HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These 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 use
`
`
` Initial U.S. Approval: 2005
`
`
`
` ----------------------------RECENT MAJOR CHANGES--------------------------
`
`10/2016
`
`
` Dosage and Administration, Hepatic Impairment (2.3)
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`
`
` VAPRISOL® is a vasopressin receptor antagonist indicated to raise serum
`
`
`
`
`sodium in hospitalized patients with euvolemic and hypervolemic
`
`
`
`
`
`hyponatremia (1).
`
`
`Limitations of Use:
`
`
`
`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/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 undesirable rapid rate of
`
`
`increase in serum sodium (2.1, 5.2).
`
`
`Hepatic impairment: Decrease the dose in patients with moderate or
`
`
`
`
`severe 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).
`
`•
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 General Dosing Information
`
`2.2 Preparation, Compatibility and Stability
`
`
`2.3 Hepatic Impairment
`
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`
`4.1 Hypovolemic Hyponatremia
`
`
`4.2 Coadministration with Potent CYP3A Inhibitors
`
`
`
`4.3 Anuric Patients
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Hyponatremia Associated with Heart Failure
`
`
`5.2 Overly Rapid Correction of Serum Sodium
`
`
`5.3 Hypovolemia or Hypotension
`
`
`5.4 Infusion Site Reactions
`
`
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`
`7 DRUG INTERACTIONS
`7.1 CYP3A Inhibitors and Substrates
`
`
`7.2 Digoxin
`8 USE IN SPECIFIC POPULATIONS
`
`Coadministration with potent CYP3A inhibitors (4.2, 5.3, 7.1).
`
`
`Anuria: no benefit can be expected (4.3).
`
`
`
`
`•
`
`
`
`-----------------------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, 5.4, 6).
`
`
`•
`
`•
`
`------------------------------ADVERSE REACTIONS------------------------------­
`Most 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 (7.2).
`
`
`•
`•
`
`
`
`------------------------USE IN SPECIFIC POPULATIONS----------------------­
`Lactation: Breastfeeding not recommended (8.2).
`
`
`
`•
`Pediatric Use: There are no studies (8.4).
`
`
`•
`Severe renal impairment: VAPRISOL is not recommended (8.7, 12.3).
`
`
`
`
`•
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`
`
`Revised: 10/2016
`
`
`
`
`8.1 Pregnancy
`
`8.2 Lactation
`
`
`8.3 Females and Males of Reproductive Potential
`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 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
`
`14 CLINICAL STUDIES
`
`14.1 Hyponatremia
`
`14.2 Heart Failure
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information
`
`are not listed.
`
`
`Reference ID: 3998770
`
`
`
` 1
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2028, Page 1
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`1 INDICATIONS AND USAGE
`VAPRISOL® is indicated to raise serum sodium in hospitalized patients with euvolemic and hypervolemic
`
`
`
`
`hyponatremia.
`
`
`Limitations of Use:
`
`
`
`
`
`
`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 (5.4)].
`
`
`
`
`
`
`
`
`Initiate with a loading dose of 20 mg VAPRISOL administered intravenously over 30 minutes.
`
`
`
`Follow the loading dose with 20 mg 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 maximum dose of 40 mg daily, administered in a continuous intravenous infusion over
`
`24 hours.
`
`
`The total duration of infusion of VAPRISOL (after the loading dose) should not exceed four days.
`Patients receiving VAPRISOL must have frequent monitoring of serum sodium and volume status [see
`
`
`
`
`
`Warnings and Precautions (5.2, 5.3)].
`
`
`
`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 ready-to-use; 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 is 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.
`
`
`
`
`Do not combine VAPRISOL with any other product in the same intravenous line or container.
`
`
`
`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
`
`
`
`
`Reference ID: 3998770
`
`
`
` 2
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2028, Page 2
`
`

`

`
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`
`
` 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.
`
`Preparation for Administration:
`
`1. Suspend container from eyelet support.
`
`
`2. Remove protector from outlet port at bottom of container.
`
`
`
`3. Attach administration set. Refer to complete directions accompanying set.
`
`
`
`
`
`2.3 Hepatic Impairment
`
`In patients with moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) 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 in
`
`
`
`flexible plastic containers.
`
`
`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)].
`
`
`
`
`
`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)].
`
`
`
`
`
`
`
`
`
`Reference ID: 3998770
`
`
`
` 3
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2028, Page 3
`
`

