VAPRISOL DEXTROSE IN PLASTIC CONTAINER

Cumberland Pharmaceuticals Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use VAPRISOL safely and effectively. See full prescribing information for VAPRISOL.VAPRISOL (conivaptan hydrochloride) Injection, for intravenous useInitial U.S. Approval: 2005 INDICATIONS AND USAGEVAPRISOL ® is a vasopressin receptor antagonist indicated to raise serum sodium in hospitalized patients with euvolemic and hypervolemic hyponatremia (1). Important Limitations: VAPRISOL has not been shown to be effective for the treatment of the signs and symptoms of heart failure (1). It has not been established that raising serum sodium with VAPRISOL provides a symptomatic benefit to patients (1). DOSAGE AND ADMINISTRATION Loading Dose: 20 mg IV administered over 30 minutes (2.1), followed by Continuous infusion: 20 mg per day over 24 hours, for 2 to 4 days (2.1). Following initial day of treatment, dosage may be increased to 40 mg/day continuous infusion as needed to raise serum sodium (2.1). Monitor volume status and serum sodium frequently and discontinue if patient develops hypovolemia, hypotension or an undesirably rapid rate of rise of serum sodium (2.1, 5.2). Hepatic impairment: Decrease the dose in patients with moderate hepatic impairment (8.6, 12.3). DOSAGE FORMS AND STRENGTHS Intravenous injection solution: conivaptan hydrochloride 20 mg/100 mL premixed in 5% Dextrose (2.2, 3). CONTRAINDICATIONS Hypovolemic hyponatremia (4.1). Coadministration with potent CYP3A inhibitors (4.2, 5.3, 7.1). Anuria: no benefit can be expected (4.3). Known allergy to corn or corn products (4.4). WARNINGS AND PRECAUTIONS Hypervolemic hyponatremia associated with heart failure: Data are limited. Consider other treatment options (5.1, 6.1). Overly rapid correction of serum sodium: Monitor serum sodium and neurologic status as serious neurologic sequelae can result from over rapid correction of serum sodium (2.1, 5.2). Infusion site reactions: Serious reactions have occurred. Administer through large veins and change infusion site every 24 hours (2.1, 5.5, 6). Side EffectsMost common adverse reactions (incidence ≥ 10%) are infusion site reactions (including phlebitis), pyrexia, hypokalemia, headache and orthostatic hypotension (6). To report SUSPECTED ADVERSE REACTIONS, contact Cumberland Pharmaceuticals Inc. at 1-887-484-2700 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Potent CYP3A inhibitors may increase the exposure of conivaptan and are contraindicated (4.2, 7.1). Generally avoid CYP3A substrates (5.3, 7.1). Exposure to coadministered digoxin may be increased and digoxin levels should be monitored (5.4, 7.2). USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm (8.1). Nursing Mothers: Discontinue drug or nursing taking into consideration importance of drug to mother (8.3). Pediatric Use: There are no studies (8.4). Severe renal impairment: VAPRISOL is not recommended (8.7, 12.3).

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 VAPRISOL DEXTROSE IN PLASTIC CONTAINER INDICATIONS AND USAGE
• 2 VAPRISOL DEXTROSE IN PLASTIC CONTAINER DOSAGE AND ADMINISTRATION
  • 2.1 General Dosing Information
  • 2.2 Preparation, Compatibility and Stability
  • 2.3 Hepatic Impairment
• 3 DOSAGE FORMS AND STRENGTHS
• 4 VAPRISOL DEXTROSE IN PLASTIC CONTAINER CONTRAINDICATIONS
  • 4.1 Hypovolemic Hyponatremia
  • 4.2 Coadministration with Potent CYP3A Inhibitors
  • 4.3 Anuric Patients
  • 4.4 Known Allergy to Corn or Corn Products
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Hyponatremia Associated with Heart Failure
  • 5.2 Overly Rapid Correction of Serum Sodium
  • 5.3 Coadministration of VAPRISOL and Drugs Eliminated Primarily by CYP3A Mediated Metabolism
  • 5.4 Coadministration of VAPRISOL and Digoxin
  • 5.5 Infusion Site Reactions
• 6 VAPRISOL DEXTROSE IN PLASTIC CONTAINER ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
• 7 DRUG INTERACTIONS
  • 7.1 CYP3A
  • 7.2 Digoxin
  • 7.3 Warfarin
  • 7.4 Captopril and Furosemide
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.2 Labor and Delivery
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Use in Patients with Hepatic Impairment
  • 8.7 Use in Patients with Renal Impairment
• 10 OVERDOSAGE
• 11 VAPRISOL DEXTROSE IN PLASTIC CONTAINER DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
  • 13.3 Developmental Toxicity
• 14 CLINICAL STUDIES
  • 14.1 Hyponatremia
  • 14.2 Heart Failure
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 Patient Counseling Information

