-----------------------------------------------------------------------
  VERSED Syrup has been associated with respiratory depression and
  respiratory arrest especially when used for sedation in noncritical
  care settings. VERSED Syrup has been associated with reports of
  respiratory depression airway obstruction desaturation hypoxia and
  apnea most often when used concomitantly with other central nervous
  system depressants (eg opioids). VERSED Syrup should be used only in
  hospital or ambulatory care settings including physicians\' and
  dentists\' offices THAT CAN PROVIDE FOR CONTINUOUS MONITORING OF
  RESPIRATORY AND CARDIAC FUNCTION. IMMEDIATE AVAILABILITY OF
  RESUSCITATIVE DRUGS AND AGE- AND SIZE-APPROPRIATE EQUIPMENT FOR
  VENTILATION AND INTUBATION AND PERSONNEL TRAINED IN THEIR USE AND
  SKILLED IN AIRWAY MANAGEMENT SHOULD BE ASSURED (see

  -----------------------------------------------------------------------

#### DESCRIPTION 

Midazolam is a benzodiazepine available as VERSED Syrup for oral
administration. Midazolam a white to light yellow crystalline compound
is insoluble in water but can be solubilized in aqueous solutions by
formation of the hydrochloride salt *in situ* under acidic conditions.
Chemically midazolam HCl is 8-chloro-6-(2-fluorophenyl)-1-methyl-4 *H*
-imidazo\[1 5 4 benzodiazepine hydrochloride. Midazolam hydrochloride
has the empirical formula C ~18~ H ~13~ ClFN ~3~ ·HCl and a calculated
molecular weight of 362.25.

Each mL of the syrup contains midazolam hydrochloride equivalent to 2 mg
midazolam compounded with sorbitol glycerin citric acid anhydrous sodium
citrate sodium benzoate sodium saccharin edetate disodium FD&C Red #33
artificial cough syrup flavor artificial bitterness modifier and water;
the pH is adjusted to approximately 3 with hydrochloric acid.

Under the acidic conditions required to solubilize midazolam in the
syrup midazolam is present as an equilibrium mixture (shown below) of
the closed ring form shown above and an open-ring structure formed by
the acid-catalyzed ring opening of the 4 5 bond of the diazepine ring.
The amount of open-ring form is dependent upon the pH of the solution.
At the specified pH of the syrup the solution may contain up to about
40% of the open-ring compound. At the physiologic conditions under which
the product is absorbed (pH of 5 to 8) into the systemic circulation any
open-ring form present reverts to the physiologically active lipophilic
closed-ring form (midazolam) and is absorbed as such.

The following chart plots the percentage of midazolam present as the
open-ring form as a function of pH in aqueous solutions. As indicated in
the graph the amount of open-ring compound present in solution is
sensitive to changes in pH over the pH range specified for the product:
2.8 to 3.6. Above pH 5 at least 99% of the mixture is present in the
closed-ring form.

  -----------------------------------------------------------------------
  **Picture Here in Label**

  -----------------------------------------------------------------------

#### CLINICAL PHARMACOLOGY 

Midazolam is a short-acting benzodiazepine central nervous system (CNS)
depressant.

***Pharmacodynamics:***   Pharmacodynamic properties of midazolam and
its metabolites which are similar to those of other benzodiazepines
include sedative anxiolytic amnesic and hypnotic activities.
Benzodiazepine pharmacologic effects appear to result from reversible
interactions with the (gamma)-amino butyric acid (GABA) benzodiazepine
receptor in the CNS the major inhibitory neurotransmitter in the central
nervous system. The action of midazolam is readily reversed by the
benzodiazepine receptor antagonist flumazenil.

Data from published reports of studies in pediatric patients clearly
demonstrate that oral midazolam provides safe and effective sedation and
anxiolysis prior to surgical procedures that require anesthesia as well
as before other procedures that require sedation but may not require
anesthesia. The most commonly reported effective doses range from 0.25
to 1.0 mg/kg in children (6 months to \<16 years). The single most
commonly reported effective dose is 0.5 mg/kg. Time to onset of effect
is most frequently reported as 10 to 20 minutes.

The effects of midazolam on the CNS are dependent on the dose
administered the route of administration and the presence or absence of
other medications.

Following premedication with oral midazolam time to recovery has been
assessed in pediatric patients using various measures such as time to
eye opening time to extubation time in the recovery room and time to
discharge from the hospital. Most placebo-controlled trials (8 total)
have shown little effect of oral midazolam on recovery time from general
anesthesia; however a number of other placebo-controlled studies (5
total) have demonstrated some prolongation in recovery time following
premedication with oral midazolam. Prolonged recovery may be related to
duration of the surgical procedure and/or use of other medications with
central nervous system depressant properties.

Partial or complete impairment of recall following oral midazolam has
been demonstrated in several studies. Amnesia for the surgical
experience was greater after oral midazolam when used as a premedicant
than after placebo and was generally considered a benefit. In one study
69 of midazolam patients did not remember mask application versus 6% of
placebo patients.

Episodes of oxygen desaturation respiratory depression apnea and airway
obstruction have been reported in \<1% of pediatric patients following
premedication (eg sedation prior to induction of anesthesia) with VERSED
Syrup; the potential for such adverse events are markedly increased when
oral midazolam is combined with other central nervous system depressing
agents and in patients with abnormal airway anatomy patients with
cyanotic congenital heart disease or patients with sepsis or severe
pulmonary disease (see

Concomitant use of barbiturates or other central nervous system
depressants may increase the risk of hypoventilation airway obstruction
desaturation or apnea and may contribute to profound and/or prolonged
drug effect. In one study of pediatric patients undergoing elective
repair of congenital cardiac defects premedication regimens (oral dose
of 0.75 mg/kg midazolam or IM morphine plus scopolamine) increased
transcutaneous carbon dioxide (PtcCO ~2~ ) decreased SpO ~2~ (as
measured by pulse oximetry) and decreased respiratory rates
preferentially in patients with pulmonary hypertension. This suggests
that hypercarbia or hypoxia following premedication might pose a risk to
children with congenital heart disease and pulmonary hypertension. In a
study of an adult population 65 years and older the preinduction
administration of oral midazolam 7.5 mg resulted in a 60% incidence of
hypoxemia (paO ~2~ \<90% for over 30 seconds) at some time during the
operative procedure versus 15% for the nonpremedicated group.