`

`
`
`
`
`
`
`
`
` 5.3 Hypovolemia or Hypotension
`
` 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.
`
` 5.4 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 (5.4)]
`
`
`
`
`•
`
`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 (5.4)].
`
`
`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.
`
`
`
`Table 1. VAPRISOL Injection: Adverse Reactions Occurring in ≥ 5% of Patients or
`
`
`
`Healthy Volunteers and VAPRISOL Incidence > Placebo Incidence
`
`
`
`
`
`
` Placebo (N=69)
` 20 mg (N=37)
`
`
`
` Term
`N (%)
`
`N (%)
`
`
`
`
` 40 mg (N=315)
`N (%)
`
`
`
`
`
`
`
`
`
` 2 (3%)
`
`
`
`
`
` 2 (5%)
`
`
`
`
`
` 18 (6%)
`
`
`
`
`
` 0 (0%)
`
`
`
`
`
` 2 (5%)
`
`
`
`
`
` 7 (2%)
`
`
`
`
`
`
`
` 2 (3%)
`
` 0 (0%)
`
` 3 (4%)
`
` 0 (0%)
`
`
`
`
`
`
`
` 3 (8%)
`
` 0 (0%)
`
` 1 (3%)
`
` 2 (5%)
`
`
`
`
`
`
`
` 20 (6%)
`
` 23 (7%)
`
` 17 (5%)
`
` 23 (7%)
`
`
`
`
`
` 1 (1%)
`
`
`
`
`
` 1 (3%)
`
`
`
`
`
` 24 (8%)
`
`
`
` 4
`
`
`
` Blood and lymphatic system disorders
`
`
` Anemia NOS
` Cardiac disorders
`
`
` Atrial fibrillation
`
`
` Gastrointestinal disorders
`
`
` Constipation
`
`
` Diarrhea NOS
`
`
`Nausea
`
`
` Vomiting NOS
` General disorders and administration site conditions
`
`
` Edema peripheral
`
`
`
`
`
`Reference ID: 3998770
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2028, Page 4
`
`

