Prescription Drugs

CLINICAL PHARMACOLOGY Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis. The mechanism of action of this antimetabolite is not completely characterized and may be multi-faceted. Phase I studies in humans have demonstrated that fludarabine phosphate is rapidly converted to the active metabolite, 2-fluoro-ara-A, within minutes after intravenous infusion. Consequently, clinical pharmacology studies have focused on 2-fluoro-ara-A pharmacokinetics. After the five daily doses of 25 mg 2-fluoro-ara-AMP/m2 to cancer patients infused over 30 minutes, 2-fluoro-ara-A concentrations show a moderate accumulation. During a 5-day treatment schedule, 2-fluoro-ara-A plasma trough levels increased by a factor of about 2. The terminal half-life of 2-fluoro-ara-A was estimated as approximately 20 hours. In vitro, plasma protein binding of fludarabine ranged between 19% and 29%. A correlation was noted between the degree of absolute granulocyte count nadir and increased area under the concentration x time curve (AUC). Special Populations Pediatric Patients Limited pharmacokinetic data for FLUDARA FOR INJECTION are available from a published study of children (ages 1-21 years) with refractory acute leukemias or solid tumors (Children's Cancer Group Study 0971). When FLUDARA FOR INJECTION was administered as a loading dose over 10 minutes immediately followed by a 5-day continuous infusion, steady-state conditions were reached early. Patients with Renal Impairment The total body clearance of the principal metabolite 2-fluoro-ara-A correlated with the creatinine clearance, indicating the importance of the renal excretion pathway for the elimination of the drug. Renal clearance represents approximately 40% of the total body clearance. Patients with moderate renal impairment (17 - 41 mL/min/m2) receiving 20% reduced Fludara dose had a similar exposure (AUC; 21 versus 20 nM • h/mL) compared to patients with normal renal function receiving the recommended dose. The mean total body clearance was 172 mL/min for normal and 124 mL/min for patients with moderately impaired renal function. Clinical Studies Two single-arm open-label studies of FLUDARA FOR INJECTION have been conducted in adult patients with CLL refractory to at least one prior standard alkylating-agent containing regimen. In a study conducted by M.D. Anderson Cancer Center (MDAH), 48 patients were treated with a dose of 22-40 mg/m2 daily for 5 days every 28 days. Another study conducted by the Southwest Oncology Group (SWOG) involved 31 patients treated with a dose of 15-25 mg/m2 daily for 5 days every 28 days. The overall objective response rates were 48% and 32% in the MDAH and SWOG studies, respectively. The complete response rate in both studies was 13%; the partial response rate was 35% in the MDAH study and 19% in the SWOG study. These response rates were obtained using standardized response criteria developed by the National Cancer Institute CLL Working Group3 and were achieved in heavily pre-treated patients. The ability of FLUDARA FOR INJECTION to induce a significant rate of response in refractory patients suggests minimal cross-resistance with commonly used anti-CLL agents. The median time to response in the MDAH and SWOG studies was 7 weeks (range of 1 to 68 weeks) and 21 weeks (range of 1 to 53 weeks) respectively. The median duration of disease control was 91 weeks (MDAH) and 65 weeks (SWOG). The median survival of all refractory CLL patients treated with FLUDARA FOR INJECTION was 43 weeks and 52 weeks in the MDAH and SWOG studies, respectively. Rai stage improved to Stage II or better in 7 of 12 MDAH responders (58%) and in 5 of 7 SWOG responders (71%) who were Stage III or IV at baseline. In the combined studies, mean hemoglobin concentration improved from 9.0 g/dL at baseline to 11.8 g/dL at the time of response in a subgroup of anemic patients. Similarly, average platelet count improved from 63,500/mm3 to 103,300/mm3 at the time of response in a subgroup of patients who were thrombocytopenic at baseline. REFERENCES 1. Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. NIOSH Alert 2004-165. 3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006: 63 1172-1193.

