Compiled by:
Rebecca L. Bass, PharmD candidate
McWhorter School of Pharmacy
Birmingham, AL

ACCOLATE (zafirlukast)- ADDERALL (amphetamine/dextroamphetamine) - ALDACTONE (spironolactone) - CARDURA (doxazosin mesylate) - CLEOCIN (clindamycin) - DEXEDRINE (dextroamphetamine sulfate) - DURAGESIC (fentanyl) - FAMVIR (famciclovir) - GARAMYCIN (gentamicin sulfate) - INTAL (cromolyn sodium) - KADIAN (morphine sulfate) - LEUCOVORIN CALCIUM - MAVIK (trandolapril) - MIACALCIN (calcitonin-salmon) - OXYCONTIN (oxycodone HCl) - PERSANTINE (dipyridamole) - RITALIN (methylphenidate HCl) - ULTRAVIST (iopromide) - VERELAN (verapamil HCl) - VIRACEPT (nelfinavir mesylate) - VOSOL (acetic acid) - VOSOL HC (hydrocortisone/acetic acid) - WYTENSIN (guanabenz acetate) - ZOLOFT (sertraline HCl)

PRECAUTIONS:

Eosinophilic Conditions (new subsection): "The reduction of the oral steroid dose, in some patients on Accolate therapy, has been followed in rare cases by the occurrence of eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy sometimes presenting as Churg Strauss Syndrome, a systemic eosinophilic vasculitis. Although a causal relationship with Accolate has not been established, caution is required when oral steroid reduction is being considered (See ADVERSE REACTIONS.)"

ADVERSE REACTIONS:

Two paragraphs added to end of section - "The reduction of the oral steroid dose, in some patients on Accolate therapy has been followed in rare cases by the occurrence of eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy sometimes presenting as Churg Strauss Syndrome, a systemic eosinophilic vasculitis. Although a causal relationship with Accolate has not been established (See PRECAUTIONS-Eosinophilic Conditions).

"Hypersensitivity reactions, including urticaria angioedema and rashes, with or without blistering, have been reported in association with Accolate therapy."

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INDICATIONS:

Deletion of the obesity indication. [Change appears in the 1997 PDR.]

WARNINGS:

Deletion of first sentence - "When tolerance to the 'anorectic' effect develops, the recommended dose should not be exceeded in an attempt to increase the effect; rather, the drug should be discontinued."

PRECAUTIONS:

Pregnancy/Teratogenic Effects: Addition of a new 3rd sentence - "While there are no adequate and well-controlled studies in pregnant women, there has been one report of severe congenital bony deformity, tracheoesophageal fistula, and anal atresia (vater association) in a baby born to a woman who took dextroamphetamine sulfate with lovastatin during the first trimester of pregnancy." [Change appears in the 1997 PDR.]

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CLINICAL PHARMACOLOGY:

Pharmacokinetics: The fifth paragraph has been revised (new text in italics) - "The pharmacokinetics of Cardura (doxazosin mesylate) in young (< 65 years) and elderly (> 65 years) subjects were similar for plasma half-life values and oral clearance. Pharmacokinetic studies in elderly patients and patients with renal impairment have shown no significant alterations compared to younger patients with normal renal function. ["There have, however, been no studies of patients with liver impairment, and" deleted] Administration of a single 2 mg dose to patients with cirrhosis (Child-Pugh Class A) showed a 40% increase in exposure to doxazosin. There are only limited data on the effects of drugs known to influence the hepatic metabolism of doxazosin [e.g., cimetidine (see PRECAUTIONS)]. As with any drug wholly metabolized by the liver, use of Cardura in patients with altered liver function should be undertaken with caution." ["Use of doxazosin in patients with altered liver function should be undertaken with particular caution, if at all, as excretion is almost wholly hepatic." deleted]

WARNINGS:

Priapism (new subsection): "Rarely (probably less frequently than once in every several thousand patients), alpha₁ antagonists such as doxazosin have been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation). Because this condition can lead to permanent impotence if not promptly treated, patients must be advised about the seriousness of the condition (see PRECAUTIONS: Information for Patients)."