`

`
`
` Term
`
`
`
`
`
` Placebo (N=69)
`N (%)
`
`
` 0 (0%)
`
`
` 1 (1%)
`
` 1 (1%)
`
` 0 (0%)
`
` 0 (0%)
`
` 1 (1%)
`
`
`
`
`
`
`
`
`
` 20 mg (N=37)
`N (%)
`
`
` 0 (0%)
`
`
` 0 (0%)
`
`
`
` 19 (51%)
`
`
` 8 (22%)
`
`
` 4 (11%)
`
`
` 1 (3%)
`
`
`
`
` 40 mg (N=315)
`N (%)
`
`
` 18 (6%)
`
`
`
` 16 (5%)
`
` 102 (32%)
`
`
` 61 (19%)
`
`
`
` 15 (5%)
`
`
` 19 (6%)
`
`
`
`
`
` 0 (0%)
`
` 2 (3%)
`
`
`
`
`
` 2 (5%)
`
` 2 (5%)
`
`
`
` 7 (2%)
`
` 14 (4%)
`
`
`
`
`
`
` 0 (0%)
`
`
`
`
`
` 2 (5%)
`
`
`
`
`
` 0 (0%)
`
`
` Infusion site erythema
`
`
`Infusion site pain
`
`
` Infusion site phlebitis
`
`
` Infusion site reaction
`
`
`Pyrexia
`
`
`
`Thirst
`
` Infections and infestations
`
` Pneumonia NOS
`
`
`
` Urinary tract infection NOS
` Injury, poisoning and procedural complications
` Post procedural diarrhea
`
`
`
` Investigations
` Electrocardiogram ST segment depression
`
`
`
` Metabolism and nutrition disorders
`
`
` Hypokalemia
`
` Hypomagnesemia
`
`
` Hyponatremia
`Nervous system disorders
`
`
`Headache
`
` Psychiatric disorders
`
` Confusional state
`
`
`
`
` Insomnia
` Respiratory, thoracic and mediastinal disorders
`
`
`
`Pharyngolaryngeal pain
` Skin and subcutaneous tissue disorders
`
`
`
` Pruritus
` Vascular disorders
`
`
`
` Hypertension NOS
`
`
` Hypotension NOS
`
`
` Orthostatic hypotension
` Adapted from MedDRA version 6.0
`
`
`
` 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 Inhibitors and Substrates
`
`
`Conivaptan is a sensitive substrate of CYP3A. Coadministration with strong CYP3A inhibitors (e.g.
`
`
`
`ketoconazole, itraconazole, clarithromycin, ritonavir and indinavir) increases conivaptan exposure and is
`
`contraindicated [see Contraindications (4.2) and Clinical Pharmacology (12.3)].
`
`
`Coadministration with CYP3A substrates results in increased exposure of the other drug. Avoid
`
`
`
`
`concomitant use with drugs eliminated primarily by CYP3A-mediated metabolism. Subsequent treatment
`
`
`
`
`
`
`
`
`
`
`
` 0 (0%)
`
`
`
`
`
` 2 (5%)
`
`
`
`
`
` 0 (0%)
`
`
`
`
`
`
`
`
`
`
` 2 (3%)
`
` 0 (0%)
`
` 1 (1%)
`
`
`
`
`
`
` 8 (22%)
`
` 2 (5%)
`
` 3 (8%)
`
`
`
` 30 (10%)
`
`
` 6 (2%)
`
` 20 (6%)
`
`
`
`
`
`
` 2 (3%)
`
`
`
`
`
` 3 (8%)
`
`
`
`
`
` 32 (10%)
`
`
`
`
`
`
`
` 2 (3%)
`
` 0 (0%)
`
`
`
`
`
` 0 (0%)
`
` 2 (5%)
`
`
`
`
`
` 16 (5%)
`
` 12 (4%)
`
`
`
`
`
` 3 (4%)
`
`
`
`
`
` 2 (5%)
`
`
`
`
`
` 3 (1%)
`
`
`
`
`
` 0 (0%)
`
`
`
`
`
`
` 0 (0%)
`
` 2 (3%)
`
` 0 (0%)
`
`
`
`
`
` 2 (5%)
`
`
`
`
`
` 2 (1%)
`
`
`
`
`
`
` 3 (8%)
`
` 3 (8%)
` 5 (14%)
`
`
`
`
`
`
`
` 20 (6%)
`
` 16 (5%)
`
` 18 (6%)
`
`
`
`
`
`Reference ID: 3998770
`
`
`
` 5
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2028, Page 5
`
`

