Zogenix, Inc.

Zogenix, Inc. Drugs

• Sumavel Dosepro
  

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  Sumavel Dosepro

  

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  2.1 Dosing Information

  The maximum single recommended dose of Sumavel DosePro for the acute treatment of migraine or cluster headache is 6 mg given subcutaneously. For the treatment of migraine, if side effects are dose limiting, a lower dose (4 mg) may be used [see Clinical Studies (14.1)]. For the treatment of cluster headache, the efficacy of a lower dose has not been established.

  The maximum cumulative injected dose that may be given in 24 hours is 12 mg, with doses of Sumavel DosePro separated by at least 1 hour. Sumavel DosePro may be given at least 1 hour following a dose of another sumatriptan product. A second dose should only be considered if some response to a first dose was observed.

  2.2 Administration Using Sumavel® DosePro®

  Sumavel DosePro is available for use as 4 mg or 6 mg needle-free delivery systems. It is intended to be given subcutaneously only. Sumavel DosePro is designed for patient self-administration to sites on the abdomen or the thigh with an adequate subcutaneous thickness to accommodate penetration of sumatriptan injection into the subcutaneous space. Administration should not be made within 2 inches of the naval. Sumavel DosePro is not to be administered to other areas of the body, including the arm.  

  Instruct patients on the proper use of Sumavel DosePro and direct them to use proper injection sites. Patients should be instructed not to use Sumavel DosePro if the tip of the device is tilted or broken off upon removal from packaging [see Patient counseling Information (17)].

  Sumavel DosePro is for single use only. Discard after use.

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• Lovaza
  

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  Lovaza

  

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  2.1 Initial Dosing 

  ZOHYDRO ER should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

  ZOHYDRO ER 50 mg capsules, a single dose of ZOHYDRO ER greater than 40 mg, or a total daily dose greater than 80 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, or an equianalgesic dose of another opioid.

  Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with ZOHYDRO ER [see Warnings and Precautions (5.2)].

  ZOHYDRO ER must be taken whole [see Patient Counseling Information (17)]. Crushing, chewing, or dissolving the beads in ZOHYDRO ER capsules will result in uncontrolled delivery of hydrocodone and can lead to overdose or death [see Warnings and Precautions (5.1)]. 

  Use of ZOHYDRO ER as the First Opioid AnalgesicInitiate treatment with ZOHYDRO ER with one 10 mg capsule every 12 hours. 

  Use of ZOHYDRO ER in Patients Who Are Not Opioid Tolerant  The starting dose for patients who are not opioid tolerant is ZOHYDRO ER 10 mg orally every 12 hours. Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, or an equianalgesic dose of another opioid. 

  Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression. 

  Conversion from Other Oral Opioids to ZOHYDRO ER Discontinue all other around-the-clock opioid drugs when ZOHYDRO ER therapy is initiated.

  While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is preferable to underestimate a patient’s 24-hour oral hydrocodone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral hydrocodone requirements which could result in adverse reactions. In a ZOHYDRO ER clinical trial with an open label titration period, patients were converted from their prior opioid to ZOHYDRO ER using Table 1 as a guide for the initial ZOHYDRO ER dose.

  Consider the following when using the information in Table 1:

  This is not a table of equianalgesic doses. The conversion factors in this table are only for the conversion from one of the listed oral opioid analgesics to ZOHYDRO ER.   The table cannot be used to convert from ZOHYDRO ER to another opioid. Doing so will result in an over-estimation of the dose of the new opioid and may result in fatal overdose.   Table 1. Conversion Factors to ZOHYDRO ER (Not Equianalgesic Doses)   Prior Oral Opioid   Oral Dose (mg)   Approximate Oral Conversion Factor   Hydrocodone   10   1   Oxycodone   10   1   Methadone   10   1   Oxymorphone   5   2   Hydromorphone   3.75   2.67   Morphine   15   0.67   Codeine   100   0.10 The conversion ratios in this table are only to be used for the conversion from current opioid therapy to ZOHYDRO ER.