***Pharmacokinetics:***    *Absorption:* Midazolam is rapidly absorbed
after oral administration and is subject to substantial intestinal and
hepatic first-pass metabolism. The pharmacokinetics of midazolam and its
major metabolite (alpha)-hydroxymidazolam and the absolute
bioavailability of VERSED Syrup were studied in pediatric patients of
different ages (6 months to \<16 years old) over a 0.25 to 1.0 mg/kg
dose range. Pharmacokinetic parameters from this study are presented in
Table 1. The mean T ~max~ values across dose groups (0.25 0.5 and 1.0
mg/kg) range from 0.17 to 2.65 hours. Midazolam exhibits linear
pharmacokinetics between oral doses of 0.25 to 1.0 mg/kg (up to a
maximum dose of 40 mg) across the age groups ranging from 6 months to
\<16 years. Linearity was also demonstrated across the doses within the
age group of 2 years to \<12 years having 18 patients at each of the
three doses. The absolute bioavailability of the midazolam syrup in
pediatric patients is about 36% which is not affected by pediatric age
or weight. The AUC ~0~ ratio of (alpha)-hydroxymidazolam to midazolam
for the oral dose in pediatric patients is higher than for an IV dose
(0.38 to 0.75 versus 0.21 to 0.39 across the age group of 6 months to
\<16 years) and the AUC ~0~ ratio of (alpha)-hydroxymidazolam to
midazolam for the oral dose is higher in pediatric patients than in
adults (0.38 to 0.75 versus 0.40 to 0.56).

Food effect has not been tested using VERSED Syrup. When a 15 mg oral
tablet of midazolam was administered with food to adults the absorption
and disposition of midazolam was not affected. Feeding is generally
contraindicated prior to sedation of pediatric patients for procedures.

+-----------------------------------------------------------------------+
|   -------                                                             |
| ----------- --------- --------- ---------- ----------- -------------- |
|   **Table 1.                                                          |
|   Pharmacokinetics                                                    |
|   of Midazolam                                                        |
|   Following Single                                                    |
|   Dose                                                                |
|   Administration of\                                                  |
|   VERSED Syrup**                                                      |
|                                                                       |
|   N                                                                   |
| umber of\         Dose\     T ~max~\  C ~max~\   t ~1~\      AUC ~0~\ |
|   su                                                                  |
| bjects/age       (mg/kg)   (h)       (ng/mL)    (h)         (ng·h/mL) |
|                                                                       |
|      6 months to\                                                     |
|      \<2 years old                                                    |
|                                                                       |
|   1                  0.25      0.17      28         5.82        67.6  |
|                                                                       |
|   1                  0.5       0.35      66         2.22        152   |
|                                                                       |
|   1                  1         0.17      61.2       2.97        224   |
|                                                                       |
|     2 to \<12 years                                                   |
|   old                                                                 |
|                                                                       |
|   18                                                                  |
|                0.25      0.72 ±    63 ± 30.0  3.16 ± 1.50  138 ± 89.5 |
|                                0.44                                   |
|                                                                       |
|   18                                                                  |
|                  0.5       0.95 ±    126 ± 75.8 2.71 ± 1.09 306 ± 196 |
|                                0.53                                   |
|                                                                       |
|   18                                                                  |
|                  1         0.88 ±    201 ± 101  2.37 ± 0.96 743 ± 642 |
|                                0.99                                   |
|                                                                       |
|     12 to \<16 years                                                  |
|   old                                                                 |
|                                                                       |
|   4                                                                   |
|                0.25      2.09 ±    29.1 ±     6.83 ± 3.84  155 ± 84.6 |
|                                1.35      8.2                          |
|                                                                       |
|   4                                                                   |
|                  0.5       2.65 ±     118 ±     4.35 ± 3.31 821 ± 568 |
|                                1.58      81.2                         |
|                                                                       |
|   2                                                                   |
|                1         0.55 ±     191 ±     2.51 ± 0.18  566 ± 15.7 |
|                                0.28      47.4                         |
|   -------                                                             |
| ----------- --------- --------- ---------- ----------- -------------- |
+-----------------------------------------------------------------------+

*Distribution*   The extent of plasma protein binding of midazolam is
moderately high and concentration independent. In adults and pediatric
patients older than 1 year midazolam is approximately 97% bound to
plasma protein principally albumin. In healthy volunteers
(alpha)-hydroxymidazolam is bound to the extent of 89%. In pediatric
patients (6 months to \<16 years) receiving 0.15 mg/kg IV midazolam the
mean steady-state volume of distribution ranged from 1.24 to 2.02 L/kg.

*Metabolism*   Midazolam is primarily metabolized in the liver and gut
by human cytochrome P450 IIIA4 (CYP3A4) to its pharmacologic active
metabolite (alpha)-hydroxymidazolam followed by glucuronidation of the
(alpha)-hydroxyl metabolite which is present in unconjugated and
conjugated forms in human plasma. The (alpha)-hydroxymidazolam
glucuronide is then excreted in urine. In a study in which adult
volunteers were administered intravenous midazolam (0.1 mg/kg) and
(alpha)-hydroxymidazolam (0.15 mg/kg) the pharmacodynamic parameter
values of the maximum effect (E ~max~ ) and concentration eliciting
half-maximal effect (EC ~50~ ) were similar for both compounds. The
effects studied were reaction time and errors in tracing tests. The
results indicate that (alpha)-hydroxymidazolam is equipotent and equally
effective as unchanged midazolam on a total plasma concentration basis.
After oral or intravenous administration 63 to 80% of midazolam is
recovered in urine as (alpha)-hydroxymidazolam glucuronide. No
significant amount of parent drug or metabolites is extractable from
urine before beta-glucuronidase and sulfatase deconjugation indicating
that the urinary metabolites are excreted mainly as conjugates.

Midazolam is also metabolized to two other minor metabolites: 4-hydroxy
metabolite (about 3% of the dose) and 1 4 metabolite (about 1% of the
dose) are excreted in small amounts in the urine as conjugates.

*Elimination*   The mean elimination half-life of midazolam ranged from
2.2 to 6.8 hours following single oral doses of 0.25 0.5 and 1.0 mg/kg
of midazolam (VERSED Syrup). Similar results (ranged from 2.9 to 4.5
hours) for the mean elimination half-life were observed following IV
administration of 0.15 mg/kg of midazolam to pediatric patients (6
months to \<16 years old). In the same group of patients receiving the
0.15 mg/kg IV dose the mean total clearance ranged from 9.3 to 11.0
mL/min/kg.

