Table of Contents
Thang La
4th year pharmacy student, UCSF
Ziprasidone (Geodon - Pfizer) is a newly approved antipsychotic for the treatment of positive, negative and affective symptoms of schizophrenia.
PHARMACOLOGY
Like the other antipsycotics in the "atypical" category, such as clozapine, risperidone, olanzapine, and quietiapine, ziprasidone is a serotonin (5HT) and dopamine (D) antagonist. It is structurally different from other atypical antipsychotic drugs, but it binds similarly with high affinity for 5HT2A receptors and D2 receptors.1-3 This selectivity is thought to reduce dopaminergic activity in the limbic system, which alleviates positive symptoms (hallucinations, delusions, bizarre thoughts and behaviors), and to increase dopaminergic activity in the prefrontal cortex, which improves negative symptoms (emotional flattening, decreased volitional behavior) and cognitive deficits associated with schizophrenia.3 Ziprasidone's lower affinity for D2 receptors also accounts for the infrequent extrapyramidal side effects (EPS) compared with conventional or "typical" antipsychotics such as haloperidol.2 Moderate inhibition of synaptic reuptake of 5HT and norepinephrine, a pharmacological mechanisms of many antidepressants, is a unique feature of ziprasidone. In addition, the drug has moderate affinity for 1 and histamine H1 receptors, and low affinity for 2, , D1, muscarinic and nicotinic receptors.1,2
PHARMACOKINETICS
Peak serum levels occur at 4-6 hours after an oral dose. High-fat meals increase oral bioavailability of ziprasidone up to 97%.4-6 Up to 99% of ziprasidone is bound to plasma proteins,7 so ziprasidone is not removed by hemodialysis.8 Ziprasidone is primarily metabolized by aldehyde oxidase and to a lesser extent by CYP3A4 and CYP2D6, to inactive metabolites. Small amounts of ziprasidone are excreted in the urine unchanged.9,10 The half-life of ziprasidone appears to be dose-related and ranges from about 4 hours at 20 mg doses to a mean half-life less than 7 hours at higher doses.4-6
CLINICAL TRIALS
In two randomized, placebo-controlled, double-blind clinical trials, ziprasidone 80, 120 and 160 mg/day was more effective than placebo in the treatment of an acute exacerbation of schizophrenia or schizoaffective disorder. The reduction in the scores on the total Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression Improvement Severity score (CGI-S) were statistically significant.1,2 Both 80 mg/day and 160 mg/day dosage resulted in clinically relevant improvement in the scores on the Positive and Negative Syndrome Scale (PANSS). The improvement in the Scale for the Assessment of Negative Symptoms (SANS) was not statistically significant for patients receiving ziprasidone 120 mg/day. In patients with clinically significant depressive symptoms, ziprasidone 160 mg/day reduced depression .1
A small 4-week comparative study has shown that ziprasidone 160 mg/day was as effective as haloperidol 15 mg/day in reducing positive symptoms in patients with an acute exacerbation of schizophrenia or schizoaffective disorder. The reductions of BPRS and CGI-S scores from baseline were greater in patients receiving ziprasidone 160 mg/day than in those receiving ziprasidone 40 mg/day or less. Overall, the ziprasidone groups experienced fewer side effects than the haloperidol group. The need for benztropine to control EPS symptoms was greater in the haloperidol group.11
ADVERSE REACTIONS
The most frequent adverse effects of ziprasidone are drowsiness, nausea, constipation, akathisia, dyspepsia, dizziness and respiratory disorders. A small prolongation of QTc interval (5.9 - 9.7 msec) occurs with 80-160 mg/day doses. QTc is unchanged in the presence of metabolic inhibition. Ziprasidone does not appear to produce weight gain. Ziprasidone has few drug interactions. The concomitant administration of carbamazepine results in a reduction of ziprasidone levels but this is believed to be clinically irrelevant.12
DOSAGE AND COST
Ziprasidone is available in 20, 40, 60 and 80 mg capsules. The dosage is 20 mg bid initially, increasing at intervals of at least 2 days up to 80 mg bid based on patient response. Ziprasidone can be taken with a meal to improve bioavailability. No adjustment in dosage is necessary in mild to moderate hepatic or renal impairment.8,13 Ziprasidone costs $3.15/ capsule for all strengths.