  To calculate the estimated daily ZOHYDRO ER dose using Table 1: 

  For patients on a single opioid, sum the current total daily dose of the opioid and then multiply the total daily dose by the conversion factor to calculate the approximate oral hydrocodone daily dose. The daily dose should then be divided in half for administration every 12 hours. For patients on a regimen of more than one opioid, calculate the approximate oral hydrocodone dose for each opioid and sum the totals to obtain approximate total hydrocodone daily dose. The daily dose should then be divided in half for administration every 12 hours. For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion. 

  Always round the dose down, if necessary, to the appropriate ZOHYDRO ER strength(s) available.

  Example conversion from a single opioid to ZOHYDRO ER

  Step 1: Sum the total daily dose of the opioid (in this case, extended-release oxymorphone); 15 mg oxymorphone twice daily = 30 mg total daily dose of oxymorphone.

  Step 2: Calculate the approximate equivalent dose of oral hydrocodone based on the total daily dose of the current opioid using Table 1; 30 mg total daily dose of oxymorphone x 2 = 60 mg of oral hydrocodone daily. The daily dose should then be divided in half for administration every 12 hours. 

  Step 3: Calculate the approximate starting dose which is 30 mg ZOHYDRO ER every 12 hours. Round down, if necessary, to the appropriate ZOHYDRO ER capsule strengths available. Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to ZOHYDRO ER.

  The dose of ZOHYDRO ER can be gradually adjusted preferably at increments of 10 mg every 12 hours every 3 to 7 days, until adequate pain relief and acceptable adverse reactions have been achieved.

  Conversion from Methadone to ZOHYDRO ERClose monitoring is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and tends to accumulate in the plasma.

  Conversion from Transdermal Fentanyl to ZOHYDRO ERZOHYDRO ER treatment can be initiated 18 hours following the removal of the transdermal fentanyl patch. Although there has been no systematic assessment of such conversion, a conservative hydrocodone dose, approximately 10 mg every 12 hours of ZOHYDRO ER, should be initially substituted for each 25 mcg/hr fentanyl transdermal patch. Follow the patient closely during conversion from transdermal fentanyl to ZOHYDRO ER, as there is limited documented experience with this conversion.

  2.2 Titration and Maintenance of Therapy

  Individually titrate ZOHYDRO ER to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving ZOHYDRO ER to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for opioid analgesics. Patients who experience breakthrough pain may require a dose increase of ZOHYDRO ER, or may need a rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain while adjusting the ZOHYDRO ER dose to decrease the level of pain. Because steady-state plasma concentrations are approximated within 3 days, ZOHYDRO ER dosage adjustments, preferably at increments of 10 mg every 12 hours, may be done every 3 to 7 days. If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

  2.3 Discontinuation of ZOHYDRO ER

  When a patient no longer requires therapy with ZOHYDRO ER, use a gradual downward titration of the dose every 2 to 4 days to prevent signs and symptoms of withdrawal in the physically-dependent patient. During the Phase 3 study, the following taper schedule was utilized for patients assigned to placebo in the treatment phase of the study (Table 2):

  Table 2.

  ZOHYDRO ER Taper Schedule Used in Phase 3 Study

  Stabilized Dose At Time of Taper Initiation Taper Schedule 20 mg to 30 mg q12h* 10 mg q12h on Days 1 and 2 Day 3, stop 40 mg to 70 mg q12h 40 mg q12h on Days 1 and 2 20 mg q12h on Days 3 and 4 10 mg q12h on Days 5 and 6 Day 7, stop 80 mg to 100 mg q12h 80 mg q12h on Days 1 and 2 60 mg q12h on Days 3 and 4 40 mg q12h on Days 5 and 6 20 mg q12h on Days 7 and 8 10 mg q12h on Days 9 and 10 Day 11, stop

  *q12h = every 12 hours

  Doses above 100 mg every 12 hours (q12h) were not studied in the Phase 3 trial. For patients exceeding 100 mg q12h use a gradual downward titration of the dose every 2 to 4 days. Patients should be monitored closely for signs and symptoms of opioid withdrawal which may indicate a need to taper more slowly. Do not abruptly discontinue ZOHYDRO ER.

  2.4 Administration of ZOHYDRO ER

  Instruct patients to swallow ZOHYDRO ER capsules whole. The beads in the capsules are not to be crushed, dissolved, or chewed due to the risk of rapid release and absorption of a potentially fatal dose of hydrocodone [see Warnings and Precautions (5.1)].