*Pharmacokinetic-Pharmacodynamic Relationships:* The relationship
between plasma concentration and sedation and anxiolysis scores of oral
midazolam syrup (single oral doses of 0.25 0.5 or 1.0 mg/kg) was
investigated in three age groups of pediatric patients (6 months to \<2
years 2 to \<12 years and 12 to \<16 years old). In this study the
patient\' sedation scores were recorded at baseline and at 10-minute
intervals up to 30 minutes after oral dosing until satisfactory sedation
(\"drowsy\" or \"asleep but responsive to mild shaking\" or \"asleep and
not responsive to mild shaking\") was achieved. Anxiolysis scores were
measured at the time when the patient was separated from his/her parents
and at mask induction. The results of the analyses showed that the mean
midazolam plasma concentration as well as the mean of midazolam plus
(alpha)-hydroxymidazolam for those patients with a sedation score of 4
(asleep but responsive to mild shaking) is significantly different than
the mean concentrations for those patients with a sedation score of 3
(drowsy) which is significantly different than the mean concentrations
for patients with a sedation score of 2 (awake/calm). The statistical
analysis indicates that the greater the midazolam or midazolam plus
(alpha)-hydroxymidazolam concentration the greater the maximum sedation
score for pediatric patients. No such trend was observed between
anxiolysis scores and the mean midazolam concentration or mean of
midazolam plus (alpha)-hydroxymidazolam concentration; however
anxiolysis is a more variable surrogate measurement of clinical
response.

*Special Populations:*

*Renal Impairment:*   Although the pharmacokinetics of intravenous
midazolam in adult patients with chronic renal failure differed from
those of subjects with normal renal function there were no alterations
in the distribution elimination or clearance of unbound drug in the
renal failure patients. However the effects of renal impairment on the
active metabolite (alpha)-hydroxymidazolam are unknown.

*Hepatic Dysfunction:*   Chronic hepatic disease alters the
pharmacokinetics of midazolam. Following oral administration of 15 mg of
midazolam C ~max~ and bioavailability values were 43% and 100% higher
respectively in adult patients with hepatic cirrhosis than adult
subjects with normal liver function. In the same patients with hepatic
cirrhosis following IV administration of 7.5 mg of midazolam the
clearance of midazolam was reduced by about 40% and the elimination
half-life was increased by about 90% compared with subjects with normal
liver function. Midazolam should be titrated for the desired effect in
patients with chronic hepatic disease.

*Congestive Heart Failure:*   Following oral administration of 7.5 mg of
midazolam elimination half-life values were 43% higher in adult patients
with congestive heart failure than in control subjects.

*Neonates:*   VERSED Syrup has not been studied in pediatric patients
less than 6 months of age.

*Drug-Drug Interactions:*   See .

INHIBITORS OF CYP3A4 ISOZYMES:

Table 2 summarizes the changes in the C ~max~ and AUC of midazolam when
drugs known to inhibit CYP3A4 were concurrently administered with oral
midazolam in adult subjects.

+-----------------------------------------------------------------------+
|                                                                       |
| --------------- ------------------- ---------------- ---------------- |
|   **Table 2.**                                                        |
|                                                                       |
|                                                                       |
|  **Interacting   **Adult Doses       **% Increase in  **% Increase in |
|   Drug**          Studied**           C ~max~ of\      AUC of\        |
|                                                                       |
|                                     Oral Midazolam** Oral Midazolam** |
|                                                                       |
|   Erythromycin    500 mg tid          170              281            |
|                                                                       |
|   Cimetidine      800 mg up to qid    6                10             |
|                   in\                                                 |
|                   divided doses                                       |
|                                                                       |
|   Diltiazem       60 mg tid           105              275            |
|                                                                       |
|   Fluconazole     200 mg qd           150              250            |
|                                                                       |
|   Grapefruit      200 mL              56               52             |
|   Juice                                                               |
|                                                                       |
|   Itraconazole    100 mg qd           80               240            |
|                                                                       |
|   Ketoconazole    400 mg qd           309              1490           |
|                                                                       |
|   Ranitidine      150 mg bid or tid;  15               9              |
|                   300 mg qd                                           |
|                                                                       |
|   Roxithromycin   300 mg qd           37               47             |
|                                                                       |
|   Verapamil       80 mg tid           97               192            |
|                                                                       |
| --------------- ------------------- ---------------- ---------------- |
+-----------------------------------------------------------------------+

Other drugs known to inhibit the effects of CYP3A4 would be expected to
have similar effects on these midazolam pharmacokinetic parameters.

INDUCERS OF CYP3A4 ISOZYMES:

Table 3 summarizes the changes in the C ~max~ and AUC of midazolam when
drugs known to induce CYP3A4 were concurrently administered with oral
midazolam in adult subjects. The clinical significance of these changes
is unclear.

+-----------------------------------------------------------------------+
|   --                                                                  |
| ------------- --------------- ---------------------- ---------------- |
|   **Table 3.**                                                        |
|                                                                       |
|   *                                                                   |
| *Interacting   **Adult Doses   **% Decrease in C      **% Decrease in |
|   Drug**          Studied**       ~max~ of\              AUC of\      |
|                                                                       |
|                               Oral Midazolam**       Oral Midazolam** |
|                                                                       |
|   Carbamazepine   Therapeutic     93                     94           |
|                   Doses                                               |
|                                                                       |
|   Phenytoin       Therapeutic     93                     94           |
|                   Doses                                               |
|                                                                       |
|   Rifampin        600 mg/day      94                     96           |
|   --                                                                  |
| ------------- --------------- ---------------------- ---------------- |
+-----------------------------------------------------------------------+

Although not tested phenobarbital rifabutin and other drugs known to
induce the effects of CYP3A4 would be expected to have similar effects
on these midazolam pharmacokinetic parameters.

Drugs that did not affect midazolam pharmacokinetics are presented in
Table 4.

+-----------------------------------------------------------------------+
|   ------------------------------ -----------------------------------  |
|   **Table 4.**                                                        |
|                                                                       |
|   **Interacting Drug**           **Adult Doses Studied**              |
|                                                                       |
|   Azithromycin                      500 mg/day                        |
|                                                                       |
|   Magnesium                         Not available                     |
|                                                                       |
|   Nitrendipine                      20 mg                             |
|                                                                       |
|   Terbinafine                       200 mg/day                        |
|   ------------------------------ -----------------------------------  |
+-----------------------------------------------------------------------+

*Clinical Trials:*    *Dose Ranging Safety and Efficacy Study With
VERSED Syrup in Pediatric Patients:* The effectiveness of VERSED Syrup
as a premedicant to sedate and calm pediatric patients prior to
induction of general anesthesia was compared among three different doses
in a randomized double-blind parallel-group study. Patients of ASA
physical status I II or III were stratified to 1 of 3 age groups (6
months to \<2 years 2 to \<6 years and 6 to \<16 years) and within each
age group randomized to 1 of 3 dosing groups (0.25 0.5 and 1.0 mg/kg up
to a maximum dose of 20 mg). Greater than 90% of treated patients
achieved satisfactory sedation and anxiolysis at at least one timepoint
within 30 minutes posttreatment. Similarly high proportions of patients
exhibited satisfactory ease of separation from parent or guardian and
were cooperative at the time of mask induction with nitrous oxide and
halothane administration. Onset time of satisfactory sedation or
anxiolysis occurred within 10 minutes after treatment for \>70% of
patients who started with an unsatisfactory baseline rating. Whereas
pairwise comparisons (0.25 mg/kg versus 0.5 mg/kg groups and 0.5 mg/kg
versus 1.0 mg/kg groups) on satisfactory sedation did not yield
significant p-values (p=0.08 in both cases) comparative analysis of the
clinical response between the high and low doses demonstrated that a
higher proportion of patients in the 1.0 mg/kg dose group exhibited
satisfactory sedation and anxiolysis as compared to the 0.25 mg/kg group
(p\<0.05).