PRECAUTIONS:

Information for Patients: Paragraph added to the end of subsection - "Patients should be advised about the possibility of priapism as a result of treatment with alpha₁ antagonists. Patients should know that this adverse event is very rare. If they experience priapism, it should be brought to immediate medical attention for if not treated promptly it can lead to permanent erectile dysfunction (impotence)."

Impaired Liver Function: Deletion of sentence - "There is no controlled experience with Cardura in patients with these conditions."

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WARNING:

Previous text in BOXED WARNING deleted and replaced with -

"Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clindamycin, and may range in severity from mild to life- threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

"Because clindamycin therapy has been associated with severe colitis which may end fatally, it should be reserved for serious infections where less toxic antimicrobial agents are inappropriate, as described in the INDICATIONS AND USAGE Section. It should not be used in patients with nonbacterial infections such as most upper respiratory tract infections. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of 'antibiotic-associated colitis'.

"After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis.

"Diarrhea, colitis, and pseudomembranous colitis have been observed to begin up to several weeks following cessation of therapy with clindamycin."

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OVERDOSAGE:

Treatment: First paragraph revised (new text in italics)- "Consult with a Certified Poison Control Center for up-to-date guidance and advice. Management of acute amphetamine intoxication is largely symptomatic and includes gastric lavage, administration of activated charcoal, administration of a cathartic, and sedation. ["with a barbiturate." deleted] Experience with hemodialysis or peritoneal dialysis is inadequate to permit recommendation in this regard. Acidification of the urine increases amphetamine excretion, but is believed to increase risk of acute renal failure if myoglobinuria is present. If acute, severe hypertension complicates amphetamine overdosage, administration of intravenous phentolamine (Regitine, CIBA) has been suggested. However, a gradual drop in blood pressure will usually result when sufficient sedation has been achieved."

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CLINICAL PHARMACOLOGY:

Pharmacokinetics: Last sentence of fourth paragraph revised (new text in italics) - "Continued absorption of fentanyl from the skin accounts for a slower disappearance of the drug from the serum than is seen after an IV infusion where the apparent half-life ["ranges from 3-12 hours" deleted] is approximately 7 (range 3-12) hours.

Graph: "Serum Fentanyl Concentrations Following Multiple Applications of Duragesic 100 ug/h" revised. See revised graph in new label/package insert.

Table A: "Range of Pharmacokinetic Parameters of Fentanyl in Patients" split into two tables - Table A and Table B (new text in italics)

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Table A
Fentanyl Pharmacokinetic Parameters Following
First 72-Hour Application of Duragesic

Dose	Mean (SD) Time to Maximal Concentration Tmax (h)	Mean (SD) Maximal Concentration Cmax (ng/mL) ["Range" deleted]
DURAGESIC 25 ug/h	38.1 (18.0)	0.6 (0.3)
DURAGESIC 50 ug/h	34.8 (15.4)	1.4 (0.5)
DURAGESIC 75 ug/h	33.5 (14.5)	1.7 (0.7)
DURAGESIC 100 ug/h	36.8 (15.7)	2.5 (1.2)

NOTE: After system removal there is continued systemic absorption from residual fentanyl in the skin so that serum concentrations fall 50%, on average, in 17 hours.

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Table B ["A" deleted]
Range of Pharmacokinetic Parameters of
Intravenous Fentanyl in Patients

	Clearance (L/h) Range [70 kg]	Volume of Distribution Vss (L/kg) Range	Half Life T1/2 (h) Range
["IV Fentanyl" deleted] Surgical Patients	27 - 75	3 - 8	3 - 12
Hepatically Impaired Patients	3 - 80+	0.8 - 8+	4 - 12+
Renally Impaired Patients	30 - 78	-	-

⁺ Estimated

NOTE: Information on volume of distribution and half-life not available for renally impaired patients.

