September 1999

FORMULARY ADDITIONS

Rizatriptan (MaxaltÒ , Maxalt-MLTÒ )
5 and 10 mg oral tablet
5 and 10 mg orally disintegrating tablets

Rizatriptan is indicated for the acute treatment of migraine with or without aura in adults. It is not intended for prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraines. Rizatriptan is a 5-hydroxytriptamine_1B/1D receptor agonist similar to sumatriptan (ImitrexÒ ). Migraine headaches are associated with activation of the trigeminovascular system, which results in vasodilatation and neurogenic inflammation. Rizatriptan like other 5-hydroxytriptamine_1B/1D receptor agonists relieve migraines by constricting cranial blood vessels and inhibit the release of neuropeptides responsible for causing pain.

The contraindications, warnings and precautions are the same with rizatriptan as they are with sumatriptan including patients who have ischemic heart disease, uncontrolled hypertension, history of cerebrovascular events, coronary artery vasospasm, or cardiovascular disease these drugs are not recommended. The drug is rated as FDA Pregnancy Category C because it has not been adequately studied in pregnant women. It is not known if rizatriptan is excreted in human breast milk. It is recommended that rizatriptan be used with caution in women who are breastfeeding. The adverse effects associated with rizatriptan are similar to those reported for sumatriptan including dizziness, asthenia/fatigue, somnolence, nausea and pain/pressure sensations. Rizatriptan should not be given within 24 hours of an ergot-containing drug because prolonged vasospastic reactions may occur, an effect that is thought to be due to additive effects. Rizatriptan should not be administered with monoamine oxidase inhibitors (MAO-A) because of prolonged systemic effects. Administration with propranolol has shown to increase rizatriptan concentrations by 70%, therefore rizatriptan therapy should be initiated at 5 mg in patients using propranolol.

Single doses of 5 and 10 mg are effective in the therapy of acute migraine. The 10 mg dose may provide greater effect than the 5 mg dose. Doses should be separated by at least 2 hours, and no more than 30 mg should be taken in any 24-hour period. Patients taking propranolol should receive the 5 mg dose, and no more than three doses (15 mg) should be used in any 24-hour period. The orally disintegrating tablets (Maxalt-MLTÒ ) should not be removed from the aluminum blister pack until immediately before administration. The tablet is placed on the tongue, where it dissolves and is swallowed with saliva. Consumption of additional liquids is not necessary.

FOOD/DRUG INTERACTIONS: Oral rizatriptan tablets may be taken with or without food. Oral disintegrating tablets should be placed directly on the tongue without liquids or food

Paricalcitrol (ZemplarÒ )
5 mcg/mL vials

Paricalcitrol is approved for the prevention and treatment of secondary hyperparathyroidism encountered with chronic renal failure. The drug is a synthetic vitamin D analogue, which produces reduction in parathyroid hormone (PTH) levels with less impact on calcium and phosphate metabolism. Unlike other vitamin D analogs, paricalcitrol is able to lower PTH levels with a lower risk of developing hypercalcemia and hyperphosphatemia. Peak plasma concentrations of paricalcitrol occur immediately after the completion of the intravenous bolus. The volume of distribution is 6 L in patients with renal disease and 20 to 25 L in healthy subjects. The mean half-life is 15 hours in patients with chronic renal failure requiring hemodialysis and 5.4 to 7.1 hours in health subjects. Systemic clearance (Cl) is 0.72 L/hr. Elimination is primarily by hepatobiliary excretion, with only 16% of the dose eliminated in the urine as metaboites. The parent compound is extensively bound to plasma protein (>99%). No gender dependent pharmacokinetic changes have been observed with paricalcitrol. The pharmacokinetics of paricalcitrol have not been evaluated in the elderly, children or patients with hepatic insufficiency.