#### INDICATIONS AND USAGE 

VERSED Syrup is indicated for use in pediatric patients for sedation
anxiolysis and amnesia prior to diagnostic therapeutic or endoscopic
procedures or before induction of anesthesia.

VERSED Syrup is intended for use in monitored settings only and not for
chronic or home use (see VERSED SYRUP MUST BE USED AS SPECIFIED IN THE
LABEL.

Midazolam is associated with a high incidence of partial or complete
impairment of recall for the next several hours (see ).

#### CONTRAINDICATIONS 

VERSED is contraindicated in patients with a known hypersensitivity to
the drug or allergies to cherries or formulation excipients.
Benzodiazepines are contraindicated in patients with acute narrow-angle
glaucoma. Benzodiazepines may be used in patients with open-angle
glaucoma only if they are receiving appropriate therapy. Measurements of
intraocular pressure in patients without eye disease show a moderate
lowering following induction of general anesthesia with injectable
VERSED; patients with glaucoma have not been studied.

#### WARNINGS 

**Serious respiratory adverse events have occurred after administration
of oral VERSED most often when VERSED was used in combination with other
central nervous system depressants. These adverse events have included
respiratory depression airway obstruction oxygen desaturation apnea and
rarely respiratory and/or cardiac arrest (see ). When oral midazolam is
administered as the sole agent at recommended doses respiratory
depression airway obstruction oxygen desaturation and apnea occur
infrequently (see ).**

Prior to the administration of VERSED in any dose the immediate
availability of oxygen resuscitative drugs age- and size-appropriate
equipment for bag/valve/mask ventilation and intubation and skilled
personnel for the maintenance of a patent airway and support of
ventilation should be ensured. VERSED Syrup must never be used without
individualization of dosage particularly when used with other
medications capable of producing central nervous system depression.

**VERSED Syrup should be used only in hospital or ambulatory care
settings including physicians\' and dentists\' offices that are equipped
to provide continuous monitoring of respiratory and cardiac function.
VERSED Syrup must only be administered to patients if they will be
monitored by direct visual observation by a health care professional. If
VERSED Syrup will be administered in combination with other anesthetic
drugs or drugs which depress the central nervous system patients must be
monitored by persons specifically trained in the use of these drugs and
in particular in the management of respiratory effects of these drugs
including respiratory and cardiac resuscitation of patients in the age
group being treated.**

For deeply sedated patients a dedicated individual whose sole
responsibility is to observe the patient other than the practitioner
performing the procedure should monitor the patient throughout the
procedure.

**Patients should be continuously monitored for early signs of
hypoventilation airway obstruction or apnea with means for detection
readily available (eg pulse oximetry). Hypoventilation airway
obstruction and apnea can lead to hypoxia and/or cardiac arrest unless
effective countermeasures are taken immediately.** The immediate
availability of specific reversal agents (flumazenil) is highly
recommended. Vital signs should continue to be monitored during the
recovery period. Because VERSED can depress respiration (see )
especially when used concomitantly with opioid agonists and other
sedatives (see ) it should be used for sedation/anxiolysis/amnesia only
in the presence of personnel skilled in early detection of
hypoventilation maintaining a patent airway and supporting ventilation.

Episodes of oxygen desaturation respiratory depression apnea and airway
obstruction have been occasionally reported following premedication
(sedation prior to induction of anesthesia) with oral midazolam; such
events are markedly increased when oral midazolam is combined with other
central nervous system depressing agents and in patients with abnormal
airway anatomy patients with cyanotic congenital heart disease or
patients with sepsis or severe pulmonary disease.

Reactions such as agitation involuntary movements (including
tonic/clonic movements and muscle tremor) hyperactivity and
combativeness have been reported in both adult and pediatric patients.
Consideration should be given to the possibility of paradoxical
reaction. Should such reactions occur the response to each dose of
VERSED and all other drugs including local anesthetics should be
evaluated before proceeding. Reversal of such responses with flumazenil
has been reported in pediatric and adult patients.

Concomitant use of barbiturates alcohol or other central nervous system
depressants may increase the risk of hypoventilation airway obstruction
desaturation or apnea and may contribute to profound and/or prolonged
drug effect. Narcotic premedication also depresses the ventilatory
response to carbon dioxide stimulation.

Coadministration of oral midazolam in patients who are taking
ketoconazole and itraconazole has been shown to result in large
increases in C ~max~ and AUC of midazolam due to a decrease in plasma
clearance of midazolam (see and

Higher risk pediatric surgical patients may require lower doses whether
or not concomitant sedating medications have been administered.
Pediatric patients with cardiac or respiratory compromise may be
unusually sensitive to the respiratory depressant effect of VERSED.
Pediatric patients undergoing procedures involving the upper airway such
as upper endoscopy or dental care are particularly vulnerable to
episodes of desaturation and hypoventilation due to partial airway
obstruction. Patients with chronic renal failure and patients with
congestive heart failure eliminate midazolam more slowly (see ).

The decision as to when patients who have received VERSED Syrup
particularly on an outpatient basis may again engage in activities
requiring complete mental alertness operate hazardous machinery or drive
a motor vehicle must be individualized. Gross tests of recovery from the
effects of VERSED Syrup (see ) cannot be relied upon to predict reaction
time under stress. It is recommended that no patient operate hazardous
machinery or a motor vehicle until the effects of the drug such as
drowsiness have subsided or until one full day after anesthesia and
surgery whichever is longer. Particular care should be taken to assure
safe ambulation.

***Usage in Pregnancy:***   Although VERSED Syrup has not been studied
in pregnant patients an increased risk of congenital malformations
associated with the use of benzodiazepine drugs (diazepam and
chlordiazepoxide) have been suggested in several studies. If this drug
is used during pregnancy the patient should be apprised of the potential
hazard to the fetus.