  2.5 Hepatic Impairment

  Patients with hepatic impairment may have higher plasma concentrations of hydrocodone than those with normal function. No adjustment in starting dose with ZOHYDRO ER is required in patients with mild or moderate hepatic impairment. However, in patients with severe hepatic impairment, start with the lowest dose, 10 mg every 12 hours. Monitor these patients closely for adverse events such as respiratory depression [see Clinical Pharmacology (12.3)].

  2.6 Renal Impairment

  Patients with renal impairment may have higher plasma concentrations of hydrocodone than those with normal function. Initiate therapy with a low initial dose of ZOHYDRO ER in patients with renal impairment and monitor closely for respiratory depression and sedation [see Clinical Pharmacology (12.3)].

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• Zohydro
  

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  Zohydro

  

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  2.1 Initial Dosing 

  ZOHYDRO ER should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

  ZOHYDRO ER 50 mg capsules, a single dose of ZOHYDRO ER greater than 40 mg, or a total daily dose greater than 80 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, or an equianalgesic dose of another opioid.    

  Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with ZOHYDRO ER [see Warnings and Precautions (5.2)].

  ZOHYDRO ER must be taken whole [see Patient Counseling Information (17)]. Crushing, chewing, or dissolving the pellets in ZOHYDRO ER capsules will result in uncontrolled delivery of hydrocodone and can lead to overdose or death [see Warnings and Precautions (5.1)]. 

  Use of ZOHYDRO ER as the First Opioid AnalgesicInitiate treatment with ZOHYDRO ER with one 10 mg capsule every 12 hours. 

  Use of ZOHYDRO ER in Patients Who Are Not Opioid Tolerant  The starting dose for patients who are not opioid tolerant is ZOHYDRO ER 10 mg orally every 12 hours.  Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, or an equianalgesic dose of another opioid. 

  Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression. 

  Conversion from Other Oral Opioids to ZOHYDRO ER Discontinue all other around-the-clock opioid drugs when ZOHYDRO ER therapy is initiated.

  While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is preferable to underestimate a patient’s 24‑hour oral hydrocodone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral hydrocodone requirements which could result in adverse reactions. In a ZOHYDRO ER clinical trial with an open label titration period, patients were converted from their prior opioid to ZOHYDRO ER using Table 1 as a guide for the initial ZOHYDRO ER dose.

  Consider the following when using the information in Table 1:

  This is not a table of equianalgesic doses. The conversion factors in this table are only for the conversion from one of the listed oral opioid analgesics to ZOHYDRO ER.   The table cannot be used to convert from ZOHYDRO ER to another opioid. Doing so will result in an over-estimation of the dose of the new opioid and may result in fatal overdose.  Table 1. Conversion Factors to ZOHYDRO ER (not equianalgesic doses)  Prior Oral Opioid  Oral Dose (mg)  Approximate Oral Conversion Factor  Hydrocodone  10  1  Oxycodone  10  1  Methadone  10  1  Oxymorphone  5  2  Hydromorphone  3.75  2.67  Morphine  15  0.67  Codeine  100  0.10

  The conversion ratios in this table are only to be used for the conversion from current opioid therapy to ZOHYDRO ER

  To calculate the estimated daily ZOHYDRO ER dose using Table 1: 

  For patients on a single opioid, sum the current total daily dose of the opioid and then multiply the total daily dose by the conversion factor to calculate the approximate oral hydrocodone daily dose. The daily dose should then be divided in half for administration every 12 hours. For patients on a regimen of more than one opioid, calculate the approximate oral hydrocodone dose for each opioid and sum the totals to obtain approximate total hydrocodone daily dose. The daily dose should then be divided in half for administration every 12 hours. For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion. 

  Always round the dose down, if necessary, to the appropriate ZOHYDRO ER strength(s) available.

  Example conversion from a single opioid to ZOHYDRO ER

  Step 1: Sum the total daily dose of the opioid (in this case, extended-release oxymorphone); 15 mg oxymorphone twice daily = 30 mg total daily dose of oxymorphone.