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

VAPRISOL ^® is indicated to raise serum sodium in hospitalized patients with euvolemic and hypervolemic hyponatremia.

Important Limitations:

VAPRISOL has not been shown to be effective for the treatment of the signs and symptoms of heart failure and is not approved for this indication.

It has not been established that raising serum sodium with VAPRISOL provides a symptomatic benefit to patients.

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Information

VAPRISOL is for intravenous use only.

VAPRISOL is for use in hospitalized patients only.

Administer VAPRISOL through large veins and change of the infusion site every 24 hours to minimize the risk of vascular irritation [see Warnings and Precaution (5.5)].

Initiate with a loading dose of 20 mg IV administered over 30 minutes.

Follow the loading dose with 20 mg of VAPRISOL administered in a continuous intravenous infusion over 24 hours. After the initial day of treatment, administer VAPRISOL for an additional 1 to 3 days in a continuous infusion of 20 mg/day. If serum sodium is not rising at the desired rate, VAPRISOL may be titrated upward to a dose of 40 mg daily, administered in a continuous intravenous infusion.

The total duration of infusion of VAPRISOL (after the loading dose) should not exceed four days. The maximum daily dose of VAPRISOL (after the loading dose) is 40 mg/day.

Patients receiving VAPRISOL must have frequent monitoring of serum sodium and volume status. An overly rapid rise in serum sodium (> 12 mEq/L/24 hours) may result in serious neurologic sequelae. For patients who develop an undesirably rapid rate of rise of serum sodium, VAPRISOL should be discontinued, and serum sodium and neurologic status should be carefully monitored. If the serum sodium continues to rise, VAPRISOL should not be resumed. If hyponatremia persists or recurs, and the patient has had no evidence of neurologic sequelae of rapid rise in serum sodium, VAPRISOL may be resumed at a reduced dose [see Warnings and Precautions (5.2)]. For patients who develop hypovolemia or hypotension while receiving VAPRISOL, VAPRISOL should be discontinued, and volume status and vital signs should be frequently monitored. Once the patient is again euvolemic and is no longer hypotensive, VAPRISOL may be resumed at a reduced dose if the patient remains hyponatremic.

2.2 Preparation, Compatibility and Stability

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter, discoloration or cloudiness is observed, the drug solution should not be used.

VAPRISOL is supplied in a single-use 100 mL flexible INTRAVIA Container containing a sterile premixed dilute, ready-to-use, nonpyrogenic solution of conivaptan hydrochloride, 0.2 mg per mL (20 mg/100 mL) in 5% Dextrose. NO FURTHER DILUTION OF THIS PREPARATION IS NECESSARY.

VAPRISOL is compatible with 5% Dextrose Injection. VAPRISOL is physically and chemically compatible with 0.9% Sodium Chloride Injection for up to 48 hours when the two solutions are co-administered via a Y-site connection at a flow rate for VAPRISOL of 4.2 mL/hour and at flow rates for 0.9% Sodium Chloride Injection of either 2.1 mL/hour or 6.3 mL/hour.

VAPRISOL has been shown to be incompatible with both Lactated Ringer's Injection and furosemide injection when these products are mixed in the same container; therefore, do not combine VAPRISOL with these products in the same intravenous line or container.

VAPRISOL should also not be combined with any other product in the same intravenous line or container.