***Usage in Preterm Infants and Neonates:***   VERSED Syrup has not been
studied in patients less than 6 months of age.

#### PRECAUTIONS 

***Use With Other CNS Depressants:***   The efficacy and safety of
VERSED in clinical use are functions of the dose administered the
clinical status of the individual patient and the use of concomitant
medications capable of depressing the CNS. Anticipated effects may range
from mild sedation to deep levels of sedation with a potential loss of
protective reflexes particularly when coadministered with anesthetic
agents or other CNS depressants. Care must be taken to individualize the
dose of VERSED based on the patient\' age underlying medical/surgical
conditions concomitant medications and to have the personnel age- and
size-appropriate equipment and facilities available for monitoring and
intervention. Practitioners administering VERSED must have the skills
necessary to manage reasonably foreseeable adverse effects particularly
skills in airway management.

***Use With Inhibitors of CYP3A4 Isozymes:***   Oral midazolam should be
used with caution in patients treated with drugs known to inhibit CYP3A4
because inhibition of metabolism may lead to more intense and prolonged
sedation (see ). Patients being treated with medications known to
inhibit CYP3A4 isozymes should be treated with lower than recommended
doses of VERSED Syrup and the clinician should expect a more intense and
prolonged effect.

***Information for Patients:***   To assure safe and effective use of
VERSED Syrup the following information and instructions should be
communicated to the patient when appropriate:

1.  Inform your physician about any alcohol consumption and medicine you
    are now taking especially blood pressure medication and antibiotics
    including drugs you buy without a prescription. Alcohol has an
    increased effect when consumed with benzodiazepines; therefore
    caution should be exercised regarding simultaneous ingestion of
    alcohol during benzodiazepine treatment.

2.  Inform your physician if you are pregnant or are planning to become
    pregnant.

3.  Inform your physician if you are nursing.

4.  Patients should be informed of the pharmacological effects of VERSED
    Syrup such as sedation and amnesia which in some patients may be
    profound. The decision as to when patients who have received VERSED
    Syrup particularly on an outpatient basis may again engage in
    activities requiring complete mental alertness operate hazardous
    machinery or drive a motor vehicle must be individualized.

5.  VERSED Syrup should not be taken in conjunction with grapefruit
    juice.

6.  For pediatric patients particular care should be taken to assure
    safe ambulation.

***Drug Interactions:***    *Inhibitors of CYP3A4 Isozymes:* Caution is
advised when midazolam is administered concomitantly with drugs that are
known to inhibit the cytochrome P450 3A4 enzyme system (ie some drugs in
the drug classes of azole antimycotics protease inhibitors calcium
channel antagonists and macrolide antibiotics). Drugs such as
erythromycin diltiazem verapamil ketoconazole fluconazole and
itraconazole were shown to significantly increase the C ~max~ and AUC of
orally administered midazolam. These drug interactions may result in
increased and prolonged sedation due to a decrease in plasma clearance
of midazolam. Although not studied the potent cytochrome P450 3A4
inhibitors ritonavir and nelfinavir may cause intense and prolonged
sedation and respiratory depression due to a decrease in plasma
clearance of midazolam. Caution is advised when VERSED Syrup is used
concomitantly with these drugs. Dose adjustments should be considered
and possible prolongation and intensity of effect should be anticipated
(see ).

*Inducers of CYP3A4 Isozymes:*   Cytochrome P450 inducers such as
rifampin carbamazepine and phenytoin induce metabolism and caused a
markedly decreased C ~max~ and AUC of oral midazolam in adult studies.
Although clinical studies have not been performed phenobarbital is
expected to have the same effect. Caution is advised when administering
VERSED Syrup to patients receiving these medications and if necessary
dose adjustments should be considered.

*CNS Depressants:*   One case was reported of inadequate sedation with
chloral hydrate and later with oral midazolam due to a possible
interaction with methylphenidate administered chronically in a
2-year-old boy with a history of William\'s syndrome. The difficulty in
achieving adequate sedation may have been the result of decreased
absorption of the sedatives due to both the gastrointestinal effects and
stimulant effects of methylphenidate.

The sedative effect of VERSED Syrup is accentuated by any concomitantly
administered medication which depresses the central nervous system
particularly narcotics (eg morphine meperidine and fentanyl) propofol
ketamine nitrous oxide secobarbital and droperidol. Consequently the
dose of VERSED Syrup should be adjusted according to the type and amount
of concomitant medications administered and the desired clinical
response (see ).

No significant adverse interactions with common premedications (such as
atropine scopolamine glycopyrrolate diazepam hydroxyzine and other
muscle relaxants) or local anesthetics have been observed.

***Drug/Laboratory Test Interactions:***   Midazolam has not been shown
to interfere with results obtained in clinical laboratory tests.

***Carcinogenesis Mutagenesis and Impairment of Fertility:**
Carcinogenesis:* Midazolam maleate was administered with diet in mice
and rats for 2 years at dosages of 1 9 and 80 mg/kg/day. In female mice
in the highest dose (10 times the highest oral dose of 1.0 mg/kg for a
pediatric patient on a mg/m ^2^ basis) group there was a marked increase
in the incidence of hepatic tumors. In high-dose (19 times the pediatric
dose) male rats there was a small but statistically significant increase
in benign thyroid follicular cell tumors. Dosages of 9 mg/kg/day of
midazolam maleate (1 to 2 times the pediatric dose) did not increase the
incidence of tumors in mice or rats. The pathogenesis of induction of
these tumors is not known. These tumors were found after chronic
administration whereas human use will ordinarily be single or
intermittent doses.

*Mutagenesis*   Midazolam did not have mutagenic activity in *Salmonella
typhimurium* (5 bacterial strains) Chinese hamster lung cells (V79)
human lymphocytes or in the micronucleus test in mice.

*Impairment of Fertility:*   A reproduction study in male and female
rats did not show any impairment of fertility at dosages up to 16
mg/kg/day PO (3 times the human dose of 1.0 mg/kg on a mg/m ^2^ basis

***Pregnancy***    *Teratogenic Effects:* Pregnancy Category D (see

Embryo-fetal development studies performed with midazolam maleate in
mice (at up to 120 mg/kg/day PO 10 times the human dose of 1.0 mg/kg on
a mg/m ^2^ basis) rats (at up to 4 mg/kg/day IV 8 times the human IV
dose of 5 mg) and rabbits (at up to 100 mg/kg/day PO 32 times the human
oral dose of 1.0 mg/kg on a mg/m ^2^ basis) did not show evidence of
teratogenicity.

*Nonteratogenic Effects:*   Studies in rats showed no adverse effects on
reproductive parameters during gestation and lactation. Dosages tested
(4 mg/kg IV and 50 mg/kg PO) were approximately 8 times each of the
human doses on a mg/m ^2^ basis

***Labor and Delivery:***   In humans measurable levels of midazolam
were found in maternal venous serum umbilical venous and arterial serum
and amniotic fluid indicating placental transfer of the drug.

The use of VERSED Syrup in obstetrics has not been evaluated in clinical
studies. Because midazolam is transferred transplacentally and because
other benzodiazepines given in the last weeks of pregnancy have resulted
in neonatal CNS depression VERSED Syrup is not recommended for
obstetrical use.