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Pharmacodynamics: Ventilatory Effects: Text deleted in first paragraph - "As a consequence, 10 of these 13 patients received naloxone, two patients had their dose reduced and one patient required no treatment beyond verbal stimulation. Of the 13 events, seven were associated with Duragesic 100 ug/h and six were associated with Duragesic 75 ug/h."

Text added at end of first paragraph - "In addition, post-marketing reports have been received of opiod-naive post-operative patients who have experienced clinically significant hypoventilation with Duragesic. Duragesic is contraindicated in the treatment of postoperative and acute pain."

New third sentence added to third paragraph - "The use of initial doses exceeding 25 ug/h is contraindicated in patients who are not tolerant to opioid therapy."

CLINICAL TRIALS:

First sentence revised to read (new text in italics) - "Duragesic was studied in patients with acute and chronic pain (postoperative and cancer pain models); however, Duragesic is contraindicated for postoperative analgesia."

PRECAUTIONS:

Patients with Fever/External Heat: In first sentence 102^o F changed to 104^o F.

Carcinogenesis, Mutagenesis, and Impairment of Fertility: Last sentence of first paragraph revised to read (new text in italics) - "There was no evidence of mutagenicity in the Ames Salmonella typhimurium mutagenicity assay, the primary rat hepatocyte unscheduled DNA synthesis assay, the BALB/c-3T3 transformation test, the mouse lymphoma assay, ("and" deleted] the human lymphocycte and CHO chromosomal aberration in-vitro assays, or the in-vivo micronucleus test."

Last paragraph in subsection deleted - "In the mouse lymphoma assay, fentanyl concentrations 2000 times greater than those seen with chronic Duragesic use were only mutagenic in the presence of metabolic activation."

Pediatric Use: First sentence revised to read (new text in italics) - "The safety and efficacy of Duragesic in pediatric patients have ["children has" deleted] not been established."

Information for Patients: Current text deleted - "Instructions for the application, removal, and disposal of Duragesic are provided in each carton."

Text added - "A patient instruction sheet is included in the package of Duragesic systems dispensed to the patients."

DOSAGE AND ADMINISTRATION:

Initial Duragesic Dose Selection: New text added before last sentence in #3 - "The recommended starting dose when converting from other opioids to Duragesic is likely too low for 50% of patients. This starting dose is recommended to minimize the potential for overdosing with the first dose."

Table B: Table revised (new text in italics) -

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TABLE C ["B" deleted] EQUIANALGESIC POTENCY CONVERSION
Name	Equianalgesic Dose (mg)
	IM b,c ["a" deleted]	PO
morphine	10	60 (30) d [ "b"deleted]
Hydromorphone (Dilaudid)	1.5	7.5
methadone (Dolophine)	10	20
oxycodone ["(Percocet)" deleted]	15	30
levorphanol (Levo-Dromoran)	2	4
oxymorphone (Numorphan)	1	10 (PR)
heroin	5	60
meperidine (Demerol)	75	---
codeine	130	200

["Note:" deleted] ^a All IM and PO doses in this chart are considered equivalent to 10 mg of IM morphine in analgesic effect. IM denotes intramuscular, PO oral, and PR rectal.

["^a" deleted] ^b Based on single-dose studies in which an intramuscular dose of each drug listed was compared with morphine to establish the relative potency. Oral doses are those recommended when changing from parenteral to an oral route. Reference: Foley, K.M. (1985) The treatment of cancer pain. NEJM 313(2): 84-95.

^c Although controlled studies are not available, in clinical practice it is customary to consider the doses of opioid given IM, IV or subcutaneously to be equivalent. There may be some differences in pharmacokinetic parametes such as C_max and T_max.