Loading Dose

Administer the content of a 20 mg/100 mL VAPRISOL flexible plastic container over 30 minutes.

Continuous Infusion

For patients requiring 20 mg VAPRISOL injection per day, administer the content of one 20 mg/100 mL VAPRISOL flexible plastic container over 24 hours.

For patients requiring 40 mg VAPRISOL injection per day, administer the content of two consecutive 20 mg/100 mL VAPRISOL flexible plastic containers over 24 hours.

Since the flexible container is for single-use only, any unused portion should be discarded.

CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed.

Do not remove container from overwrap until ready for use. The overwrap is a moisture and light barrier. The inner container maintains the sterility of the product.

Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. After removing overwrap, check for minute leaks by squeezing inner container firmly. If leaks are found, discard solution as sterility may be impaired. Do not use if the solution is cloudy or a precipitate is present.

DO NOT ADD SUPPLEMENTARY MEDICATION.

Preparation for Administration:

• Suspend container from eyelet support.
• Remove protector from outlet port at bottom of container.
• Attach administration set. Refer to complete directions accompanying set.

2.3 Hepatic Impairment

In patients with moderate hepatic impairment, initiate VAPRISOL with a loading dose of 10 mg over 30 minutes followed by 10 mg per day as a continuous infusion for 2 to 4 days. If serum sodium is not rising at the desired rate, VAPRISOL may be titrated upward to 20 mg per day [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

Intravenous injection solution: conivaptan hydrochloride 20 mg/100 mL premixed in 5% Dextrose [see Dosage and Administration (2.2)].

4 CONTRAINDICATIONS

4.1 Hypovolemic Hyponatremia

VAPRISOL is contraindicated in patients with hypovolemic hyponatremia.

4.2 Coadministration with Potent CYP3A Inhibitors

The coadministration of VAPRISOL with potent CYP3A inhibitors, such as ketoconazole, itraconazole, clarithromycin, ritonavir, and indinavir, is contraindicated [see Drug Interactions (7.1)].

4.3 Anuric Patients

In patients unable to make urine, no benefit can be expected [see Clinical Pharmacology (12.3)].

4.4 Known Allergy to Corn or Corn Products

Solutions containing dextrose are contraindicated in patients with known allergy to corn or corn products.

5 WARNINGS AND PRECAUTIONS

5.1 Hyponatremia Associated with Heart Failure

The amount of safety data on the use of VAPRISOL in patients with hypervolemic hyponatremia associated with heart failure is limited. VAPRISOL should be used to raise serum sodium in such patients only after consideration of other treatment options [see Adverse Reactions (6.1)].

5.2 Overly Rapid Correction of Serum Sodium

Osmotic demyelination syndrome is a risk associated with overly rapid correction of hyponatremia (i.e., > 12 mEq/L/24 hours). Osmotic demyelination results in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma or death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, use slower rates of correction. In controlled clinical trials of VAPRISOL, about 9% of patients who received VAPRISOL in doses of 20-40 mg/day IV had rises of serum sodium >12 mEq/L/24 hours, but none of these patients had evidence of osmotic demyelination or permanent neurologic sequelae. 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 [see Dosage and Administration (2.1)].

5.3 Coadministration of VAPRISOL and Drugs Eliminated Primarily by CYP3A Mediated Metabolism

In clinical trials of oral conivaptan, two cases of rhabdomyolysis occurred in patients who were also receiving a CYP3A-metabolized HMG-CoA reductase inhibitor. Avoid concomitant use of VAPRISOL with drugs eliminated primarily by CYP3A-mediated metabolism. Subsequent treatment with CYP3A substrate drugs may be initiated no sooner than 1 week after the infusion of VAPRISOL is completed [see Drug Interactions (7.1)].

5.4 Coadministration of VAPRISOL and Digoxin

Coadministration of digoxin with oral conivaptan resulted in a 1.8- and 1.4-fold increase in digoxin C_max and AUC, respectively. Monitor digoxin levels [see Drug Interactions (7.2)].

5.5 Infusion Site Reactions

Infusion site reactions are common and can include serious reactions, even with proper infusion rates [see Adverse Reactions (6.1)]. Administer VAPRISOL via large veins, and rotate the infusion site every 24 hours [see Dosage and Administration (2.1)].