***Nursing Mothers:***   Midazolam is excreted in human milk. Caution
should be exercised when VERSED Syrup is administered to a nursing
woman.

***Geriatric Use:***   The safety and efficacy of this product have not
been fully studied in geriatric patients. Therefore there are no
available data on a safe dosing regimen. One study in geratric subjects
using midazolam 7.5 mg as a premedicant prior to general anesthesia
noted a 60% incidence of hypoxemia (pO ~2~ \<90% for over 30 seconds) at
sometime during the operative procedure versus 15% for the
nonpremedicated group. Until further information is available it is
recommended that this product should not be used in geriatric patients.

***Use in Patients With Heart Disease:***   Following oral
administration of 7.5 mg of midazolam to adult patients with congestive
heart failure the half-life of midazolam was 43% higher than in control
subjects. One study suggests that hypercarbia or hypoxia following
premedication with oral midazolam might pose a risk to children with
congenital heart disease and pulmonary hypertension although there are
no known reports of pulmonary hypertensive crises that had been
triggered by premedication. In the study 22 children were premedicated
with oral midazolam (0.75 mg/kg) or IM morphine plus scopolamine prior
to elective repair of congenital cardiac defects. Both premedication
regimens increased PtcCO ~2~ and decreased SpO ~2~ and respiratory rates
preferentially in patients with pulmonary hypertension.

#### ADVERSE REACTIONS 

The distribution of adverse events occurring in patients evaluated in a
randomized double-blind parallel-group trial are presented in Tables 5
and 6 by body system in order of decreasing frequency: for the
premedication period (eg sedation period prior to induction of
anesthesia) alone see Table 5; for over the entire monitoring period
including premedication anesthesia and recovery see Table 6.

The distribution of adverse events occurring during the premedication
period before induction of anesthesia is presented in Table 5. Emesis
which occurred in 31/397 (8%) patients over the entire monitoring period
occurred in 3/397 (0.8%) of patients during the premedication period
(from midazolam administration to mask induction). Nausea which occurred
in 14/397 (4%) patients over the entire monitoring period (premedication
anesthesia and recovery) occurred in 2/397 (0.5%) patients during the
premedication period.

The distribution of all adverse events occurring in \>/=1% of patients
over the entire monitoring period are presented in Table 6. For the
entire monitoring period (premedication anesthesia and recovery) adverse
events were reported by 82/397 (21%) patients who received midazolam
overall. The most frequently reported adverse events were emesis
occurring in 31/397 (8%) patients and nausea occurring in 14/397 (4%)
patients. Most of these gastrointestinal events occurred after the
administration of other anesthetic agents.

For the respiratory system overall adverse events (hypoxia laryngospasm
rhonchi coughing respiratory depression airway obstruction upper-airway
congestion shallow respirations) occurred during the entire monitoring
period in 31/397 (8%) patients and increased in frequency as dosage was
increased: 71/132 (5%) patients in the 0.25 mg/kg dose group 9 (7%)
patients in the 0.5 mg/kg dose group and 15/133 (11%) patients in the
1.0 mg/kg dose group.

Most of the respiratory adverse events occurred during induction general
anesthesia or recovery. One patient (0.25%) experienced a respiratory
system adverse event (laryngospasm) during the premedication period.
This adverse event occurred precisely at the time of induction. Although
many of the respiratory complications occurred in settings of upper
airway procedures or concurrently administered opioids a number of these
events occurred outside of these settings as well. In this study
administration of VERSED Syrup was generally accompanied by a slight
decrease in both systolic and diastolic blood pressures as well as a
slight increase in heart rate.

