDA website: drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory

Tenofovir for adolescent use

On 24 March 2010, the FDA approved revised labeling for tenofovir disproxil fumarate (Viread) to expand the indication to include patients aged 12–18 years of age and >35 kg, at the adult dose of 300mg once-daily.

This was based on 48-week clinical data from Study GS-321 which randomised 87 treatment-experienced adolescents 12 to <18 years of age were treated with tenofovir (n=45) or placebo (n=42) in combination with an optimised background regimen (OBR) for 48 weeks. The mean baseline CD4 cell count was 374  cells/mm3 and the mean baseline plasma viral load was 4.6 log copies/mL.

At baseline, 90% of patients had NRTI-associated mutations. Overall, the trial failed to show a difference in virologic response between the tenofovir and placebo treatment groups. Subgroup analyses suggest the lack of difference in virologic response may be attributable to imbalances between treatment arms in baseline viral susceptibility to tenofovir and OBR. Although changes in HIV-1 RNA in these highly treatment-experienced adolescent subjects were less than anticipated, the comparability of the pharmacokinetic and safety data to that observed in adults supports the use of tenofovir in patients =12 years of age who weigh =35 kg and whose HIV-1 isolate is expected to be sensitive to tenofovir.

Assessment of bone mineral density (BMD) should be considered for adults and adolescents who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. In Study 321, bone effects were similar to adult subjects.  Under normal circumstances BMD increases rapidly in adolescents. In this study, the mean rate of bone gain was less in the tenofovir-treated group compared to the placebo group. Six tenofovir-treated adolescents and one placebo-treated adolescent had significant (>4%) lumbar spine BMD loss at 48 weeks. Among 28 subjects receiving 96 weeks of tenofovir, Z-scores declined by -0.341 for lumbar spine and -0.458 for total body. Skeletal growth (height) appeared to be unaffected. Markers of bone turnover in tenofovir-treated adolescents suggest increased bone turnover, consistent with the effects observed in adults.

Tenofovir exposure achieved in eight adolescent subjects was similar to exposures achieved in adult studies. Pharmacokinetic studies have not been performed in pediatric subjects <12 years of age.

Efavirenz label changes on pregnancy, hepatotoxicty and drug interactions

On 14 April 2010, the Food and Drug Administration approved revisions to the package insert for efavirenz (Sustiva), for both capsules and tablets.

Under warnings and precautions during pregnancy, the update stated: ‘As of July 2009, the Antiretroviral Pregnancy Registry has received prospective reports of 661 pregnancies exposed to efavirenz-containing regimens, nearly all of which were first trimester exposures (606 pregnancies). Birth defects occurred in 14 of 501 live births (first trimester exposure) and 2 of 55 live births (second/third-trimester exposure). One of these prospectively reported defects with first-trimester exposure was a neural tube defect. A single case of anophthalmia with first-trimester exposure to efavirenz has also been prospectively reported; however, this case included severe oblique facial clefts and amniotic banding, a known association with anophthalmia. There have been six retrospective reports of findings consistent with neural tube defects, including meningomyelocele.

Monitoring of liver enzymes before and during treatment is recommended for all patients with underlying hepatic disease, including hepatitis B or C infection; patients with marked transaminase elevations; and patients treated with other medications associated with liver toxicity. Postmarketing reports of hepatic failure include patients with no pre-existing hepatic disease or other identifiable risk factors, and were characterised by a fulminant course, progressing in some cases to transplantation or death Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors. In patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range, the benefit of continued therapy with efavirenz needs to be weighed against the unknown risks of significant liver toxicity.

Drug interactions included posaconazole (avoid concomitant use unless the benefit outweighs the risks) and maraviroc (refer to the full prescribing information for maraviroc for guidance on coadministration with efavirenz).

New dosing regimen for lopinavir/r (Kaletra)

On 27 April 2010, FDA approved a new dosing regimen for Kaletra (lopinavir/ritonavir) tablets and oral solution in the US.

Kaletra can be administered once daily (800/200 mg) in patients with less than three lopinavir resistance associated substitutions. Once daily administration of Kaletra is not recommended for adult patients with three or more of the following lopinavir resistance-associated substitutions: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V. Of note, once daily administration of Kaletra is not recommended in pediatric patients.

The was based on similar virologic and immunologic response rates in study 802.

Class drug-interaction changes for all protease inhibitors

On 27 April 2010 an update was released for all protease inhibitors.

The approved protease inhibitors for the treatment of HIV-1 infection now all include the following drug-drug interaction information. Specific details of dose modifications are included in each new label.

  • Sildenafil (Revatio) as a contraindicated medication when prescribed for the treatment of pulmonary arterial hypertension
  • Alfuzosin (Uroxatral) as a contraindicated medication
  • Recommendation that salmeterol (brand names are Advair and Serevent) should not be coadministered
  • New dosing recommendation for bosentan (Tracleer) and tadalafil (Adcirca) when prescribed for the treatment of pulmonary arterial hypertension. Note, coadministration of bosentan and atazanavir (Reyataz) without ritonavir is not recommended.
  • New dosing recommendations for colchicine when prescribed for the treatment of familial Mediterranean fever or gout
  • New dosing recommendations for colchicine when prescribed for the prophylaxis of gout
  • Recommendation that colchicine should not be coadministered with protease inhibitors in patients with hepatic or renal impairment


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