6 ADVERSE REACTIONS

The following adverse reactions are discussed elsewhere in labeling:

• Osmotic demyelination syndrome [see Warnings and Precautions (5.2)]
• Infusion site reactions [see Warnings and Precautions (5.5)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse event information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

The most common adverse reactions reported with VAPRISOL administration were infusion site reactions. In studies in patients and healthy volunteers, infusion site reactions occurred in 73% and 63% of subjects treated with VAPRISOL 20 mg/day and 40 mg/day, respectively, compared to 4% in the placebo group. Infusion site reactions were the most common type of adverse event leading to discontinuation of VAPRISOL. Discontinuations from treatment due to infusion site reactions were more common among VAPRISOL-treated patients (3%) than among placebo-treated patients (0%). Some serious infusion site reactions did occur [see Dosage and Administration (2.1) and Warnings and Precautions (5.5)].

The adverse reactions presented in Table 1 are derived from 72 healthy volunteers and 243 patients with euvolemic or hypervolemic hyponatremia who received VAPRISOL 20 mg IV as a loading dose followed by 40 mg/day IV for 2 to 4 days, from 37 patients with euvolemic or hypervolemic hyponatremia who received VAPRISOL 20 mg IV as a loading dose followed by 20 mg/day IV for 2 to 4 days in an open-label study, and from 40 healthy volunteers and 29 patients with euvolemic or hypervolemic hyponatremia who received placebo. The adverse reactions occurred in at least 5% of patients treated with VAPRISOL and at a higher incidence for VAPRISOL-treated patients than for placebo-treated patients.

Although a dose of 80 mg/day of VAPRISOL was also studied, it was associated with a higher incidence of infusion site reactions and a higher rate of discontinuation for adverse events than was the 40 mg/day VAPRISOL dose. The maximum recommended daily dose of VAPRISOL (after the loading dose) is 40 mg/day.

Heart failure with hypervolemic hyponatremia

In clinical trials where 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) [see Warnings and Precautions (5.1)].

7 DRUG INTERACTIONS

7.1 CYP3A

Conivaptan is a sensitive substrate of CYP3A. The effect of ketoconazole, a potent CYP3A inhibitor, on the pharmacokinetics of intravenous conivaptan has not been evaluated. Coadministration of oral conivaptan hydrochloride 10 mg with ketoconazole 200 mg resulted in 4- and 11-fold increases in C_max and AUC of conivaptan, respectively [see Contraindications (4.2)].

Conivaptan is a potent mechanism-based inhibitor of CYP3A. The effect of conivaptan on the pharmacokinetics of co-administered CYP3A substrates has been evaluated with the coadministration of conivaptan with midazolam, simvastatin, and amlodipine. VAPRISOL 40 mg/day increased the mean AUC values by approximately 2- and 3-fold for 1 mg intravenous or 2 mg oral doses of midazolam, respectively. VAPRISOL 30 mg/day resulted in a 3-fold increase in the AUC of simvastatin. Oral conivaptan hydrochloride 40 mg twice daily resulted in a 2-fold increase in the AUC and half-life of amlodipine [see Warnings and Precautions (5.3)].

7.2 Digoxin

Coadministration of a 0.5 mg dose of digoxin, a P-glycoprotein substrate, with oral conivaptan hydrochloride 40 mg twice daily resulted in a 30% reduction in clearance and 79% and 43% increases in digoxin C_max and AUC values, respectively [see Warnings and Precautions (5.4)].

7.3 Warfarin

VAPRISOL (40 mg/day for 4 days) administered with a single 25 mg dose of warfarin, which undergoes major metabolism by CYP2C9 and minor metabolism by CYP3A, increased the mean S-warfarin AUC and S-warfarin C_max by 14% and 17%, respectively. The corresponding prothrombin time and international normalized ratio values were unchanged.