SUMMARY
Ziprasidone is a new atypical antipsychotic that is effective for the treatment of positive, negative and affective symptoms of schizophrenia.. Unlike other atypical antipsychotics, it has not been associated with weight gain.
REFERENCES1. Daniel DG et al. Ziprasidone 80 mg/day and 160 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 6-week placebo-controlled trial. Neuropsychopharmacology 1999;20:491-505.
2 Keck P et al. Ziprasidone 40 and 120 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 4-week placebo-controlled trial. Psychopharmacology 1998;140:173-84.
3 Ichikawa J, Meltzer HY. Relationship between dopaminergic and serotonergic neuronal activity in the frontal cortex and the action of typical and atypical antipsychotic drugs. Eur Arch Psychiatry Clin Neurosci 1999;249 (suppl 4): IV90-8.
4 Miceli JJ et al. The pharmacokinetics (PK) of CP-88,059 (CP) in healthy male volunteers following oral (PO) and intravenous (IV) administration. Clin Pharmacol Ther 1994;55:142. Abstract PI-78.
5 Miceli JJ et al. Single- and multiple-dose pharmacokinetics of ziprasidone under non-fasting conditions in healthy male volunteers. Br J Clin Pharmacol 2000;49(suppl 1):5S-13S.
6 Hamelin BA et al. The effect of timing of a standard meal on the pharmacokinetics and pharmacodynamics of the novel atypical antipsychotic agent ziprasidone. Pharmacotherapy 1998;18:9-15.
7 Wilner KD et al. Ziprasidone and the activity of cytochrome P450 2D6 in healthy extensive metabolizers. Br J Clin Pharmacol 2000;49(suppl 1):43S-7S.
8 Aweeka F et al. The pharmacokinetics of ziprasidone in subjects with normal and impaired renal function. Br J Clin Pharmacol 2000;49(suppl 1):27S-33S.
9 Prakash C et al. Identification of the major human liver cytochrome P450 isoform(s) resp-onsible for the formation of the primary metabolites of ziprasidone and prediction of possible drug interactions. Br J Clin Pharmacol 2000;49(suppl 1):35S-42S.
10 Prakash C et al. Metabolism and excretion of a new antipsychotic drug, ziprasidone, in humans. Drug Metab and Dispos 1997;25:863-72.
11 Goff DC et al. An exploratory haloperidol-controlled dose-finding study of ziprasidone in hospitalized patients with schizophrenia or schizoaffective disorder. J Clin Psychopharmcol 1998;18:296-304.
12 Miceli JJ et al. The effect of carbamazepine on the steady-state pharmacokinetics of ziprasidone in healthy volunteers. Br J Clin Pharmacol 2000;49(suppl 1):65S-70S.
13 Everson G et al. The pharmacokinetics of ziprasidone in subjects with normal and impaired hepatic function. Br J Clin Pharmacol 2000;49(suppl 1):21S-6S.
Katherine A. Raymond
Pharmacy Resident
Naval Medical Center San Diego
Insulin glargine (Lantus-Aventis) is a new long-acting insulin. It is indicated for subcutaneous administration at bedtime for control of hyperglycemia in adults and children 6 years of age and older with diabetes mellitus.
