Pharmacy & Therapeutics - November 2008 - (Page 664)

(conivaptan hydrochloride injection) BRIEF SUMMARY OF PRESCRIBING INFORMATION CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION. INDICATIONS AND USAGE VAPRISOL is indicated for the treatment of euvolemic and hypervolemic hyponatremia in hospitalized patients. Important Limitation: VAPRISOL is not indicated for the treatment of congestive heart failure. VAPRISOL should only be used for the treatment of hyponatremia in patients with underlying heart failure when the expected clinical benefit of raising serum sodium outweighs the increased risk of adverse events for heart failure patients. (See PRECAUTIONS and ADVERSE REACTIONS) CONTRAINDICATIONS VAPRISOL is contraindicated in patients with hypovolemic hyponatremia. The coadministration of VAPRISOL with potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, clarithromycin, ritonavir, and indinavir, is contraindicated. (See PRECAUTIONS: Drug Interactions for details and other important considerations) PRECAUTIONS Congestive Heart Failure: The number of heart failure patients with hypervolemic hyponatremia who have been treated with intravenous VAPRISOL is too small to establish safety in patients with underlying congestive heart failure. (See ADVERSE REACTIONS) Overly Rapid Correction of Serum Sodium: An overly rapid increase in serum sodium concentration (>12 mEq/L/24 hours) may result in serious sequelae. In controlled clinical trials of VAPRISOL, about 9% of patients who received VAPRISOL in doses of 20-40 mg/day IV met laboratory criteria for overly rapid correction of serum sodium, but none of these patients had permanent neurologic sequelae. Although not observed in the clinical studies with VAPRISOL, osmotic demyelination syndrome has been reported following rapid correction of low serum sodium concentrations. Serum sodium concentration and neurologic status should be monitored appropriately during VAPRISOL administration, and VAPRISOL administration should be discontinued if the patient develops an undesirably rapid rate of rise of serum sodium. If the serum sodium concentration continues to rise, VAPRISOL should not be resumed. If hyponatremia persists or recurs (after initial discontinuation of VAPRISOL for an undesirably rapid rate of rise of serum sodium concentration), and the patient has had no evidence of neurologic sequelae of rapid rise in serum sodium, VAPRISOL may be resumed at a reduced dose. Hepatic Impairment: The use of VAPRISOL in patients with hepatic impairment (including ascites, cirrhosis, or portal hypertension) has not been systematically evaluated. Increased systemic exposures after oral administration of conivaptan have been seen in patients with stable cirrhosis and moderate hepatic impairment. Intravenous VAPRISOL resulted in higher conivaptan exposure than did oral conivaptan, in study subjects without hepatic function impairment. Caution should be used when administering VAPRISOL to patients with hepatic impairment. Renal Impairment: The effect of renal impairment on the elimination of conivaptan after intravenous administration has not been evaluated. However, following oral administration of conivaptan, the AUC for conivaptan was up to 80% higher after a single oral dose and 35% higher with repeated oral dosing in patients with renal impairment (CLcr< 60 mL/min/1.73 m2) as compared to those with normal renal function. Intravenous VAPRISOL resulted in higher conivaptan exposure than did oral conivaptan, in study subjects without renal function impairment. Caution should be used when administering VAPRISOL to patients with renal impairment. Injection Site Reactions: Conivaptan may cause significant injection site reactions, even with proper dilution and infusion rates. (See ADVERSE REACTIONS) Conivaptan must only be administered when properly prepared and diluted (see Preparation) via large veins, and the infusion site should be rotated every 24 hours. (See DOSAGE AND ADMINISTRATION) Drug Interactions (See CLINICAL PHARMACOLOGY: Drug-Drug Interactions) CYP3A4: Conivaptan is a substrate of CYP3A4. Coadministration of VAPRISOL with CYP3A4 inhibitors could lead to an increase in conivaptan concentrations. The consequences of increased conivaptan concentrations are unknown. Concomitant use of VAPRISOL with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, clarithromycin, ritonavir, and indinavir is contraindicated. Conivaptan is a potent inhibitor of CYP3A4. VAPRISOL may increase plasma concentrations of coadministered drugs that are primarily metabolized by CYP3A4. In clinical trials of oral conivaptan hydrochloride, two cases of rhabdomyolysis occurred in patients who were also receiving a CYP3A4-metabolized HMG-CoA reductase inhibitor. Concomitant use of VAPRISOL with drugs that are primarily metabolized by CYP3A4 should be closely monitored or the combination should be avoided. If a clinical decision is made to discontinue concomitant medications at recommended doses, allow an appropriate amount of time following the end of VAPRISOL administration before resuming these medications. Digoxin: Coadministration of digoxin, a P-glycoprotein substrate, with oral conivaptan resulted in a reduction in clearance and increases in digoxin