["^b" deleted] ^d The conversion ratio of 10 mg parenteral morphine = 30 mg oral morphine is based on clinical experience in patients with chronic pain. The conversion ratio of 10 mg parenteral morphine = 60 mg oral morphine is based on a potency study in acute pain. Reference: Ashburn and Lipman (1993) Management of pain in the cancer patient. Anesth Analg 76:402-416.

["References" moved to within footnotes above]

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Table C: Table revised (new text in italics) -

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TABLE D 1 ["C" deleted] RECOMMENDED INITIAL DURAGESIC DOSE BASED UPON DAILY ORAL MORPHINE DOSE
Oral 24-hour Morphine (mg/day)	DURAGESIC Dose (ug/h)
45-134	25
135-224	50
225-314	75
315-404	100
405-494	125
495-584	150
585-674	175
675-764	200
765-854	225
855-944	250
945-1034	275
1035-1124	300

Note: In clinical trials these ranges of daily oral morphine doses were used as a basis for conversion to Duragesic.

["Although controlled studies are not available, in clinical practice it is customary to consider the doses of opioid given IM, IV or subcutaneously to be equivalent. There may be some differences in pharmacokinetic parameters such as C_max and T_max." deleted]

¹ This table should not be used to convert from Duragesic to other therapies, because this conversion to duragesic is conservative. Use of Table D for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible. (See DOSAGE AND ADMINISTRATION - Discontinuation of Duragesic)

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First sentence in last paragraph revised - "During the initial application of Duragesic, patients should use short-acting analgesics ["for the first 24 hours" deleted] as needed until analgesic efficacy with Duragesic is attained."

Dose Titration: First sentence revised (new text in italics) -

["The conversion ratio from oral morphine to Duragesic is conservative," deleted] The recommended initial Duragesic dose based upon the daily oral morphine dose is conservative, and 50% of patients are likely to require a dose increase after initial application of Duragesic."

Discontinuation of Duragesic: Text added at end of subsection -

"Table D should not be used to convert from Duragesic to other therapies, because the conversion to Duragesic is conservative. Use of Table D for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible."

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PRECAUTIONS:

General:Deletion of sentence in second paragraph - "There is no information from clinical trials about the safety of administering Famvir to patients with renal dysfunction."

Addition of sentence- "In patients with underlying renal disease who have received inappropriately high doses of Famvir for their level of renal function, acute renal failure has been reported."

Pregnancy: Pregnancy Exposure Registry (new subsection): "To monitor maternal-fetal outcomes of pregnant women exposed to Famvir, SmithKline Beecham maintains a Famvir Pregnancy Registry. Physicians are encouraged to register their patients by calling (800) 366-8900, ext. 5231."

ADVERSE REACTIONS:

Deletion of last paragraph in section which read - "During clinical practice, confusion (including delirium, disorientation, confusional state) has been reported very rarely. Most of these spontaneous reports have occurred in the elderly."

Addition of new last paragraph - "The following adverse events have been infrequently reported during post-marketing use of Famvir: rash, urticaria, hallucinations and confusion (including delirium, disorientation, confusional state, occurring predominantly in the elderly)."

OVERDOSAGE:

Deletion of the first sentence - "No acute overdosage has been reported."

Addition to the end of section - "(See PRECAUTIONS, General)."

DOSAGE AND ADMINISTRATION:

Genital Herpes: Addition to end of paragraph before Table 4 - "(See PRECAUTIONS, General)."