PHARMACOLOGY AND PHARMACOKINETICS
Insulin glargine is produced by recombinant DNA technology in E. coli. It differs from human insulin at the A21 position of the A-chain (amino acid asparagine is replaced with glycine) and the carboxy terminus of the B-chain (two arginines are added, thus the name glargine). Insulin glargine is soluble at a pH of 4, when injected subcutaneously it is neutralized and forms a precipitate that delays absorption. The formulation contains 30 mcg/mL of zinc to further delay absorption.1-3
Insulin glargine has a nearly peakless profile of action. The onset is 2-4 hours with a duration of greater than 24 hours.4,5 There was no clinically relevant difference in absorption of 125I-labeled insulin glargine from different SC injection sites including abdominal, deltoid, or thigh in healthy men and patients with type 2 diabetes.6,7
CLINICAL TRIALS
When compared with NPH insulin, similar effects on hemoglobin A1C (HbA1C) were observed.2,6,8 These trials were not blinded, because insulin glargine is a clear solution and can be readily distinguished from NPH insulin. In all the trials insulin glargine was administered once or twice daily. Patients remained on their regular preprandial short-acting insulin regimens.
Type 1 Diabetics-Adult. Some clinical trials concluded that some patients receiving insulin glargine had better control of fasting blood glucose (FBG) and/or HbA1C compared with NPH once daily or at bedtime.8-11 The most dramatic responses to insulin glargine were in patients who could not achieve glycemic control with NPH insulin regimens without unacceptable levels of hypoglycemia.12
Type 2 Diabetics-Adult. In four studies, similar control of FBG and HbA1C was achieved in patients receiving insulin glargine once daily or NPH insulin once or twice daily. Patients in one of these studies were previously receiving maximum doses of a sulfonylurea or sulfonylurea plus metformin (oral medications were stopped prior to initiation of insulin therapy).4,6,8,13
Type 1 Diabetics-Children. Effects on FBG and HbA1C were similar when insulin glargine was compared with NPH in one 6-month study in children aged 5 to 16 years.2,6
ADVERSE REACTIONS
The most common side effects reported during clinical trials were injection site reactions and hypoglycemia. A higher frequency of injection site pain was observed with insulin glargine than NPH in some trials; however this did not lead to an increased rate of discontinuation.6,8,12 The frequency of hypoglycemia with insulin glargine was similar to NPH in most studies.1,6,8 However, some studies did report a reduction in hypoglycemia.4,10,12,13 Of these studies, a few noted reductions of nocturnal hypoglycemia than once daily NPH administration, but not compared to twice daily administration of NPH.4,10,11,13
A meta-analysis of four studies found no meaningful 3-step progression of retinopathy when insulin glargine was compared with NPH. However, two of the studies reported an increased frequency of 3-step progression of retinopathy with insulin glargine. This negative finding prompted the FDA to require further evaluation of retinopathy progression, in a phase IV clinical study comparing insulin glargine with NPH. 3,14,15
DOSAGE, ADMINISTRATION AND COST
Insulin glargine is administered by subcutaneous injection once daily at bedtime. It is not intended for IV administration. It should not be mixed with other insulins or diluted with other solutions and does not need to be shaken prior to administration.
Insulin glargine is available as 100 units/mL and is supplied in 5 and 10 mL vials and 3 mL cartridges (cartridges are to be used in OptiPen One insulin delivery devices only). Unopened vials and cartridges should be stored in the refrigerator. If refrigeration is not possible, 10 mL vials can be stored for 28 days and 5 mL vials can be stored for 14 days, at room temperature. Once a cartridge is placed in the OptiPen One device it should be stored at room temperature, for up to 28 days, it should not be stored in the refrigerator. A 10 mL vial of insulin glargine costs UCSD $33.70 compared to $11.04 for a 10 mL vial of human NPH insulin.
A summary of insulin glargine therapy initiation in specific patient populations, is listed below:2
Initiation of insulin glargine. In clinical studies insulin naïve patients with type 2 diabetes mellitus were started on an average of 10 units/day. Following insulin glargine adjustments, based on patient's need, doses ranged from 2 to 100 units/day.
Changing to insulin glargine. Changing from an intermediate or long-acting insulin to insulin glargine is based on administration intervals. Patients who were on once daily insulin can be started at the same dose. Patients who were on twice daily insulin should be started at 20% less than the total daily dosage. Use in children less than 6 years of age has not been studied.
