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Deconstructing a Full Prescribing Information – Part VI Sunday 1/23/11

Posted by smcgamer in Archive, Deconstucting The, Post-A-Week 2011.

This is my first post of Post-A-Week 2011, and today, I’m continuing with the deconstruction of Lunesta’s full prescribing information.  We continue with the pharmacokinetics of eszopiclone, specifically the elimination, and we will continue with the effect of food, and special populations.


After oral administration, eszopiclone is eliminated with a mean t1/2 of approximately 6 hours.  Up to 75% of an oral dose of racemic zopiclone is excreted in the urine, primarily as metabolites.

A racemic mixture is a mixture that has equal amounts of left- and right-handed enantiomers of a chiral molecule.  An enantiomers is basically a mirror-copy of another molecule.

A similar excretion profile would be expected for eszopiclone, the S-isomer of racemic zopiclone.  Less than 10% of the orally administered eszopiclone dose is excreted in the urine as parent drug.

While less than ten percent may sound bad, remember that they are referring to the parent drug – the remainder is used up.  Isomers are molecules with the same formula, but they are not structured the same.

Effect of Food

In healthy adults, administration of a 3 mg dose of eszopiclone after a high-fat meal resulted in no change in AUC, a reduction in mean Cmax of 21%, and delayed tmax by approximately 1 hour.  The half-life remained unchanged, approximately 6 hours.  The effects of LUNESTA on sleep onset may be reduced if it is taken with or immediately after a high-fat/heavy meal.

AUC, or area under the curve, in the case of pharmaceuticals, is a complex topic that wouldn’t fit into a paragraph, but I provided a link to a wonderful source of data on it.  Cmax is basically the highest concentration level of a drug in the blood serum.  Tmax is when maximum plasma concentration is reached; absorption equals elimination.

Basically, eating a high-fat meal will delay or hurt the effectiveness of eszopiclone.

Special Populations


Compare with non-elderly adults, subjects 65 years and older had an increase of 41% in total exposure (AUC) and a slightly prolonged elimination of eszopiclone (t1/2 approximately 9 hours).  Cmax was unchanged.  Therefore, in elderly patients the starting dose of LUNESTA should be decreased to 1 mg and the dose should not exceed 2 mg.

Apparently, the older you are, the more exposure you get from eszopiclone.  It also takes longer to get rid of it.


The pharmacokinetics of eszopiclone in men and women are similar.


In an analysis of data on all subjects participating in Phase 1 studies of eszopiclone, the pharmacokinetics for all races studied appeared similar.

There are six phases of study in a clinical trial.

Hepatic impairment

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Pharmacokinetics of a 2 mg eszopiclone dose were assessed in 16 healthy volunteers and in 8 subjects with mild, moderate, and severe liver disease.  Exposure was increased 2-fold in severly impaired patients compared with healthy volunteers.  Cmax and tmax were unchanged.  The dose of LUNESTA should not be increased above 2 mg in patients with severe hepatic impairment.  No dose adjustment is necessary for patients with mild-to-moderate hepatic impairment.  LUNESTA should be used with caution in patients with hepatic impairment.

Hepatic impairment is when the liver can’t function as well as it used to.

A hemodialysis machine, used to physiologicall...

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Renal impairment

The pharmacokinetics of eszopiclone were studied in 24 patients with mild, moderate, or severe renal impairment.  AUC and Cmax were similar in the patients compared with demographically matched healthy control subjects.  No dose adjust is necessary in patients with renal impairment, since less than 10% of the orally administered eszopiclone dose is excreted in the urine as parent drug.

Renal impairment is when the kidneys can’t function as well as they used to.

Drug Interactions

Paroxetine pill

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Eszopiclone is metabolized by CYP3A4 and CYP2E1 via demethylation and oxidation.  There were no pharmacokinetic or pharmacodynamic interactions between eszopiclone and paroxetine, digoxin, or warfarin.  When eszopiclone was coadministered with olanzapine, no pharmacokinetic interaction was detected in levels of eszopiclone or olanzapine, but a pharmacodynamic interaction was seen on a measure of psychomotor function.  Eszopiclone and lorazepam decreased each other’s Cmax by 22%.  Coadministration of eszopiclone 3 mg to subjects receiving ketoconazole 400 mg, a potent inhibitor of CYP3A4, resulted in a 2.2-fold increase in exposure to eszopiclone.  LUNESTA would not be expected to alter the clearance of drugs metabolized by common CYP450 enzymes.

Holy big words, Batman!

Ribbon diagram of human cytochrome P450 isozym...

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Cytochrome P450 3A4 is “one of the most important enzymes involved in the metabolism of xenobiotics in the body.”  A xenobiotic is a chemical found but not produced in the body.  Cytochrome P450 2E1 is involved in the metabolism of xenobiotics in the body.

Paroxetine (brand names Aropax, Paxil, and Seroxat) is an SSRI antidepressant.  Digoxin is a purified cardiac glycoside extracted from the foxglove plant, and used for treatment of heart failure.  Warfarin, also known as coumadin,  is an anticoagulant, used to make blood thinner.  It is used as rat poison, but is also used as a blood thinners to fight clots.

Olanzapine is an atypical antipsychotic, used to treat schizophrenia.  Lorazepam is a benzodiazepine, another type of relaxant.  Ketoconazole is an anti-fungal drug used to treat skin infections.  A CYP450 enzyme is a member of the Cytochrome P450 superfamily of enzymes, whose primary functions is to catalyze the oxidation of organic substances.

Wow, that was a lot of text.  LUNESTA was tried with an antidepressant, a heart-failure treatment, a blood thinner, an antipsychotic, another sleep aid, and an anti-fungal drug.  I’m surprised they forgot aspirin, ibuprofen, or acetaminophen.


While keeping up the quality with Post-A-Week, I’ve also decided to do something new with WordPress’s Aside function: Aside-A-Day, where I write a simple, short thought each day.

My Post-A-Week posts are scheduled to come out on Fridays.


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