The drug is rated as FDA Pregnancy Category C. It is unknown if paricalcitrol is excreted in human breast milk. Caution should be used if a nursing mother requires paricalcitrol therapy, and the baby should be monitored for the signs and symptoms of vitamin D intoxication and hypercalcemia. The contraindications, warnings and precautions for patients taking paricalcitrol for which the product is not to be used, are patients who show evidence of vitamin D toxicity, hypercalcemia or hypersensitivity to any product ingredients (paricalcitrol, propylene glycol and alcohol). The only warning regarding paricalcitrol therapy is the risk of an overdose.

Common adverse reactions for paricalcitrol in patients who have chronic renal failure are nausea, vomiting and edema. Other adverse events reported during paricalcitrol therapy include headache, asthenia, dizziness, ear pain, ecchymosis, chills, feeling unwell, fever, flu, sepsis, peripheral vascular disease, leg cramps, vasodilation, rash, urticaria, somnolence, palpitation, dry mouth, gastrointestinal bleeding, lightheadedness and pneumonia. Monitoring parameters include checking a serum calcium and phosphorus level twice weekly until a maintenance dose is established. After maintenance dose is established levels should be checked monthly. Patients who are receiving digoxin or other digitalis glycosides should be monitored for toxicity in patients with hypercalcemia.

The initial starting dose of paricalcitrol should be 0.04 mcg/kg to 0.1 mcg/kg administered as an intravenous bolus. The frequency should be no less than every other day and can be done anytime during dialysis. Dosing adjustments should be considered after 2 to 4 weeks of therapy and should be adjusted based on serum PTH levels (see Table 1). Dosing changes should occur in 2 to 4 mcg increments. If hypercalcemia develops, the dose should be decreased or the injection held until the serum calcium levels are within normal range. If the dose is held, it should be decreased prior to restarting the regimen. In addition, patients need to be reminded to adhere to the phosphorus restriction in the diet and to maintain the calcium supplement throughout therapy. The maximum recommended dose is 0.24 mcg/kg. Patients should not be receiving phosphate or other vitamin D related compounds while taking paricalcitrol.

Table 1. Adjustments in Paricalcitrol Dose Based on Serum PTH Levels:

PTH Level	Paricalcitrol Dose
Same or increasing	Increase
Decreased by <30%	Increase
Decreased by >30% & <60%	Maintain
Decreased by >60%	Decrease
1.5 to 3 times Upper Limit of Normal	Maintain

Rofecoxib (VioxxÒ )
12.5 and 25 mg tablets
12.5 mg and 25 mg/5 ml suspension

Rofecoxib, a nonsteroidal anti-inflammatory agent, is indicated for the treatment of osteoarthritis, primary dysmenorrhea, and pain. The mechanism of action for rofecoxib is inhibition of the enzyme cyclooxygenase (cox)-2. Cyclooxygenase is responsible for converting arachidonic acid into prostaglandins. Normal expression of prostaglandins occurs in tissues, gastrointestinal tract and renal tubules and are formed from the conversion of arachidonic acid by the enzyme cyclooxygenase. Studies have recently demonstrated that two isoforms of the enzyme exist: cyclooxygenase (COX)-1 and cyclooxygenase (COX)-2. COX-1 is constitutive because it exists in most tissues, while COX-2 is inducible because it is overexpressed during inflammatory processes, resulting in excess production of prostaglandins considered to be harmful. Traditional NSAIDS inhibit both isoforms of cyclooxygenase, COX-1 inhibition limits use due to gastric irritation and renal damage, but COX-2 inhibition decreases inflammation. Celecoxib and rofecoxib are selective COX-2 inhibitors and display no COX-1 inhibition at therapeutic doses.

Table 1. Comparison of FDA-Approved Indications

Indication	Celecoxib (Celebrex)	Rofecoxib (Vioxx)
Dysmenorrhea		X
Osteoarthritis	X	X
Pain		X
Rheumatoid arthritis, adult	X

Both agents when administered with food do not show any decrease in absorption, however when given with high-fat meals, time to peak plasma concentrations can be delayed by one to two hours. Pharmacokinetic parameters for Celecoxib and Rofecoxib are compared in Table 2.

