On July 27, Abbott Laboratories arranged a last-minute conference call to announce that unforeseen ritonavir (Norvir) production problems had forced the company to discontinue manufacture of the capsule formulation. By mid-August, Abbott announced, all available capsules would be gone from pharmacy shelves and the oral formulation would be substituted.
Although the production problem first occurred in June, Abbott waited until the end of July to inform the community, probably hoping to resolve the situation in time to avoid a shortage. Unfortunately, by the time Abbott made its announcement, there was less than a month's worth of capsules left. In order to prevent a run on the supply and stretch out the remaining stock, Abbott controlled inventory by shipping wholesalers only their usual size orders. No additional quantities were sent out nor special orders filled.
On the retail level, pharmacies scrambled to manage supply and demand. At least one major drug store in New York City reported limited quantities of both capsules and liquid by the first week of August and was rationing out seven-day allotments of the drug. Abbott is increasing production of the oral formulation so that by the time pharmacies completely run out of the capsules, there should be enough liquid to meet the demand. Problems obtaining ritonavir or concerns about the situation can be reported to Abbott at 800/637-2400.
Crystals in the Capsules
In June, ritonavir crystals started turning up in new batches of the capsules. The crystal structure slows down the rate at which ritonavir dissolves and lowers its bioavailability to the point that therapeutic drug levels are not attained in the bloodstream. Ritonavir capsules currently in circulation are unaffected by this problem. Abbott checked all phases of the production process from raw materials to manufacturing facilities but could not pinpoint the cause. Despite flushing out the pipes and other systems, the crystals continued to develop and Abbott stopped manufacture of the capsules. Since the source of the crystallization is unknown, Abbott cannot predict when production will resume. For the foreseeable future, the capsules will be unavailable and ritonavir users will have to make do with liquid ritonavir, in which the crystals have not appeared.
Substituting the Liquid for the Capsule
The liquid and capsule formulations of ritonavir have identical antiretroviral activity. Using the liquid in place of the capsule will not reduce the potency of a combination regimen nor increase the likelihood of resistance developing, provided there is no interruption in treatment. Ritonavir users should refill their prescriptions with the oral solution as soon as their capsules run out and take the liquid at their next scheduled dose.
Each capsule contains 100 mg of active drug and each milliliter (ml) of the liquid contains 80 mg of active drug. Six capsules (600 mg) equal 7.5 ml or 1 1/2 teaspoons of ritonavir liquid. Four capsules (400 mg) equal 5 ml or 1 teaspoon of ritonavir liquid. The liquid comes with a dosing cup that can be used to measure the appropriate amount. It should be placed on a flat surface and filled at eye level. Properly calibrated measuring spoons should be used for dosing as opposed to ordinary teaspoons. The liquid needs to be shaken well before each use and doses should be taken with food.
In addition, the liquid should not be refrigerated, but rather stored at room temperature, between 68° F and 77° F. Ensuring the right storage conditions may be problematic in the summer, especially for people who do not have air conditioners or need to travel with their medicine. The liquid must be used within 30 days of dispensing.
Improving the Taste
Aside from the obvious inconvenience of using a liquid instead of a pill, the ritonavir oral solution is notorious for its unpleasant flavor and bitter aftertaste, which is often compared to "motor sludge." Liquid ritonavir's high alcohol content (43%) may help explain a burning or tingling sensation commonly felt as the ritonavir goes down the esophagus.
In order to improve the taste, Abbott suggests mixing ritonavir liquid with chocolate milk, Advera or Ensure (two nutritional supplements, the latter manufactured by Abbott). The bioavailability of the ritonavir oral solution is unaffected by these three beverages (R. Bertz et al. Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Sept. 1996; Abstract A25).
Since the liquid has always been used in pediatrics, many ideas have been explored to make the flavor more palatable for children. The federal Guidelines for Antiretroviral Use in Pediatric HIV Infection suggest:
Mixing the oral solution with milk, chocolate milk, or vanilla or chocolate pudding or ice cream.
Dulling the taste buds prior to dosing by chewing ice or sucking popsicles.
Coating the mouth by giving peanut butter first.
Administering strong-flavored foods such as maple syrup, cheese or gum (one pediatric nurse suggested Bubble Yum) immediately after the dose.
Other ideas include taking ritonavir liquid with yogurt or Kool Aid. It may be best to take food or drink before and after the dose to disguise the flavor and aftertaste as much as possible.
Life Without Capsules
Some people will be able to make the transition from capsule to liquid and will continue to take the ritonavir oral solution until Abbott resolves the problem. There will also be those who are unable to make the necessary adjustments to already difficult treatment regimens and who will have to find other options. It is crucial that ritonavir users do not just discontinue or interrupt therapy. While someone on a maximally suppressive combination would not ordinarily switch drugs, that would be a better alternative than taking ritonavir erratically or not at all.
Many people on highly active antiretroviral therapy (HAART) have limited treatment options, however it might be possible to substitute another protease inhibitor for ritonavir in some cases. This will depend on a person's treatment history and whether they have already developed resistance to the other available protease inhibitors.
For people who take ritonavir and saquinavir concurrently (both at 400 mg twice daily), one option would be to drop the ritonavir and take Fortovase (the soft gel formulation of saquinavir) at full strength (3600 mg). This would entail an extra dose in the afternoon as Fortovase is administered three times a day. Another alternative is to take Fortovase with a protease inhibitor other than ritonavir.
Two recent studies from Hoffmann La-Roche have looked at saquinavir plus nelfinavir in treatment-naïve and -experienced patients. At week 16, the TIDBID study found 69% of participants in the saquinavir/nelfinavir/one new nucleoside analog group reduced viral load to below 400 copies/ml. At week 48, the SPICE study found 51% of participants maintained viral load down below 50 copies/ml on saquinavir plus nelfinavir and two nucleoside analogs (one new).
Deciding whether to change background therapy at the same time as switching protease inhibitors will depend on many factors including present viral load and the available options. Ritonavir users need to make carefully considered decisions based on their individual circumstances.
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