`

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`
`
`
`
`
`
`
`
`
` with CYP3A substrates may be initiated no sooner than 1 week after the infusion of VAPRISOL is
`
`
`
` completed [see Clinical Pharmacology (12.3)].
`
` 7.2 Digoxin
`
` Coadministration of digoxin with oral conivaptan resulted in a 1.8- and 1.4-fold increase in digoxin Cmax
`
`and AUC, respectively. Monitor digoxin levels.
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`Risk Summary
`There are no available data with VAPRISOL in pregnant women to inform a drug-associated risk for major
`
`
`
`
`
`birth defects and miscarriage.
`
`
`
`The estimated background risk of major birth defects and miscarriage for the indicated population is
`
`
`
`unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the
`
`
`
`
`U.S. general population, the estimated background risk of major malformations and miscarriage in
`
`
`
`
`clinically recognized pregnancies is 2-4%, and 15-20%, respectively.
`
`
`
`Data
`
`Animal Data
`
`When pregnant rats were given intravenous conivaptan hydrochloride up to 2.5 mg/kg/day on gestation
`
`days 7 through 17 (systemic exposures less than human therapeutic exposure based on AUC comparisons),
`
`
`no significant fetal or maternal effects were noted. However, when the same doses were administered to
`
`
`
`
`
`
`pregnant rats from gestation day 7 through lactation day 20 (weaning), the pups showed decreased neonatal
`
`
`
`viability and weaning indices, decreased body weight, and delayed reflex and physical development
`
`
`
`
`(including sexual maturation). These effects occurred only at the highest dose administered (2.5
`
`
`mg/kg/day). No maternal adverse effects of conivaptan were seen in this study. When pregnant rabbits were
`
`
`
`administered intravenous doses of conivaptan hydrochloride up to 12 mg/kg/day on gestation days 6
`
`through 18 (at about twice the human therapeutic exposure), there were no fetal or maternal findings.
`
`
`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.
`
`
`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).
`
`
`8.2 Lactation
`
`
`Risk Summary
`
`There is no information regarding conivaptan or its metabolites in human milk, the effects of conivaptan on
`
`
`
`
`the breastfed infant, or the effects of conivaptan on milk production. Conivaptan is present in rat milk;
`
`
`however, due to species-specific differences in lactation physiology, the clinical relevance of these data are
`
`
`not clear [see Data]. Because of the potential for serious adverse reactions, including electrolyte
`
`
`
`abnormalities (e.g., hypernatremia), hypotension, and volume depletion in breastfed infants, advise a
`
`
`
`
`
`woman not to breastfeed during treatment with VAPRISOL.
`
`
`
`
`Data
`
`Milk levels of conivaptan in rats reached maximal levels at 1 hour following intravenous administration
`
`
`
`and were up to 3 times maternal plasma levels following an intravenous dose of 1 mg/kg (systemic
`
`
`
`
`exposure less than human therapeutic exposure based on AUC comparison).
`
`
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`Reference ID: 3998770
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`
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` 8.3 Females and Males of Reproductive Potential
`
` Infertility
`Females
`
`Based on findings of decreased fertility in female rats, conivaptan may impair fertility in females of
`
`
`
`
`reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical
`
`
`Toxicology (13.1)].
`
`
`
`8.4 Pediatric Use
`
`Safety and effectiveness in pediatric patients have not been established.
`
`
`
`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 systemic exposure to unbound conivaptan
`
`
`
`
`
`doubled in subjects with moderate and severe hepatic impairment [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 (CLcr 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 (CLcr<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:
`
`
`
`Reference ID: 3998770
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`
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`PGR2019-00048
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`
`Conivaptan hydrochloride is a white to off-white or pale orange-white powder that is very slightly soluble
`
`
`
`
`
`in water (0.15 mg/mL at 23° C). Conivaptan hydrochloride injection is supplied as a sterile premixed
`
`
`
`
`
`solution with dextrose in a flexible plastic container.
`
`
`
`Each container contains a clear, colorless, sterile, non-pyrogenic solution of conivaptan hydrochloride in
`
`dextrose injection for intravenous use. Each 100 mL, single-use premixed INTRAVIA Container contains
`
`
`
`20 mg of conivaptan hydrochloride and 5 g of Dextrose Hydrous, USP. Lactic Acid, USP is added for pH
`
`
`
`adjustment to pH 3.4 to 3.8. The flexible plastic container is fabricated from a specially designed multilayer
`
`
`
`
`plastic (PL 2408). Solutions in contact with the plastic container leach out certain of the chemical
`
`
`components from the plastic in very small amounts; however, biological testing was supportive of the
`
`
`
`
`
`safety of the plastic container materials. The flexible container has a foil overwrap. Water can permeate the
`
`plastic into the overwrap, but the amount is insufficient to affect the premixed solution significantly.
`
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`Conivaptan hydrochloride is a dual arginine vasopressin (AVP) antagonist with nanomolar affinity for
`
`
`
`
`
`
`
`
`
`human V1A and V2 receptors in vitro. The level of AVP in circulating blood is critical for the regulation of
`
`
`water and electrolyte balance and is usually elevated in both euvolemic and hypervolemic hyponatremia.
`
`
`The AVP effect is mediated through V2 receptors, which are functionally coupled to aquaporin channels in
`
`
`
`the apical membrane of the collecting ducts of the kidney. These receptors help to maintain plasma
`
`osmolality within the normal range. The predominant pharmacodynamic effect of conivaptan hydrochloride
`
`
`in the treatment of hyponatremia is through its V2 antagonism of AVP in the renal collecting ducts, an
`
`
`effect that results in aquaresis, or excretion of free water.
`
`
`12.2 Pharmacodynamics
`
`The pharmacodynamic effects of conivaptan hydrochloride include increased free water excretion (i.e.,
`
`effective water clearance [EWC]) generally accompanied by increased net fluid loss, increased urine
`
`
`output, and decreased urine osmolality. Studies in animal models of hyponatremia showed that conivaptan
`
`
`
`
`
`hydrochloride prevented the occurrence of hyponatremia-related physical signs in rats with the syndrome of
`
`inappropriate antidiuretic hormone secretion.
`
`
`Electrophysiology
`The effect of VAPRISOL 40 mg IV and 80 mg IV on the QT interval was evaluated after the first dose
`
`(Day 1) and at the last day during treatment (Day 4) in a randomized, single-blind, parallel group, placebo-
`
`
`and positive-controlled (moxifloxacin 400 mg IV) study in healthy male and female volunteers aged 18 to
`
`
`
`45 years. Digital ECGs were obtained at baseline and on Days 1 and 4. Moxifloxacin elicited placebo-
`
`
`corrected changes from baseline in individualized QT correction (QTcI) of +7 to +10 msec on Days 1 and
`
`
`
`4, respectively, indicating that the study had assay sensitivity. The placebo-corrected changes from baseline
`
`
`
`in QTcI in the VAPRISOL 40 mg and 80 mg dose groups on Day 1 were -3.5 msec and -2.9 msec,
`
`
`
`respectively, and -2.1 msec for both dose groups on Day 4. The results suggest that conivaptan has no
`
`
`
`clinically significant effect on cardiac repolarization.
`
`
`
`12.3 Pharmacokinetics
`
`The pharmacokinetics of conivaptan have been characterized in healthy subjects, specific populations and
`
`
`
`
`patients following both oral and intravenous dosing regimens. The pharmacokinetics of conivaptan
`
`
`following intravenous infusion (40 mg/day to 80 mg/day) and oral administration are non-linear, and
`
`
`
`
`
`Reference ID: 3998770
`
`
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` 8
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2028, Page 8
`
`