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PRECAUTIONS:

Carcinogenesis, Mutagenesis, and Impairment of Fertility: Subsection revised (new text in italics) -

"Long-term studies of cromolyn sodium in mice (12 months intraperitoneal ["treatment followed by 6 months observation" deleted] administration at doses up to 150 mg/kg/day three days per week), hamsters ["12 months" deleted] (intraperitoneal ["treatment followed by 12 months observation" deleted] administration at doses up to 53 mg/kg/day three days per week for 15 weeks followed by 17.5 mg/kg/day three days per week for 37 weeks), and rats (18 months subcutaneous treatment at doses up to 75 mg/kg/day six days per week) showed no neoplastic effects. ["of cromolyn sodium." deleted] These doses in mice, hamsters, and rats correspond to approximately 40, 10, and 80 times, respectively, the maximum recommended daily inhalation dose in adults on a mg/m² basis, or, approximately 20, 5, and 40 times, respectively, the maximum recommended daily inhalation dose in children on a mg/m² basis.

"Cromolyn sodium showed no mutagenic potential in Ames Salmonella/microsome plate assays, mitotic gene conversion in Saccharomyces cerevisiae and in an in vitro cytogenetic study in human peripheral lymphocytes.["No evidence of chromosomal damage or cytotoxicity was obtained in various mutagenesis studies." deleted]

"No evidence of impaired fertility was shown in laboratory reproduction studies conducted subcutaneously in rats at the highest doses tested, 175 mg/kg/day in males and 100 mg/kg/day in females. These doses are approximately 220 and 130 times, respectively, the maximum recommended daily inhalation dose in adults on a mg/m² basis."

Pregnancy: Pregnancy Category B: Subsection revised (new text in italics) -

"Reproduction studies with cromolyn sodium administered ["parenterally" deleted] subcutaneously to pregnant mice and rats at maximum daily doses of 540 mg/kg/day and 160 mg/kg/day, respectively, and intravenously to rabbits ["in doses up to 338 times the human clinical dose" deleted] at a maximum daily dose of 485 mg/kg/day produced no evidence of fetal malformations. These doses represent approximately 340, 210, and 1200 times, respectively, the maximum recommended daily inhalation dose in adults on a mg/m² basis. Adverse fetal effects (increased resorption and decreased fetal weight) were noted only at ["the" deleted] very high parenteral doses that produced maternal toxicity. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Intal Inhaler [ "this drug" deleted] should be used during pregnancy only if clearly needed."

Drug Interaction During Pregnancy: Subsection revised (new text in italics) -

" Cromolyn sodium and isoproterenol were studied following subcutaneous injections in pregnant mice. Cromolyn sodium alone in doses ["of 60 to 540 mg/kg (38 to 338 times the human dose)" deleted] up to 540 mg/kg/day (approximately 340 times the maximum recommended daily inhalation dose in adults on a mg/m² basis) did not cause significant increases in resorptions or major malformations. Isoproterenol alone at a dose of 2.7 mg/kg/day ["90 times the human dose" deleted] (approximately 7 times the maximum recommended daily inhalation dose in adults on a mg/m² basis) increased both resorptions and malformations . The addition of 540 mg/kg/day of cromolyn sodium ["(338 times the human dose) to isoproterenol (90 times the human dose)" deleted] (approximately 340 times the maximum recommended daily inhalation dose in adults on a mg/m² basis ) to 2.7 mg/kg/day of isoproterenol (approximately 7 times the maximum recommended daily inhalation dose in adults on a mg/m² basis) appears to have increased the incidence of both resorptions and malformations."

OVERDOSAGE:

Deletion of the sentence- "No action other than medical observation should be necessary."

Addition of paragraph- "There is no clinical syndrome associated with an overdosage of cromolyn sodium. In several animal species acute toxicity with cromolyn sodium occurs only with very high exposure levels. No deaths occurred at the highest oral doses tested in mice, 8000 mg/kg/day (approximately 5,100 and 2,700 times the maximum recommended daily inhalation doses in adults and children, respectively, on a mg/m² basis) or in rats, 8000 mg/kg (approximately 10,000 and 5,400 times the maximum recommended daily inhalation doses in adults and children , respectively, on a mg/m² basis)."

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DOSAGE AND ADMINISTRATION:

First paragraphs revised (new text in italics) - "Kadian capsules should be swallowed whole (not chewed, crushed, or dissolved).

"Alternatively, Kadian capsules may be opened and the entire contents sprinkled on a small amount of applesauce immediately prior to ingestion. ["The capsules should not be opened , chewed, crushed, dissolved, or mixed with food." deleted] The pellets in Kadian capsules should not be chewed, crushed, or dissolved due to the risk of overdose.

"Taking ["broken," deleted] chewed or crushed Kadian capsules or pellets will lead to the rapid release and absorption of a potentially toxic dose of morphine."

Alternative Method of Administration (new subsection): "In a study of healthy volunteers, KADIAN pellets sprinkled over applesauce were found to be bioequivalent to KADIAN capsules swallowed whole with applesauce under fasting conditions. Other foods have not been tested. Patients who have difficulty swallowing whole capsules or tablets may benefit from this alternative method of administration.

• Sprinkle the pellets onto a small amount of applesauce. Applesauce should be room temperature or cooler.

• Use immediately.

• Rinse mouth to ensure all pellets have been swallowed.

• Patients should consume entire portion and should not divide applesauce into separate doses."

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WARNINGS:

Paragraph added to the end of section - "Seizures and/or syncope have been reported rarely in cancer patients receiving leucovorin, usually in association with fluoropyrimidine administration, and most commonly in those with CNS metastases or other predisposing factors, however, a casual relationship has not been established.⁵" [Change appears in 1997 PDR.]

REFERENCES:

Addition of reference- "5. Meropol NJ, Creaven PJ, White RM, et al, 'Seizures Associated With Leucovorin Administration in Cancer Patients'. J NCI 1995:87(1):56-58. [Change appears in 1997 PDR.]"

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WARNINGS:

Allergic Reactions: Second paragraph deleted and replaced with -

"For patients with suspected sensitivity to calcitonin, skin testing should be considered prior to treatment utilizing a dilute, sterile solution of Miacalcin (calcitonin-salmon) Injection, Synthetic. Physicians may wish to refer patients who require skin testing to an allergist. A detailed skin testing protocol is available from the Medical Services Department of Sandoz Pharmaceuticals Corporation."

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PRECAUTIONS:

Post-Operative Use (new subsection): "Morphine and other opioids have been shown to reduce bowel motility. Ileus is a common postoperative complication, especially after intra-abdominal surgery with opioid analgesia. Caution should be taken to monitor for decreased bowel motility in postoperative patients receiving opioids. Standard supportive therapy should be implemented."

ADVERSE REACTIONS:

Digestive: - "Ileus" added

Skin: - "Urticaria" added

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ADVERSE REACTIONS:

New paragraph added to end of section - "In postmarketing reporting experience, there have been rare reports of larynx edema, fatigue, malaise, myalgia, arthritis, nausea, dyspepsia, paresthesia, hepatitis, alopecia, cholelithiasis, palpitation, and tachycardia."

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CLINICAL PHARMACOLOGY:

New paragraph added to the end of section - "In a clinical study involving adult subjects who received SR tablets, plasma concentrations of Ritalin's major metabolite appeared to be greater in females than in males. No gender differences were observed for Ritalin plasma concentration in the same subjects." [Change appears in 1997 PDR.]

ADVERSE REACTIONS: Last sentence in the first paragraph was revised (new text in italics) - "Although a definite causal relationship has not been established, the following have been reported in patients taking this drug: instances of abnormal liver function, ranging from transaminase elevation to hepatic coma; isolated cases of cerebral arteritis and/or occlusion; leukopenia and/or anemia; transient depressed mood; a few instances of scalp hair loss." [Change appears in 1997 PDR.]

OVERDOSAGE: Added as new second paragraph - "Consult with a Certified Poison Control Center regarding treatment for up-to-date guidance and advice." [Change appears in 1997 PDR.)

New sentence added to the end of what is now 3rd paragraph - "Other measures to detoxify the gut include administration of activated charcoal and a cathartic." (Change appears in 1997 PDR.)

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ADVERSE REACTIONS:

Special Senses - "Tinnitus" added

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WARNINGS:

Second paragraph revised (new text in italics)-

"Viracept should not be administered concurrently with terfenadine, astemizole, cisapride, triazolam, ["or" deleted] midazolam, ["because competition for CYP3A by nelfinavir could result in inhibition of" deleted] ergot derivatives, amiodarone or quinidine because Viracept may effect the hepatic metabolism of these drugs and create the potential for serious and/or life-threatening ["cardiac arrhythmias or prolonged sedation." deleted] adverse events. (see PRECAUTIONS, Drug Interactions)"

New paragraph added to end of section -

"New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hyperglycemic agents for treatment of these events. In some cases diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established."

PRECAUTIONS:

Drug Interactions: Anti-HIV protease inhibitors: IndinavirSubsection has been revised (new text in italics): - "Coadministration of indinavir with Viracept resulted in an 83% increase in nelfinavir plasma AUC and a 51% increase in indinavir plasma AUC. ["The safety of this combination has not been established." deleted] Currently, there are no safety and efficacy data available from the use of this combination."

Ritonavir: Subsection has been revised (new text in italics): "Coadministration of ritonavir with Viracept resulted in a 152% increase in nelfinavir plasma AUC and very little change in ritonavir plasma AUC. ["The safety of this combination has not been established." deleted] Currently, there are no safety and efficacy data available from the use of this combination."

Saquinavir: Subsection has been revised (new text in italics)- "Coadministration of saquinavir (using an experimental soft-gelatin capsule formulation of saquinavir 1200 mg) with Viracept resulted in an 18% increase in nelfinavir plasma AUC and a ["392%" deleted] 4-fold increase in saquinavir plasma AUC. If used in combination with saquinavir hard gelatin capsules at the recommended dose of 600 mg tid, no adjustments are needed. Currently, there are no safety and efficacy data available from the use of this combination."

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PRECAUTIONS:

Pediatric Use (new subsection): "Safety and effectiveness in pediatric patients below the age of 3 years have not been established."

DOSAGE AND ADMINISTRATION:

Addition of sentence to end of section - "In pediatric patients, 3 to 4 drops may be sufficient due to the smaller capacity of the ear canal."

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CONTRAINDICATIONS:

Section revised (new text in italics) -

"Wytensin is contraindicated in patients with a known sensitivity to the drug or any of the tablet ingredients."

PRECAUTIONS:

Carcinogenesis, Mutagenesis, Impairment of Fertility: First sentence deleted -

"No evidence of carcinogenic potential emerged in rats during a two-year oral study with Wytensin at doses up to 9.5 mg/kg/day, i.e., about 10 times the maximum recommended human dose."

New paragraph added at beginning of section -

"Two-year studies were conducted with oral Wytensin administered in the diet to mice and rats. No evidence of carcinogenic potential was seen in mice given doses of up to 11.5 mg/kg/day (41.4 mg/m²/day) or in rats given doses of up to 9.5 mg/kg/day (83.8 mg/m²/day). On a body-weight basis, these doses are 9X and 7X, respectively, the maximum recommended human daily dose (MRHDD) of 64 mg (based on a 50 kg individual). On a body-surface-area basis, these doses are 1X (mice) and 2X (rats) the MRHDD."

Nursing Mothers: Entire subsection deleted -

"Because no information is available on the excretion of Wytensin in human milk, it should not be administered to nursing mothers."

Replaced with the following text -

"It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Wytensin is administered to a nursing woman."

Pediatric Use: Subsection revised (new text in italics) -

"The safey and effectiveness of Wytensin in ["children less than 12 years of age" deleted] pediatric patients have not been established." ["demonstrated. Therefore its use in this age group cannot be recommended at this time." - deleted]

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