SUMMARY
Insulin glargine is an alternative to NPH insulin. It may be most advantageous in patients who experience hypoglycemia at night with NPH insulin regimens. Patients who use insulin glargine must be instructed not to mix the medication with any other insulin.
REFERENCES
1 Bolli GB et al. Insulin analogues and their potential in the management of diabetes mellitus. Diabetologia 1999;42:1151-67.
2 Insulin glargine package insert. Aventis Pharmaceuticals Inc. Kansas City, MO:2000 April.
3 European Public Assessment Report. Scientific Discussion, Lantus. http://www2.eudra.org/humandocs/Humans/EPAR/Lantus/Lantus.htm (accessed 2001 Mar 12).
4 Insulin glargine. Glargine, HOE71GT15, HOE71GT80, HOE901. Drugs R&D 1999;2:107-9.
5 Lepore M et al. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes 2000;49:2142-8.
6 Gillies PS et al. Insulin glargine. Drugs 2000;59:253-60.
7 Owens DR et al. Pharmacokinetics of 125I-labeled insulin glargine (HOE 901) in healthy men. Comparison with NPH insulin and the influence of different subcutaneous injection sites. Diabetes Care 2000;23:813-9.
8 Raskin P et al. A 16-week comparison of the novel insulin analog insulin glargine (HOE901) and NPH human insulin used with insulin lispro in patients with type 1 diabetes. Diabetes 2000;23:1666-7.
9 Rosenstock J et al. Efficacy and safety of HOE 901 in patients with type 1 DM: four-week randomized NPH insulin-controlled trial. Diabetes 1999;47(suppl.1):0357. Abstract.
10 Pieber T et al. Efficacy and safety of HOE 901 in patients with type 1 diabetes: A four-week randomized, NPH insulin-controlled trial. Diabetes 1998;47(suppl.1):0242. Abstract.
11 Pieber TR et al. Efficacy and safety of HOE 901 versus NPH insulin in patients with type 1 diabetes. Diabetes Care 2000;23:157-62.
12 Ratner RA et al. Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. Diabetes Care 2000;23:639-43.
13 Hannele YJ et al. Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. Diabetes Care 2000;23:1130-6.
14 Berger B. Safety of insulin glargine. Lancet 2000;356:2013-4.
15 Bolli GB et al. Insulin glargine. Lancet 2000;356:443-4.
Jennifer L. Cole, Pharm.D.
Pharmacy Resident
Sedation and analgesia are often required in intubated, mechanically ventilated patients in the intensive care unit. The current agents of choice include sedatives (e.g., propofol, midazolam) and narcotics (e.g., morphine).1 There are limitations associated with these therapies including respiratory depression, severe hypotension and gastrointestinal hypomotility. Consequently, new drugs are being developed that work at different sites in the CNS. Dexmedetomidine hydrochloride (Precedex®--Abbott) is indicated for the sedation of intubated and mechanically ventilated patients during treatment in an intensive care setting.5
PHARMACOLOGY
Dexmedetomidine is an imidazole compound that has demonstrated sedative, analgesic and anxiolytic effects after intravenous administration while avoiding respiratory depression.1,2 It is a highly selective 2 adrenergic agonist with an affinity eight times that of clonidine for the adrenoceptor (2 : 1 ratio 1600:1).5 Activation of postsynaptic receptors by 2 agonists in the CNS causes inhibition of sympathetic activity. This leads to decreases in blood pressure and heart rate, and sedation, while binding of agonists to 2 adrenoceptors in the spinal cord produces analgesia.2 Following slow IV infusion of low to medium doses (10-300 mcg/kg), 2 selectivity predominates in animals. Rapid IV administration or slow IV infusion of high doses (1000 mcg/kg) reveals 1 and 2 activity.5
PHARMACOKINETICS