`

`inhibition by conivaptan of its own metabolism seems to be the major factor for the non-linearity. The
`intersubject variability of conivaptan pharmacokinetics is high (94% CV in CL).
`The pharmacokinetics of conivaptan and its metabolites were characterized in healthy male subjects
`administered conivaptan hydrochloride as a 20 mg loading dose (infused over 30 minutes) followed by a
`continuous infusion of 40 mg/day for 3 days. Mean Cmax for conivaptan was 619 ng/mL and occurred at the
`end of the loading dose. Plasma concentrations reached a minimum at approximately 12 hours after start of
`the loading dose, then gradually increased over the duration of the infusion to a mean concentration of 188
`ng/mL at the end of the infusion. The mean terminal elimination half-life after conivaptan infusion was
`5.0 hours, and the mean clearance was 253.3 mL/min.
`In an open-label safety and efficacy study, the pharmacokinetics of conivaptan were characterized in
`hypervolemic or euvolemic hyponatremia patients (ages 20 - 92 years) receiving conivaptan hydrochloride
`as a 20 mg loading dose (infused over 30 minutes) followed by a continuous infusion of 20 or 40 mg/day
`for 4 days. The median-plasma conivaptan concentrations are shown in Figure 1. The median (range)
`elimination half-life was 5.3 (3.3 - 9.3) or 8.1 (4.1 - 22.5) hours in the 20 mg/day or 40 mg/day group,
`respectively, based on data from rich PK sampling.
`
`Figure 1. Median Plasma Concentration-Time Profiles from Rich PK Sampling Post 20 mg
`Loading Dose and 20 mg/day (open circle) or 40 mg/day (closed circle) Infusion for 4 Days
`
`
`
`
`Distribution
`Conivaptan is extensively bound to human plasma proteins, being 99% bound over the concentration range
`of approximately 10 to 1000 ng/mL.
`Metabolism and Excretion
`CYP3A was identified as the sole cytochrome P450 isozyme responsible for the metabolism of conivaptan.
`Four metabolites have been identified. The pharmacological activity of the metabolites at V1A and V2
`receptors ranged from approximately 3-50% and 50-100% that of conivaptan, resp