Levbid® (hyoscyamine sulfate, 0.375 mg) Extended-Release Tablets DESCRIPTION Levbid® (hysocyamine sulfate extended release tablets) extended-release tablets contain 0.375 mg of hyoscyamine sulfate in a formulation designed for oral b.i.d. dosage. Hyoscyamine sulfate is one of the principal anticholinergic/antispasmodic components of belladonna alkaloids. The empirical formula is (C17H23NO3)2•H2SO4•2H2O and the molecular weight is 712.85. Chemically, it is benzeneacetic acid, a-(hydroxymethyl)-, 8-methyl-8-azabicyclo [3.2.1.] oct-3-yl ester, [3(S)-endo]-, sulfate (2:1), dihydrate with the following structure: Each Levbid® (hysocyamine sulfate extended release tablets) extended-release tablet also contains as inactive ingredients: calcium phosphate dibasic, ethylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and stearic acid.

INDICATIONS Levbid® (hysocyamine sulfate extended release tablets) is effective as adjunctive therapy in the treatment of peptic ulcer. It can also be used to control gastric secretion, visceral spasm and hypermotility in spastic colitis, spastic bladder, cystitis, pylorospasm, and associated abdominal cramps. May be used in functional intestinal disorders to reduce symptoms such as those seen in mild dysenteries, diverticulitis, and acute enterocolitis. For use as adjunctive therapy in the treatment of irritable bowel syndrome (irritable colon, spastic colon, mucous colitis) and functional gastrointestinal disorders. Also used as adjunctive therapy in the treatment of neurogenic bladder and neurogenic bowel disturbances (including the splenic flexure syndrome and neurogenic colon). Levbid® (hysocyamine sulfate extended release tablets) is indicated along with morphine or other narcotics in symptomatic relief of biliary and renal colic; as a “drying agent” in the relief of symptoms of acute rhinitis; in the therapy of parkinsonism to reduce rigidity and tremors and to control associated sialorrhea and hyperhidrosis. May be used in the therapy of poisoning by anticholinesterase agents. DOSAGE AND ADMINISTRATION Dosage may be adjusted according to the conditions and severity of symptoms. Adults and pediatric patients 12 years of age and older 1 to 2 tablets every 12 hours. Do not crush or chew tablets. Do not exceed 4 tablets in 24 hours. HOW SUPPLIED Levbid® (hysocyamine sulfate extended release tablets) (hyoscyamine sulfate 0.375 mg) extended-release tablets are white, capsule-shaped tablets. They are coded AP on one side and 115 on the other. Bottles of 100 NDC 68220-115-10 Store at controlled room temperature 20°- 25°C (68° - 77°F); excursions permitted to15°- 30°C (59°- 86°F). Please refer to current USP. Dispense in tight, light-resistant containers as defined in USP/NF with a child-resistant closure. KEEP OUT OF REACH OF CHILDREN Also available as: Levsin® Dosage Strength Package Size NDC Tablets 0.125mg 100 68220-112-10 Tablets 0.125mg 500 68220-112-50 Sub-lingual Tablets 0.125mg 100 68220-113-10 Sub-lingual Tablets 0.125mg 500 68220-113-50 Elixir 0.125mg/5 mL Pint 0091-4532-16 Drops 0.125mg/mL 15mL 0091-4538-15 Injection 0.5mg/mL Box of 5-1mL 0091-1536-05 Levsinex® timecaps™ 0.375mg 100 0091-3537-01 Levsinex® timecaps™ 0.375mg 500 0091-3537-05 Levbid® extended- 0.375mg 100 68220-115-10 release tablets 0.375mg 500 68220-115-50 Manufactured for: Alaven Pharmaceutical LLC, Marietta, GA 30067. Address medical inquiries to: Alaven Pharmaceutical LLC, 2260 Northwest Parkway, Suite A Marietta, GA 30067 Or call toll free 1-888-317-0001. Rev. 01/08.

PATIENT INFORMATION Like other anticholinergic agents, Levbid® (hysocyamine sulfate extended release tablets) may produce drowsiness, dizziness, or blurred vision. In this event, the patient should be warned not to engage in activities requiring mental alertness such as operating a motor vehicle or other machinery or to perform hazardous work while taking this drug. Use of Levbid® (hysocyamine sulfate extended release tablets) may decrease sweating resulting in heat prostration, fever or heat stroke; febrile patients or those who may be exposed to elevated environmental temperatures should use caution. Tablets may not completely disintegrate and may be excreted by some patients.