After IV administration, dexmedetomidine is rapidly distributed to tissues. Sedation occurs within 5 minutes. The steady-state volume of distribution is 1.33 L/kg. Protein binding is 94%. Dexmedetomidine undergoes biotransformation by glucuronidation and cytochrome P450 metabolism with a half-life of about 2 hours. Ninety-five percent of the drug is excreted in the urine as inactive metabolites and about 4% is excreted in the feces. Total body clearance is estimated at 0.54 L/hr/kg. Pharmacokinetic parameters are not significantly different in subjects with severe renal impairment (CLcr <30 mL/min). In subjects with varying degrees of hepatic impairment, the mean clearance values for subjects with mild, moderate, and severe hepatic impairment were 74%, 64% and 53% of those observed in healthy subjects.3.5
CLINICAL TRIALS
In two placebo-controlled, multicenter studies7,8 assessing safety and efficacy, clinically effective sedation was achieved in 60% of patients on dexmedetomidine (n=371) who required no additional sedative medication as compared to 24% in the placebo (n=373) group. Additionally, 19% of patients in the dexmedetomidine group required >50 mg of propofol as compared to 59% in the placebo group. In a study evaluating dexmedetomidine for analgesia in 401 postoperative patients, dexmedetomidine patients required less morphine for pain control than placebo-treated patients (0.43 mg/hour and 0.89 mg/hour, respectively) during the entire study period. These results suggest that the analgesic effects of dexmedetomidine may be useful for patients in the ICU.1,5,6
ADVERSE REACTIONS
The most frequently observed adverse events with dexmedetomidine include hypotension and bradycardia, both of which are related to the dose and infusion rate. Nausea was common.1,4,5 Rapid infusion of a potent 2 agonist, like dexmedetomidine, can also result in transient hypertension because of peripheral 2 receptors in blood vessels which mediate vascular smooth muscle contraction.5
Dexmedetomidine is an 2-adrenergic agonist similar to clonidine, so abrupt discontinuation after administration for more than 24 hours may result in withdrawal symptoms (e.g., nervousness, agitation, headaches, rapid increase in blood pressure).5
DOSAGE
Dexmedetomidine is usually initiated with a loading infusion of 1 mcg/kg over 10 minutes, followed by a maintenance infusion of 0.2 to 0.7 mcg/kg/hr.5 Dexmedetomidine is not indicated for infusions exceeding 24 hours. Dexmedetomidine has been continuously infused in mechanically ventilated patents prior to extubation, during extubation, and post-extubation. Consequently, discontinuation prior to extubation is not necessary. The pharmacokinetic profile of dexmedetomidine is not altered by age, but the risk of bradycardia and hypotension is higher following dexmedetomidine infusion in elderly patients. Therefore, a dosage reduction may be considered in these populations.1,5
COST AND AVAILABILITY
Dexmedetomidine is available in injectable form as 100 mcg/mL, 2 mL ampules.
Drug Availability Dosage* UCSD Cost
Dexmedetomidine 100 mcg/mL, 0.2-0.7 mcg/kg/hr
2 mL ampule
Propofol 10 mg/mL,
20 mL ampule 0.3-5 mg/kg/hr $20-331 / day
50, 100 mL bottle
* 70kg person
SUMMARY
Current agents widely used for short-term sedation in the intubated, mechanically ventilated patient population in the ICU include propofol, midazolam and lorazepam. Propofol, in addition to being expensive, is associated with adverse effects such as hypotension, bradycardia and hyperlipidemia. Lorazepam is a cost-effective choice but oversedation may be problematic. Midazolam is associated with a prolonged recovery time (2 to 6 hours) and, depending on length of therapy, caution needs to be observed with abrupt discontinuation. Dexmedetomidine may offer a safer, alternative for sedation in the ventilated, ICU patient. Additionally, the use of dexmedetomidine shows promise of having analgesic and anxiolytic effects, which may decrease the use of other agents.1
REFERENCES
1. Bhana N et al. Dexmedetomidine. Drugs 2000;59:263-8.
2. Venn RM et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia 1999;54:1136-42.
3. Dyck JB, Shafer SL. Dexmedetomidine pharmacokinetics and pharmacodynamics. Anaesth Pharmacol Rev 1993;1:238-45.
4. Talke P et al. Postoperative pharmacokinetics and sympatholytic effects of dexmedetomidine. Anesth Analg 1997:85:1136-42.