+-----------------------------------------------------------------------+
|   -                                                                   |
| ------------------------- ------------------------ --------- -------- |
| - --------- --------- --------- --------------------------- --------- |
|   **Table 5. Adverse Events                                           |
|                                                                       |
|   Occurring During the                                                |
|                                                                       |
|   Premedication Period                                                |
|                                                                       |
|   Before Mask\                                                        |
|                                                                       |
|   Induction in the                                                    |
|                                                                       |
|   Randomized Double-Blind                                             |
|                                                                       |
|   Parallel-Group Trial**                                              |
|                                                                       |
|                                                                       |
|   **[Body                    **[Treatment                             |
|                                          **[Overall]{.underline}**    |
|   System]{.underline}**      Regimen]{.underline}**                   |
|                                                                       |
|                                                                       |
|   No. Patients with Adverse  0.25 mg/kg\                              |
|  0.5                 1 mg/kg\            (n=397)\                     |
|   Events\                    (n=132)                                  |
|  mg/kg\              (n=133)                                          |
|                                                                       |
|  (n=132)                                                              |
|                                                                       |
|                              No.                      (%)       No    |
| .       (%)       No.       (%)       No.                         (%) |
|                                                                       |
|   Gastrointestinal System                                             |
|                                                                       |
|   Disorders                                                           |
|                                                                       |
|                                                                       |
|                                                                       |
|    Emesis                   1                        (0.76%)   1      |
|     (0.76%)   1         (0.75%)   3                           (0.76%) |
|                                                                       |
|                                                                       |
|    Nausea                                                             |
|               2         (1.5%)    2                           (0.50%) |
|                                                                       |
|   Respiratory System                                                  |
|                                                                       |
|   Disorders                                                           |
|                                                                       |
|                                                                       |
|                                                                       |
|    Laryngospasm                                                       |
|                1        (0.75%)   1                           (0.25%) |
|                                                                       |
|                                                                       |
|    Sneezing/Rhinorrhea                                                |
|               1         (0.75%)   1                           (0.25%) |
|                                                                       |
|                                                                       |
|  ALL BODY SYSTEMS           1                        (0.76%)   1      |
|     (0.76%)   5         (3.8%)    7                           (1.8%)  |
|                                                                       |
|   \*This adverse event                                                |
|                                                                       |
|   occurred precisely at the                                           |
|                                                                       |
|   time of induction.                                                  |
|                                                                       |
|   -                                                                   |
| ------------------------- ------------------------ --------- -------- |
| - --------- --------- --------- --------------------------- --------- |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
|   --------------------------- ------------------------ -------- ----- |
| ---- -------- --------- -------- --------------------------- -------- |
|   **Table 6. Adverse Events                                           |
|                                                                       |
|   (\>/=1 %) From the                                                  |
|                                                                       |
|   Randomized Double-Blind                                             |
|                                                                       |
|   Parallel-Group\                                                     |
|                                                                       |
|   Trial on Entire Monitoring                                          |
|                                                                       |
|   Period (premedication                                               |
|                                                                       |
|   anesthesia recovery)**                                              |
|                                                                       |
|                                                                       |
|   **[Body                     **[Treatment                            |
|                                          **[Overall]{.underline}**    |
|   System]{.underline}**       Regimen]{.underline}**                  |
|                                                                       |
|                                                                       |
|   No. Patients with Adverse   0.25 mg/kg\                             |
|    0.5                1 mg/kg\           (n=397)\                     |
|   Events                      (n=132)                                 |
|    mg/kg\             (n=133)                                         |
|                                                                       |
|    (n=132)                                                            |
|                                                                       |
|                               No.                      (%)            |
| No.       (%)      No.       (%)      No.                         (%) |
|                                                                       |
|   Gastrointestinal System                                             |
|                                                                       |
|   Disorders                                                           |
|                                                                       |
|                                                                       |
|     Emesis                    11                       (8%)     5     |
|          (4%)     15        (11%)    31                          (8%) |
|                                                                       |
|     Nausea                    6                        (5%)     2     |
|          (2%)     6         (5%)     14                          (4%) |
|                                                                       |
|   Overall                     16                       (12%)    8     |
|         (6%)     16        (12%)    40                          (10%) |
|                                                                       |
|   Respiratory System                                                  |
|                                                                       |
|   Disorders                                                           |
|                                                                       |
|                                                                       |
|     Hypoxia                   0                                 5     |
|          (4%)     4         (3%)     9                           (2%) |
|                                                                       |
|     Laryngospasm              0                                 1     |
|          (\<1%)   5         (4%)     6                           (2%) |
|                                                                       |
|     Respiratory Depression    2                        (2%)     1     |
|          (\<1%)   2         (2%)     5                           (1%) |
|                                                                       |
|     Rhonchi                   2                        (2%)     1     |
|          (\<1%)   2         (2%)     5                           (1%) |
|                                                                       |
|     Airway Obstruction        2                        (2%)     2     |
|          (2%)     0                  4                           (1%) |
|                                                                       |
|     Upper Airway Congestion   2                        (2%)     0     |
|                   2         (2%)     4                           (1%) |
|                                                                       |
|   Overall                     7                        (5%)     9     |
|          (7%)     15        (11%)    31                          (8%) |
|                                                                       |
|   Psychiatric Disorders                                               |
|                                                                       |
|                                                                       |
|     Agitated                  1                        (\<1%)   2     |
|          (2%)     3         (2%)     6                           (2%) |
|                                                                       |
|   Overall                     1                        (\<1%)   3     |
|          (2%)     4         (3%)     8                           (2%) |
|                                                                       |
|   Heart Rate Rhythm Disorders                                         |
|                                                                       |
|                                                                       |
|     Bradycardia               1                        (\<1%)   3     |
|          (2%)     0                  4                           (1%) |
|                                                                       |
|     Bigeminy                  2                        (2%)     0     |
|                 0                  2                           (\<1%) |
|                                                                       |
|   Overall                     3                        (2%)     3     |
|          (2%)     1         (\<1%)   7                           (2%) |
|                                                                       |
|   Central & Peripheral                                                |
|                                                                       |
|   Nervous  System Disorders                                           |
|                                                                       |
|                                                                       |
|     Prolonged Sedation        0                                 0     |
|                 2         (2%)     2                           (\<1%) |
|                                                                       |
|   Overall                     2                        (2%)     0     |
|                   3         (2%)     5                           (1%) |
|                                                                       |
|   Skin and Appendages                                                 |
|                                                                       |
|   Disorders                                                           |
|                                                                       |
|                                                                       |
|    Rash                       2                        (2%)     0     |
|                 0                  2                           (\<1%) |
|                                                                       |
|   Overall                     2                        (2%)     2     |
|          (2%)     0                  4                           (1%) |
|                                                                       |
|   ALL BODY SYSTEMS            26                       (20%)    23    |
|         (17%)    33        (25%)    82                          (21%) |
|   --------------------------- ------------------------ -------- ----- |
| ---- -------- --------- -------- --------------------------- -------- |
+-----------------------------------------------------------------------+

There were no deaths during the study and no patient withdrew from the
study due to adverse events. Serious adverse events (both respiratory
disorders) were experienced postoperatively by two patients: one case of
airway obstruction and desaturation (SpO ~2~ of 33%) in a patient given
VERSED Syrup 0.25 mg/kg and one case of upper airway obstruction and
respiratory depression following 0.5 mg/kg. Both patients had received
intravenous morphine sulfate (1.5 mg total for both patients).

Other adverse events that have been reported in the literature with the
oral administration of midazolam (not necessarily VERSED Syrup) are
listed below. The incidence rate for these events was generally \<1%.

*Respiratory:  *  apnea hypercarbia desaturation stridor.

*Cardiovascular:*   decreased systolic and diastolic blood pressure
increased heart rate.

*Gastrointestinal:*   nausea vomiting hiccoughs gagging salivation
drooling.

*Central Nervous System:*   dysphoria disinhibition excitation
aggression mood swings hallucinations adverse behavior agitation
dizziness confusion ataxia vertigo dysarthria.

*Special Senses:*   diplopia strabismus loss of balance blurred vision.

#### DRUG ABUSE AND DEPENDENCE 

VERSED Syrup is a benzodiazepine and is a Schedule IV controlled
substance that can produce drug dependence of the diazepam-type.
Therefore VERSED Syrup may be subject to misuse abuse and addiction.
Benzodiazepines can cause physical dependence. Physical dependence
results in withdrawal symptoms in patients who abruptly discontinue the
drug. Withdrawal symptoms (ie convulsions hallucinations tremors
abdominal and muscle cramps vomiting and sweating) similar in
characteristics to those noted with barbiturates and alcohol have
occurred following abrupt discontinuation of midazolam following chronic
administration. Abdominal distention nausea vomiting and tachycardia are
prominent symptoms of withdrawal in infants.

The handling of VERSED Syrup should be managed to minimize the risk of
diversion including restriction of access and accounting procedures as
appropriate to the clinical setting and as required by law.

#### OVERDOSAGE 

The manifestations of VERSED overdosage reported are similar to those
observed with other benzodiazepines including sedation somnolence
confusion impaired coordination diminished reflexes coma and deleterious
effects on vital signs. No evidence of specific organ toxicity from
VERSED overdosage has been reported.

*Treatment of Overdosage:*   Treatment of VERSED overdosage is the same
as that followed for overdosage with other benzodiazepines. Respiration
pulse rate and blood pressure should be monitored and general supportive
measures should be employed. Attention should be given to the
maintenance of a patent airway and support of ventilation including
administration of oxygen. Should hypotension develop treatment may
include intravenous fluid therapy repositioning judicious use of
vasopressors appropriate to the clinical situation if indicated and
other appropriate countermeasures. There is no information as to whether
peritoneal dialysis forced diuresis or hemodialysis are of any value in
the treatment of midazolam overdosage.

