FDA Safety Changes: Combivent, Qualaquin, Sucraid

Yael Waknine

March 04, 2009

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March 4, 2009 — The US Food and Drug Administration (FDA) has approved safety labeling revisions to provide additional counseling information for patients receiving combination therapy with ipratropium bromide plus albuterol sulfate inhalation solution, advise of drug interactions with quinine sulfate, and warn of contraindications to sacrosidase oral therapy.

Ocular Exposure to Ipratropium Plus Albuterol Spray (Combivent) May Cause Adverse Events

On November 10, 2008, the FDA approved safety labeling revisions for ipratropium bromide and albuterol sulfate inhalation aerosol (Combivent; Boehringer Ingelheim Pharmaceuticals, Inc) to provide additional patient counseling information and warn of the potential for albuterol-related teratogenic effects.

Patients should be cautioned to avoid spraying the inhalation aerosol into their eyes and are advised that doing so may result in precipitation or worsening of narrow-angle glaucoma, mydriasis, increased intraocular pressure, acute eye pain or discomfort, temporary blurring of vision, and visual halos or colored images in association with red eyes from conjunctival and corneal congestion. A clinician should be contacted if any of these symptoms develop.

The FDA also warned that ipratropium plus albuterol inhalation aerosol should be used in pregnancy only if the potential benefit to the mother justifies fetal risk. Although no animal studies have been conducted with the combination product, a 4.5% rate of cleft palate formation was observed in rodents receiving doses equivalent to the maximal recommended human dose of albuterol.

Ipratropium plus albuterol aerosol is indicated as add-on therapy to control bronchospasm in patients who are already using a regular aerosol bronchodilator to treat chronic obstructive pulmonary disease.

Quinine Sulfate (Qualaquin) Linked to Drug Interactions with H2-Blockers and Statins

On November 14, 2008, the FDA approved safety labeling revisions for quinine sulfate capsules (Qualaquin; AR Holding Co, Inc) to advise of drug interactions with histamine type 2 (H2)-blockers and 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors.

In vitro studies have demonstrated that quinine is primarily metabolized by the hepatic cytochrome P 450 isoenzyme 3A4 (CYP3A4); some roles were also observed for CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1.

Although inhibitors of quinine metabolism generally increase the risk for adverse events, this effect may not be consistent within a single class of drug. Cimetidine and ranitidine are H2-blockers and nonspecific CYP450 inhibitors that inhibit quinine clearance to different degrees.

Pharmacokinetic study data have demonstrated that the apparent oral clearance of quinine (one 600-mg dose) is decreased, and the mean elimination half-life is significantly increased with coadministration of cimetidine (200 mg 3 times daily and 400 mg at bedtime for 7 days) but not ranitidine (150 mg twice a day for 7 days). Although both H2-blockers increase quinine exposure (area under the receiver operating characteristic curve) relative to controls, the effect is much greater with cimetidine vs ranitidine (42% vs 20%).

Ranitidine is therefore preferred vs cimetidine when coadministration of an H2-blocker is required, and patients should still be closely monitored for quinine-related adverse events.

Citing a case of rhabdomyolosis with acute renal failure secondary to myoglobinuria, the FDA also warned that metabolic competition with quinine may increase plasma concentrations and the risk for adverse events related to the CYP3A4 substrate atorvastatin.

Clinicians considering combination therapy with quinine and atorvastatin or other HMG-CoA reductase inhibitors (also known as statins) that are CYP3A4 substrates (eg, simvastatin and lovastatin) should therefore carefully weigh the potential risks and benefits of each medication.

If concomitant therapy with quinine is required, lower starting and maintenance doses of statins should be considered and patients monitored closely for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy.

Statin therapy should be discontinued if marked creatine phosphokinase elevations or myopathy (defined as muscle aches/weakness in conjunction with creatine phosphokinase levels > 10 times the upper limit of normal) is diagnosed or suspected.

Quinine tablets are indicated for the treatment of uncomplicated Plasmodium falciparum malaria.

Sacrosidase (Sucraid) Therapy Nixed in Patients Allergic to Yeast Products, Glycerin, or Papain

On November 20, 2008, the FDA approved safety labeling revisions for sacrosidase oral solution (Sucraid; QOL Medical, LLC) to advise of contraindications to its use.

Sacrosidase is derived from baker's yeast (Saccharomyces cerevisiae) and is manufactured with papain, a protein-cleaving enzyme that is introduced to digest cell walls and may not be completely removed by subsequent steps in the manufacturing process. The finished enzyme product also contains 50% glycerol (w/w).

Use of sacrosidase is therefore contraindicated in patients known to be hypersensitive to yeast, yeast products, glycerin (glycerol), or papain.

Care should be taken to administer initial doses near a facility where acute hypersensitivity reactions can be adequately treated; alternatively, skin abrasion testing for hypersensitivity may be performed.

Sacrosidase oral solution is indicated as replacement therapy for genetically determined sucrase deficiency, which is part of a congenital sucrase-isomaltase deficiency.

Combivant Prescribing Information

Qualaquin Prescribing Information

Sucraid Prescribing Information

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