7.4 Captopril and Furosemide

The pharmacokinetics of oral conivaptan (20 - 40 mg/day) were unchanged with coadministration of either captopril 25 mg or furosemide up to 80 mg/day.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C. Conivaptan has been shown to have adverse effects on the fetus when given to rats during pregnancy at systemic exposures less than those achieved at the human therapeutic dose based on AUC comparisons [see Nonclinical Toxicology (13.3)]. There are no adequate and well-controlled studies of VAPRISOL use 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. Rat fetal tissue levels were < 10% of maternal plasma concentrations while placental levels were 2.2-fold higher than maternal plasma concentrations. Conivaptan that is taken up by fetal tissue is slowly cleared, suggesting that fetal accumulation is possible.

8.2 Labor and Delivery

The effect of VAPRISOL on labor and delivery in humans has not been studied. Conivaptan hydrochloride delayed delivery in rats dosed at 10 mg/kg/day by oral gavage (systemic exposure equivalent to the human therapeutic exposure based on AUC comparison). Administration of conivaptan hydrochloride at 2.5 mg/kg/day intravenously increased peripartum pup mortality (systemic exposure less than the human therapeutic exposure based on AUC comparison). These effects may be associated with conivaptan activity on oxytocin receptors in the rat. The relevance to humans is unclear [see Nonclinical Toxicology (13.3)].

8.3 Nursing Mothers

It is not known whether conivaptan is excreted in human milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from VAPRISOL, a decision should be made to discontinue nursing or VAPRISOL, taking into consideration the importance of VAPRISOL to the mother. Conivaptan is excreted in milk and detected in neonates when given by intravenous administration to lactating rats. Milk levels of conivaptan in rats reached maximal levels at 1 hour post dose following intravenous administration and were up to 3 times greater than maternal plasma levels following an intravenous dose of 1 mg/kg (systemic exposure less than human therapeutic exposure based on AUC comparison).

8.4 Pediatric Use

The safety and effectiveness of VAPRISOL in pediatric patients have not been studied.

8.5 Geriatric Use

In clinical studies of VAPRISOL administered as a 20 mg IV loading dose followed by 20 mg/day or 40 mg/day IV for 2 to 4 days, 89% (20 mg/day regimen) and 60% (40 mg/day regimen) of participants were greater than or equal to 65 years of age and 60% (20 mg/day regimen) and 40% (40 mg/day regimen) were greater than or equal to 75 years of age. In general, the adverse event profile in elderly patients was similar to that seen in the general study population.

8.6 Use in Patients with Hepatic Impairment

No clinically relevant increase in exposure was observed in subjects with mild hepatic impairment; therefore no dose adjustment of VAPRISOL is necessary. The exposure to VAPRISOL approximately doubles with moderate hepatic impairment. The impact of severe hepatic impairment on the exposure to conivaptan has not been studied [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

8.7 Use in Patients with Renal Impairment

No clinically relevant increase in exposure was observed in subjects with mild and moderate renal impairment (CL_cr 30 – 80 mL/min). No dose adjustment of VAPRISOL is necessary.

Because of the high incidence of infusion site phlebitis (which can reduce vascular access sites) and unlikely benefit, use in patients with severe renal impairment (CL_cr<30 mL/min) is not recommended [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Although no data on overdosage in humans are available, VAPRISOL has been administered as a 20 mg loading dose on Day 1 followed by continuous infusion of 80 mg/day for 4 days in hyponatremia patients and up to 120 mg/day for 2 days in CHF patients. No new toxicities were identified at these higher doses, but adverse events related to the pharmacologic activity of VAPRISOL, e.g. hypotension and thirst, occurred more frequently at these higher doses.

In case of overdose, based on expected exaggerated pharmacological activity, symptomatic treatment with frequent monitoring of vital signs and close observation of the patient is recommended.

11 DESCRIPTION

Conivaptan hydrochloride is chemically [1,1'-biphenyl]-2-carboxamide, N-[4-[(4,5-dihydro-2-methylimidazo[4,5-d][1]benzazepin-6(1H)-yl)carbonyl]phenyl]-, monohydrochloride, having a molecular weight of 535.04 and molecular formula C₃₂H₂₆N₄O₂∙HCl. The structural formula of conivaptan hydrochloride is: