ISSUE/QUESTION: Are the pharmacokinetics of two different formulations of
Lorazepam (oral and sublingual) similar in a way that po can be replaced by
sublingual?
SUMMARY OF FINDINGS
Lorazepam Monograph [1]
Absorption: ~ 90%
Peak plasma conc. within 2 hours of an oral dose
Onset of action: Within 1 hour after an oral dose
Maximal effect within 2 hours
Time to peak plasma level (Cmax)
Oral: Mean 2 h (range 1-6 h) [2, 3]
SL: 60 min [2, 3].
PO vs. SL: Comparable extent of absorption, SL form has faster absorption
Doses for oral or sublingual formulation are same [1]
Pharmacokinetic comparison of SL lorazepam with IV, IM and oral lorazepam
An experiment was conducted to compare pharmacokinetics of sublingual lorazepam
with IV, IM and oral lorazepam [4].
Methods: A randomized, single-dose five-way crossover design was utilized [4]. Each
subject was given single 2 mg dose of lorazepam at five different times via five different
routes (IV, IM, Oral, SL oral tabs, SL special tabs; named trial A, B, C, D and E
respectively) separated by at least 1 week [4]. For trials C, D and E, subjects fasted
overnight prior to dose and remained fasting for 3 hours post dose [4]. Venous blood
samples were obtained prior to administration of the drug and at 5 min, 0.25, 0.5, 0.75,
1.0, 1.5, 2.0, 2.5, 3, 4, 6, 8, 12, 24, 30, 36 and 48 hr [4]. The table below shows effect of
route on lorazepam pharmacokinetics:
Lag time: Time elapsed prior to
start of absorption
Minimal differences were observed between trials C, D and E in terms of peak plasma
levels, absorption half-life, and absolute systemic availability [4]. The authors added that
absorption patterns of oral and SL forms resemble and the absorption completeness of
tabs whether given as oral or specially formulated was nearly 100% [4].
It was concluded that rate and completeness of lorazepam absorption following SL
administration are comparable to oral dosage on an empty stomach and both dosage
forms are likely to be therapeutically equivalent [4]. However, the authors added that the
findings of the study only apply to tablet preparations studied and the absorption could be
more rapid with formulations having more rapid dissolution rates [4].
RECOMMENDATION / CONCLUSION:
A detailed literature search was conducted to find differences between pharmacokinetics
of oral and sublingual form by RCH librarian Brooke Scott and myself. However, results
generated were limited in number and only relevant study found was a randomized open
label trial from 1981.
Lorazepam monographs indicate that SL peak plasma concentration reaches faster with
SL form vs. oral form. The study (published in 1982) comparing pharmacokinetic
profiles of different routes of lorazepam administration used two different formulations
of SL lorazepam: sublingual dosage of oral tablets and specially formulated tablets in the
fasting state. Minimal and insignificant differences were found between trials C, D and E.
However, it is not stated what kind of specially formulated tablets were used and the
pharmacokinetic profiles might differ depending on the kind of formulations available
today. From the information collected, it is concluded that it is appropriate to switch to
sublingual Lorazepam vs. having both oral and sublingual forms available in the
pharmacy. Sublingual form has similar bioavailability, distribution, metabolism and
excretion characteristics except that it is absorbed much faster leading to a peak in shorter
amount of time. No significant differences were noted in any of the references utilized to
answer this question.
References:
1. Lorazepam drug monograph. In: Cadario BJ, Leathem AM, editors. Drug Information
Reference. 5th ed. Vancouver. The BC Drug and Poison Information Centre; 2003.
2. Pfizer Canada. Prescribing information: Ativan [Internet]. Sept 23, 2010 [cited 2012
Jan 5]. Available from: http://www.pfizer.ca/en/our_products/products/monograph/279
3. Comparison of the benzodiazepines. In: Virani AS, Bezchlibnyk-Butler Kalyna Z.,
Jefries JJ, editors. Clinical Handbook of Psychotropic Drugs. 18th ed. Hogrefe & Huber
Publishers; 2009.
4. Greenblatt DJ, Divoll M, Harmatz JS, Shader RI. Pharmacokinetic comparison of
sublingual lorazepam with intravenous, intramuscular, and oral lorazepam. J Pharm Sci.
1982 Feb; 71(2):248-52