Comments Off on Methamphetamine-Deterring Pseudoephedrine Product, Nexafed, Bioequivalent to Sudafed

Nexafed, a tamper-resistant dosage form of the nasal decongestant pseudoephedrine, has been shown to be pharmacokinetically equivalent to Sudafed brand of the same nasal decongestant.

These data, referred to in my December article on Nexafed, have now been published in the peer-reviewed journal, The American Journal of Drug and Alcohol Abuse.

The authors include two scientists from the manufacturer, Acura Pharmaceuticals, and a pharmacokinetics investigator from the contract research organization, Worldwide Clinical Trials, Inc.  The American Journal of Drug and Alcohol Abuse is currently ranked 10th in impact factor out of 29 substance abuse journals according to Journal Citation Reports at Thomson Reuters.

The advantage of Nexafed over other formulations of pseudoephedrine is the use of Acura’s proprietary IMPEDE technology that prevents extraction of the drug for illicit synthesis of methamphetamine. But as with any such abuse-deterrent technology, the formulation must not interfere with the desired therapeutic use of the drug.

In this study with human volunteers, the investigators demonstrate that Nexafed brand of pseudoephedrine is bioequivalent to Sudafed, meaning that the drug is absorbed into the blood and metabolized to an essentially equal extent in terms of both concentration and time after oral dosing. The report has been named Editor’s Pick of the Month for September 2013 by the Journal’s Editor-in-Chief Bryon Adinoff, M.D., Distinguished Professor in Drug and Alcohol Abuse Research at the University of Texas Southwestern Medical Center. As such, the article is currently freely available for download and viewing.

Public Dangers of Methamphetamine Use and Manufacture

Methamphetamine is a chemical relative of amphetamine but gets to the brain faster and to higher concentrations when taken orally, snorted (insufflation), smoked, or injected. According to the illicit drug education site, methamphetamine produces a stimulant effect characterized by increased alertness and energy with an elevation of mood, or euphoria, increased sociability, and heightened perception of one’s surroundings or “intellectual expansion.” The overlap between the effects of methamphetamine and amphetamine owe to the fact that the former is metabolized to the latter. Most of these effects are due to the release of the neurotransmitters dopamine and norepinephrine in the brain’s pleasure and reward center.

However, long-term methamphetamine use leads to addiction, psychotic behavior, severe damage to the teeth and gums, severe depression and even suicidal ideation. Some effects are due to the drug itself while others occur from carryover of highly-toxic chemicals used in the synthesis of the drug.

Over 1.2 million U.S. citizens have used methamphetamine over the last year according to the 2012 National Survey on Drug Use and Health (NSDUH). In 2011, methamphetamine was cited in 103,000 U.S. hospital emergency department visits.

Clandestine laboratories are commonly located in rural areas and present health risks and potential for explosions due to the chemicals used in meth manufacture. A modified, small scale meth synthesis approach called the one-pot method, or shake-and-bake, or rolling the bottle involves the combination of all reactants in a two-liter soda bottle allowing the drug to be made quickly, without a heat source, and in cars or homes. Roadside trash collection volunteers have been warned to not handle two-liter bottles containing liquid that is not soda due to the explosion hazard and risk of exposure to toxic reactants (PDF example).

Believe it or not, methamphetamine was actually approved as a drug in the U.S. in December, 1943. Sold under the brand name Desoxyn, methamphetamine has a legitimate use in treating attention deficit disorder with hyperactivity and in short-term treatment for refractory obesity. Desoxyn was originally sponsored and marketed by Lundbeck as a Schedule II drug but was sold earlier this year to Recordati Rare Diseases (PDF). As one might expect, prescription sales of methamphetamine are highly scrutinized. However, therapeutic doses of methamphetamine (5-10 mg) are much lower than those misused for recreational purposes.

Gumming Up Pseudoephedrine Use in Methamphetamine Synthesis

As noted earlier, pseudoephedrine is an easily accessible starting material for illicit synthesis of an important drug of abuse, methamphetamine, and, to a lesser extent, ephedrone or methcathinone. As anyone in the U.S. knows from visiting the pharmacy counter, sales of pseudoephedrine are restricted to a limit of 3.6 grams per day or 9 grams per 30 days as a result of the 2005 Combat Methamphetamine Epidemic Act (CMEA). The typical 96-pack of 30 mg pseudoephedrine tablets adds up to 2.88 grams of pseudoephedrine base (Although it’s usually sold as a hydrochloride salt, all calculations are normalized back to the pseudoephedrine free base). The act also limited sales of other starting materials such as phenylpropanolamine and ephedrine, both withdrawn from the market for other health concerns. (Ephedrine can be sold in some states).

Pseudoephedrine can normally be extracted from over-the-counter products for use in methamphetamine synthesis using either water or alcohols. But Acura has been one of several companies to develop tamper-resistant formulations to prevent misuse of either addictive substances or, in this case, unregulated manufacture of an addictive substance.

Acura’s IMPEDE technology creates an unmanageable viscous gelatinous mess when any attempt is made to selectively dissolve the pseudoephedrine for meth synthesis (below). In fact, Acura has seven other tamper-resistant drug formulations in development and currently sells Oxecta, an aversion-based formulation of oxycodone that includes a highly-irritating ionic detergent to prevent crushing and snorting of the powdered drug.

According to the report, 97% of pseudoephedrine could be extracted from Sudafed using water and 89% with methanol. In contrast, no pseudoephedrine could be extracted with either solvent or even a solution of hydrochloric acid.

But regardless of the tamper-resistant technology, the challenge remains that the formulation should not impair the legitimate medical use of the drug. Acura has now effectively demonstrated this for their Nexafed product.

The study used a cross-over design, meaning that the 30 human volunteers would first receive the same 60 milligram dose of either Nexafed or Sudafed, have blood drawn at various times for pseudoephedrine measurements, and then be subject to a “washout” period during which the drug is completely metabolized and eliminated. Only then would the other version of the drug be administered and the process of blood collection repeated. The advantage of the crossover design is that each subject receives both versions of the drug, allowing the researchers to account for any interindividual variations in drug absorption, metabolism, distribution, and excretion.

The time-concentration summary curve for this study demonstrates that Nexafed (Impede) is 92-96% as bioavailable as the control formulation (Sudafed brand). This value is well within the FDA guidelines of 80% to 125% for bioequivalence of two products. The authors of the report provided me with a version of the curve that includes error bars at each blood draw timepoint.

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