Gastrointestinal decontamination with lavage and/or activated charcoal
once the patient\' airway is secure is also recommended.

Flumazenil a specific benzodiazepine-receptor antagonist is indicated
for the complete or partial reversal of the sedative effects of VERSED
and may be used in situations when an overdose with a benzodiazepine is
known or suspected. There are anecdotal reports of adverse hemodynamic
responses associated with VERSED following administration of flumazenil
to pediatric patients. Prior to the administration of flumazenil
necessary measures should be instituted to secure the airway assure
adequate ventilation and establish adequate intravenous access.
Flumazenil is intended as an adjunct to not as a substitute for proper
management of benzodiazepine overdose. Patients treated with flumazenil
should be monitored for resedation respiratory depression and other
residual benzodiazepine effects for an appropriate period after
treatment. The prescriber should be aware of a risk of seizure in
association with flumazenil treatment particularly in long-term
benzodiazepine users and in cyclic antidepressant overdose. The complete
flumazenil package insert including

#### DOSAGE AND ADMINISTRATION 

VERSED Syrup is indicated for use as a single dose (0.25 to 1.0 mg/kg
with a maximum dose of 20 mg) for preprocedural sedation and anxiolysis
in pediatric patients. VERSED Syrup is not intended for chronic
administration.

*Monitoring*   VERSED Syrup should only be used in hospital or
ambulatory care settings including physicians\' and dentists\' offices
that can provide for continuous monitoring of respiratory and cardiac
function. Immediate availability of resuscitative drugs and age- and
size-appropriate equipment for bag/valve/mask ventilation and intubation
and personnel trained in their use and skilled in airway management
should be assured (see

**VERSED Syrup must be given only to patients if they will be monitored
by direct visual observation by a health care professional.** VERSED
Syrup should only be administered by persons specifically trained in the
use of anesthetic drugs and the management of respiratory effects of
anesthetic drugs including respiratory and cardiac resuscitation of
patients in the age group being treated.

Patient response to sedative agents and resultant respiratory status is
variable. Regardless of the intended level of sedation or route of
administration sedation is a continuum; a patient may move easily from
light to deep sedation with potential loss of protective reflexes
particularly when coadministered with anesthetic agents and other CNS
depressants. This is especially true in pediatric patients. The health
care practitioner who uses this medication in pediatric patients should
be aware of and follow accepted professional guidelines for pediatric
sedation appropriate to their situation.

Sedation guidelines recommend a careful presedation history to determine
how a patient\' underlying medical conditions or concomitant medications
might affect their response to sedation/analgesia as well as a physical
examination including a focused examination of the airway for
abnormalities. Further recommendations include appropriate presedation
fasting.

Intravenous access is not thought to be necessary for all pediatric
patients sedated for a diagnostic or therapeutic procedure because in
some cases the difficulty of gaining IV access would defeat the purpose
of sedating the child; rather emphasis should be placed upon having the
intravenous equipment available and a practitioner skilled in
establishing vascular access in pediatric patients immediately
available.

VERSED Syrup must never be used without individualization of dosage
particularly when used with other medications capable of producing CNS
depression. Younger (\<6 years of age) pediatric patients may require
higher dosages (mg/kg) than older pediatric patients and may require
close monitoring.

When VERSED Syrup is given in conjunction with opioids or other
sedatives the potential for respiratory depression airway obstruction or
hypoventilation is increased. For appropriate patient monitoring see
subsection of . The health care practitioner who uses this medication in
pediatric patients should be aware of and follow accepted professional
guidelines for pediatric sedation appropriate to their situation.

The recommended dose for pediatric patients is a single dose of 0.25 to
0.5 mg/kg depending on the status of the patient and desired effect up
to a maximum dose of 20 mg. In general it is recommended that the dose
be individualized and modified based on patient age level of anxiety and
medical need. The younger (6 months to \<6 years of age) and less
cooperative patients may require a higher than usual dose up to 1.0
mg/kg. A dose of 0.25 mg/kg may suffice for older (6 to \<16 years of
age) or cooperative patients especially if the anticipated intensity and
duration of sedation is less critical. For all pediatric patients a dose
of 0.25 mg/kg should be considered when VERSED Syrup is administered to
patients with cardiac or respiratory compromise other higher risk
surgical patients and patients who have received concomitant narcotics
or other CNS depressants. As with any potential respiratory depressant
these patients must be monitored for signs of cardiorespiratory
depression after receiving VERSED Syrup. In obese pediatric patients the
dose should be calculated based on ideal body weight. VERSED Syrup has
not been studied nor is it intended for chronic use.

#### *INSERTION OF PRESS-IN BOTTLE ADAPTER (PIBA)* 

1.  Remove the cap and push bottle adapter into neck of bottle.

2.  Close the bottle tightly with cap. This will assure the proper
    seating of the bottle adapter in the bottle.

  -----------------------------------------------------------------------
  **Picture Here in Label**

  -----------------------------------------------------------------------

#### *USE OF ORAL DISPENSERS AND PIBA* 

1.  Remove the cap.

2.  Before inserting the tip of the oral dispenser into bottle adapter
    push the plunger completely down toward the tip of the oral
    dispenser. Insert tip firmly into opening of the bottle adapter.

3.  Turn the entire unit (bottle and oral dispenser) upside down.

4.  Pull the plunger out slowly until the desired amount of medication
    is withdrawn into the oral dispenser.

  -----------------------------------------------------------------------
  **Picture Here in Label**

  -----------------------------------------------------------------------

5.  Turn the entire unit right side up and remove the oral dispenser
    slowly from the bottle.

6.  The tip of the dispenser may be covered with a tip cap until time of
    use.

  -----------------------------------------------------------------------
  **Picture Here in Label**

  -----------------------------------------------------------------------

7.  

  -----------------------------------------------------------------------
  **Picture Here in Label**

  -----------------------------------------------------------------------

8.  Close bottle with cap after each use.

9.  Dispense directly into mouth. Do not mix with any liquid (such as
    grapefruit juice) prior to dispensing.

#### DISPOSAL OF VERSED SYRUP 

The disposal of Schedule IV controlled substances must be consistent
with State and Federal Regulations.

#### HOW SUPPLIED 

VERSED Syrup is supplied as a clear red to purplish-red cherry-flavored
syrup containing midazolam hydrochloride equivalent to 2 mg of
midazolam/mL; each amber glass bottle of 118 mL of syrup is supplied
with 1 press-in bottle adapter 4 single-use graduated oral dispensers
and 4 tip caps (NDC 0004-0168-51).

***Storage***   Store at 25°C (77°F); excursions permitted to 15° to
30°C (59° to 86°F). \[See USP Controlled Room Temperature\]

Revised: December 1998