Cmax and AUC values. Therefore, if digoxin is administered with VAPRISOL, the clinician should be alert to the possibility of increases in digoxin levels. Carcinogenesis, Mutagenesis, Impairment of Fertility: Standard lifetime (104 week) carcinogenicity bioassays were conducted in mice and rats. Mice were given oral doses of 3, 10 or 30 mg/kg/day in males and 1, 3 or 10 mg/kg/day in females by gavage. Rats were given oral doses of 0.3, 1, 3 or 10 mg/kg/day in males and 1, 3, 10 or 30 mg/kg/day in females by gavage. No increased incidence of tumors was observed at doses up to 30 mg/kg/day in mice (6 times human systemic exposure of an IV bolus of 20 mg on Day 1 followed by IV infusion 40 mg/day for 3 days based on AUC comparison) or rats (2 times human systemic exposure of an IV bolus of 20 mg on Day 1 followed by IV infusion 40 mg/day for 3 days based on AUC comparison). Conivaptan was not mutagenic or clastogenic with or without metabolic activation in the Ames test with Salmonella typhimurium and Escherichia coli, in human peripheral blood lymphocytes, or in vivo rat micronucleus assay. VAPRISOL ® In fertility studies after 4 weeks treatment by intravenous bolus at 0.5, 1.25 or 2.5 mg/kg/day, male fertility was unaffected. However, in females given IV bolus conivaptan 15 days before mating through gestation day 7 there was prolonged diestrus, decreased fertility and increased pre- and post-implantation loss at 2.5 mg/kg/day (systemic exposures less than the therapeutic dose). Pregnancy: Pregnancy Category C Conivaptan has been shown to have adverse effects on the fetus when given to animals during pregnancy at systemic exposures less than those achieved at a therapeutic dose based on AUC comparisons. There are no adequate and well-controlled studies in pregnant women. VAPRISOL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The patient should be apprised of the potential hazard to the fetus. Conivaptan crosses the placenta and is found in fetal tissue in rats. Fetal tissue levels were Placebo Incidence Hyponatremia and Healthy Volunteer Studies Placebo 20 mg N=69 N=37 Term n (%) n (%) Blood and lymphatic system disorders Anemia NOS 2 (3%) 2 (5%) Cardiac disorders Atrial fibrillation 0 (0%) 2 (5%) Gastrointestinal disorders Constipation 2 (3%) 3 (8%) Diarrhea NOS 0 (0%) 0 (0%) Nausea 3 (4%) 1 (3%) Vomiting NOS 0 (0%) 2 (5%) General disorders and administration site conditions Edema peripheral 1 (1%) 1 (3%) Infusion site erythema 0 (0%) 0 (0%) Infusion site pain 1 (1%) 0 (0%) Infusion site phlebitis 1 (1%) 19 (51%) Infusion site reaction 0 (0%) 8 (22%) Pyrexia 0 (0%) 4 (11%) Thirst 1 (1%) 1 (3%) Infections and infestations Pneumonia NOS 0 (0%) 2 (5%) Urinary tract infection NOS 2 (3%) 2 (5%) Injury, poisoning and procedural complications Post procedural diarrhea 0 (0%) 2 (5%) Investigations Electrocardiogram ST segment depression 0 (0%) 2 (5%) Metabolism and nutrition disorders Hypokalemia 2 (3%) 8 (22%) Hypomagnesemia 0 (0%) 2 (5%) Hyponatremia 1 (1%) 3 (8%) Nervous system disorders Headache 2 (3%) 3 (8%) Psychiatric disorders Confusional state 2 (3%) 0 (0%) Insomnia 0 (0%) 2 (5%) Respiratory, thoracic and mediastinal disorders Pharyngolaryngeal pain 3 (4%) 2 (5%) Skin and subcutaneous tissue disorders Pruritus 0 (0%) 2 (5%) Vascular disorders Hypertension NOS 0 (0%) 3 (8%) Hypotension NOS 2 (3%) 3 (8%) Orthostatic hypotension 0 (0%) 5 (14%) 40 mg N=315 n (%) 18 (6%) 7 (2%) 20 (6%) 23 (7%) 17 (5%) 23 (7%) 24 (8%) 18 (6%) 16 (5%) 102 (32%) 61 (19%) 15 (5%) 19 (6%) 7 (2%) 14 (4%) 0 (0%) 0 (0%) 30 (10%) 6 (2%) 20 (6%) 32 (10%) 16 (5%) 12 (4%) 3 (1%) 2 (1%) 20 (6%) 16 (5%) 18 (6%) Adapted from MedDRA version 6.0 Although a dose of 80 mg/day of intravenous VAPRISOL was also studied, it was associated with a higher incidence of infusion site reactions and a higher rate of discontinuation due to adverse events than was the 40 mg/day intravenous VAPRISOL dose. The maximum daily dose of VAPRISOL (after the loading dose) is 40 mg/day. Congestive Heart Failure In clinical trials where intravenous VAPRISOL was administered to 79 hypervolemic hyponatremic patients with underlying heart failure and intravenous placebo administered to 10 patients, adverse cardiac failure events, atrial dysrhythmias, and sepsis occurred more frequently among patients treated with VAPRISOL (32%, 5% and 8% respectively) than among patients treated with placebo (20%, 0% and 0% respectively). The number of heart failure patients with hypervolemic hyponatremia who have been treated with intravenous VAPRISOL is too small to establish safety in this specific population. VAPRISOL should only be used in patients with underlying heart failure when the expected

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Pharmacy & Therapeutics - November 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Heparin-Induced Thrombocytopenia Medication Utilization Patterns and Hypertension-Related Expenditures among Patients Who Were Switched From Fixed-Dose to Free-Combination Antihypertensive Therapy European Society for Medical Oncology and Association for the Study of Bone and Mineral Research Pharmaceutical Approval Update

Pharmacy & Therapeutics - November 2008

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