5. Abbott Laboratories. Dexmedetomidine package insert. North Chicago, IL:2000 Feb.
6. Bachand RT et al. A phase III study evaluating dexmedetomidine for analgesia in postoperative patients. Anesthesiology 1999;91:A940. Abstract.
7. Bachand RT et al. A phase III study evaluating dexmedetomidine for sedation in postoperative patients. Anesthesiology 1999;91:A296. Abstract.
The following new drugs were added to the Formulary by the Pharmacy and Therapeutics Committee.
Caspofungin (Cancidas) An injectable antifungal from a new class, currently approved only for resistant Aspergillus infections. It is a restricted drug, limited to approval by Infectious Diseases.
Esomeprazole (Nexium) The S-isomer of omeprazole. Pharmacy will include this drug for consideration in choosing the least expensive proton-pump inhibitor (PPI) for inpatient use.
Levonorgestrel 0.75 mg (Plan B). A progestin-only postcoital contraceptive. It is a two-dose regimen with the first dose given within 72 hours of intercourse and the second dose 12 hours later. It causes much less nausea than estrogen-containing regimens.
Pantoprazole IV (Protonix). The first injectable PPI. Because of its relatively high cost, its use is restricted to 1. patients on a PPI unable to take an oral medication; 2.
In the two-year process of reviewing the entire formulary, the final section, dermatologics were reviewed. The changes below are the result of this process.
The following dermatologicals and topical agents were added to the inpatient formulary:
Critic-Aid ointment, Curasol Wound Dressing, Aloe Ointment, Bacitracin Ointment, Benzamycin Gel, Benzocaine in Orabase, Clindamycin Gel & Lotion, Clotrimazole Cream & Lotion, Clotrimazole/Betamethasone Cream, Dibucaine Ointment, Erythromycin (Erygel) Gel & Ointment, Fluocinonide Gel, Cream & Ointment, Ketoconazole Cream, Lidocaine Jelly & Ointment, Lubriderm Lotion, Menthol/Camphor/Phenol Lotion, Metronidazole Cream & Gel, Miconazole Nitrate Cream, Mometasone Furoate Cream & Ointment, Mupirocin Ointment, Mycolog Cream, Orabase Paste, Orajel-Baby Gel, Orajel-Maximum Strength Gel, Papain/Urea (Accuzyme) Ointment, Penciclovir Cream, Permethrin Cream & Lotion, Polysporin Ointment,
Selenium Sulfide Lotion, Sween Cream, Terbinafine Cream, Triamcinolone Acetonide Dental Ointment, Urea Cream & Lotion.
Dermatologicals and topical agents deleted from the inpatient formulary:
Aluminum Chloride Hexahydrate (Drysol), Amcinonide (Cyclocort), Anthralin, Bath Oil (Nutraderm), Compound Benzoin Tincture, Clioquinol and Hydrocortisone (Vioform-HC), Coal Tar, Coal Tar Compound (Sebutone), Coal Tar, Crude (Estar, Fototar), Desonide (Desowen), Diflorasone Diacetate (Psorcon), Dyclonine (Dyclone), Ferric Subsulfate (Monsel Solution), Fluorouracil (Efudex, Fluoroplex), Flurandrenolide (Cordran Tape), Iodine, Methoxsalen (Oxsoralen-Ultra), Oatmeal, Colloidal (Aveeno, Aveeno Oilated), Para Aminobenzoic Acid (PABA, Presun), Phenol Compound (P&S), Podophyllum Resin (Podocon-25), Safflower Oil, Tretinoin (Retin-A), Triple Sulfonamide Compound (Sultrin), Zinc Oxide Compound (Dome-Paste Bandage, Unna's Boot Bandage).
Editor
Philip O. Anderson, Pharm.D.
Consulting Editor
Michael G. Ziegler, M.D.
Volume 23 Number 4 July-August 2001