Table 2: Pharmacokinetic Parameters of Celecoxib and Rofecoxib:

Pharmacokinetic Parameter	Celecoxib	Rofecoxib
Bioavailability	NA	93%
Time to peak (hr)	<3	2-3
Food	Delays Cpmax 1-2 hrs; increase absorption 10-20%	Delays Cpmax 1-2 hrs
Protein binding	97%	87%
T 1/2 (hr)	11.2	17

NA = not available

Vdss = apparent volume of distribution B steady-state

fe = fraction excreted unchanged in the urine

Cp_max = peak plasma concentration

The most commonly cited adverse effects noted with both agents in clinical trials include headache, diarrhea, nausea, dyspepsia and abdominal pain. Although COX-2 inhibitors were believed to have less adverse effect on the gastrointestinal tract, this has not been studied completely and thus, both drugs carry the standard NSAID class warnings for risk of gastrointestinal ulceration, bleeding, and perforation. These drugs are not recommended for use in patients who have severe hepatic damage, history of gastrointestinal bleeds, or ulcers.

Celecoxib and rofecoxib are contraindicated in patients with a history of allergic reactions to the drug or the product ingredients. Also, celecoxib is contraindicated in patients with a documented allergic-type reaction to sulfonamides. Aspirin and NSAIDs may cause severe bronchospasm, which can be fatal, in patients with aspirin-sensitive asthma. The safety of celecoxib and rofecoxib in this patient group is unknown. These agents should therefore be avoided in patients with aspirin sensitivity and used with caution in patients with asthma. Neither of these agents are recommended in those with severe renal or hepatic insufficiency.

Both drugs display microsomal p450 metabolism and they yield no pharmacologically active metabolites. Celecoxib and rofecoxib undergo CYP2C9 and CYP3A metabolism respectively. Specific interactions with other drugs that affect the cytochrome p450 isoenzyme system are described in Table 3. Patients currently taking lithium or starting lithium should be monitored closely for increases in lithium steady state concentrations while taking celecoxib.

Table 3. Drug Interactions for rofecoxib and celecoxib:

Interacting Drug	Celecoxib	Rofecoxib
CYP 450 2C9 Inhibitors	Potential interactions
Fluconazole	Two fold increase in celecoxib concentration
Lithium	Lithium levels increased 17%
Furosemide	Reduced natriuretic effect
Antacids	Celecoxib is decreased 37%	Rofecoxib is decreased 20%
Rifampin		Rofecoxib is decreased 50%
Methotrexate (MTX)		Increased MTX levels
Warfarin		Increased INR
ACE Inhibitors	Potential for diminished antihypertensive effect	Potential for diminished antihypertensive effect

For treatment of osteoarthritis the starting dose is recommended at 12.5 mg daily. An additional 12.5 mg may be given for a total daily dose of 25 mg if needed. For treatment of primary dysmenorrhea or acute pain the daily dose should be 50 mg. Rofecoxib should not be used for more than five days when treating pain. Rofecoxib can be administered without regard to meals. Information is not available regarding the use of rofecoxib beyond five days when administered for acute pain.

Dosing:	Celecoxib	Rofecoxib
Osteoarthritis	200 mg QD or 100 mg BID	12.5 mg QD up to 25 mg QD
Rheumatoid Arthritis	100 mg to 200 mg BID
Acute Pain & Dysmenorrhea		50 mg QD for 5 days*

*Studies not have been done for more than five days in treatment of acute pain and dysmenorrhea.

FOOD/DRUG INTERACTIONS: Rofecoxib may be taken with or without food.

FORMULARY DELETIONS

Trovafloxacin (Trovan⁷): 100 mg, 200 mg tablets
Altrovafloxacin (Trovan⁷):200 mg/40 ml injection

Based on numerous reports of Trovan associated hepatic toxicity, the FDA had issued an advisory to physicians that the use of Trovan should be reserved for use ONLY in the treatment of serious life- or limb-threatening infections. Recommendations from the Antibiotic Subcommittee were made to remove this product from the formulary based on the potential for serious hepatic problems.

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