OVERDOSE The signs and symptoms of overdose are headache, nausea, vomiting, blurred vision, dilated pupils, hot dry skin, dizziness, dryness of the mouth, difficulty in swallowing, and CNS stimulation. Measures to be taken are immediate lavage of the stomach and injection of physostigmine 0.5 to 2 mg intravenously and repeated as necessary up to a total of 5 mg. Fever may be treated symptomatically (tepid water sponge baths, hypothermic blanket). Excitement to a degree which demands attention may be managed with sodium thiopental 2% solution given slowly intravenously or chloral hydrate (100-200 mL of a 2% solution) by rectal infusion. In the event of progression of the curare-like effect to paralysis of the respiratory muscles, artificial respiration should be instituted and maintained until effective respiratory action returns. In rats, the LD50 for hyoscyamine is 375 mg/kg. Levbid® (hysocyamine sulfate extended release tablets) is dialyzable. CONTRAINDICATIONS None reported in the prescribing information.

SIDE EFFECTS All of the following adverse reactions have been reported with hyoscyamine sulfate. Adverse reactions may include dryness of the mouth; urinary hesitancy and retention; blurred vision; tachycardia; palpitations; mydriasis; increased ocular tension; loss of taste; headache; nervousness; drowsiness; weakness; fatigue; dizziness; insomnia; nausea; vomiting; impotence; constipation; bloated feeling; abdominal pain; diarrhea; allergic reactions or drug idiosyncrasies; urticaria and other dermal manifestations; ataxia; speech disturbance; some degree of mental confusion and/or excitement (especially in elderly persons); short-term memory loss; hallucinations; and decreased sweating. DRUG INTERACTIONS Additive adverse effects resulting from cholinergic blockade may occur when Levbid® (hysocyamine sulfate extended release tablets) is administered concomitantly with other antimuscarinics, amantadine, haloperidol, phenothiazines, monoamine oxidase (MAO) inhibitors, tricyclic antidepressants or some antihistamines. Antacids may interfere with the absorption of Levbid® (hysocyamine sulfate extended release tablets) .

WARNINGS In the presence of high environmental temperature, heat prostration can occur with drug use (fever and heat stroke due to decreased sweating). Diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy. In this instance, treatment with this drug would be inappropriate and possibly harmful. Like other anticholinergic agents, Levbid® (hysocyamine sulfate extended release tablets) may produce drowsiness, dizziness or blurred vision. In this event, the patient should be warned not to engage in activities requiring mental alertness such as operating a motor vehicle or other machinery or to perform hazardous work while taking this drug. Psychosis has been reported in sensitive individuals given anticholinergic drugs including hyoscyamine sulfate. CNS signs and symptoms include confusion, disorientation, short term memory loss, hallucinations, dysarthria, ataxia, euphoria, anxiety, fatigue, insomnia, agitation and mannerisms, and inappropriate affect. These CNS signs and symptoms usually resolve within 12 to 48 hours after discontinuation of the drug. PRECAUTIONS General Use with caution in patients with: autonomic neuropathy, hyperthyroidism, coronary heart disease, congestive heart failure, cardiac arrhythmias, hypertension, and renal disease. Investigate any tachycardia before giving any anticholinergic drugs since they may increase the heart rate. Use with caution in patients with hiatal hernia associated with reflux esophagitis. Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies in animals have been performed to determine the carcinogenic, mutagenic or impairment of fertility potential of Levbid® (hysocyamine sulfate extended release tablets) ; however, 40 years of marketing experience with hyoscyamine sulfate shows no demonstrable evidence of a problem. Pregnancy–Pregnancy Category C Animal reproduction studies have not been conducted with Levbid® (hysocyamine sulfate extended release tablets) . It is also not known whether Levbid® (hysocyamine sulfate extended release tablets) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Levbid® (hysocyamine sulfate extended release tablets) should be given to a pregnant woman only if clearly needed. Nursing Mothers Levbid® (hysocyamine sulfate extended release tablets) is excreted in human milk. Caution should be exercised when Levbid® (hysocyamine sulfate extended release tablets) is administered to a nursing woman. Geriatric Use Reported clinical experience has not identified differences in safety between patients aged 65 and over and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.