  Step 2: Calculate the approximate equivalent dose of oral hydrocodone based on the total daily dose of the current opioid using Table 1; 30 mg total daily dose of oxymorphone x 2 = 60 mg of oral hydrocodone daily. The daily dose should then be divided in half for administration every 12 hours. 

  Step 3: Calculate the approximate starting dose which is 30 mg ZOHYDRO ER every 12 hours. Round down, if necessary, to the appropriate ZOHYDRO ER capsule strengths available. Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to ZOHYDRO ER.

  The dose of ZOHYDRO ER can be gradually adjusted preferably at increments of 10 mg every 12 hours every 3 to 7 days, until adequate pain relief and acceptable adverse reactions have been achieved.

  Conversion from Methadone to ZOHYDRO ERClose monitoring is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and tends to accumulate in the plasma.

  Conversion from Transdermal Fentanyl to ZOHYDRO ERZOHYDRO ER treatment can be initiated 18 hours following the removal of the transdermal fentanyl patch. Although there has been no systematic assessment of such conversion, a conservative hydrocodone dose, approximately 10 mg every 12 hours of ZOHYDRO ER, should be initially substituted for each 25 mcg/hr fentanyl transdermal patch. Follow the patient closely during conversion from transdermal fentanyl to ZOHYDRO ER, as there is limited documented experience with this conversion.

  2.2 Titration and Maintenance of Therapy

  Individually titrate ZOHYDRO ER to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving ZOHYDRO ER to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for opioid analgesics. Patients who experience breakthrough pain may require a dose increase of ZOHYDRO ER, or may need a rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain while adjusting the ZOHYDRO ER dose to decrease the level of pain. Because steady-state plasma concentrations are approximated within 3 days, ZOHYDRO ER dosage adjustments, preferably at increments of 10 mg every 12 hours, may be done every 3 to 7 days. If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

  2.3 Discontinuation of ZOHYDRO ER

  When a patient no longer requires therapy with ZOHYDRO ER, use a gradual downward titration of the dose every 2 to 4 days to prevent signs and symptoms of withdrawal in the physically-dependent patient. During the Phase 3 study, the following taper schedule was utilized for patients assigned to placebo in the treatment phase of the study (Table 2):

  Table 2.

  ZOHYDRO ER Taper Schedule Used in Phase 3 Study

  Stabilized Dose At Time of Taper Initiation

  Taper Schedule

  20 mg to 30 mg q12h*

  10 mg q12h on Days 1 and 2 Placebo on Day 3

  40 mg to 70 mg q12h

  40 mg q12h on Days 1 and 2 20 mg q12h on Days 3 and 4 10 mg q12h on Days 5 and 6 Placebo on Day 7

  80 mg to 100 mg q12h

  80 mg q12h on Days 1 and 2 60 mg q12h on Days 3 and 4 40 mg q12h on Days 5 and 6 20 mg q12h on Days 7 and 8 10 mg q12h on Days 9 and 10 Placebo on Day 11

  *q12h = every 12 hours

  Doses above 100 mg every 12 hours (q12h) were not studied in the Phase 3 trial. For patients exceeding 100 mg q12h use a gradual downward titration of the dose every 2 to 4 days. Patients should be monitored closely for signs and symptoms of opioid withdrawal which may indicate a need to taper more slowly. Do not abruptly discontinue ZOHYDRO ER.

  2.4 Administration of ZOHYDRO ER

  Instruct patients to swallow ZOHYDRO ER capsules whole. The pellets in the capsules are not to be crushed, dissolved, or chewed due to the risk of rapid release and absorption of a potentially fatal dose of hydrocodone [see Warnings and Precautions (5.1)].

  2.5 Hepatic Impairment

  Patients with hepatic impairment may have higher plasma concentrations of hydrocodone than those with normal function. No adjustment in starting dose with ZOHYDRO ER is required in patients with mild or moderate hepatic impairment. However, in patients with severe hepatic impairment, start with the lowest dose, 10 mg every 12 hours. Monitor these patients closely for adverse events such as respiratory depression [see Clinical Pharmacology (12.3)].

  2.6 Renal Impairment

  Patients with renal impairment may have higher plasma concentrations of hydrocodone than those with normal function. Initiate therapy with a low initial dose of ZOHYDRO ER in patients with renal impairment and monitor closely for respiratory depression and sedation [see Clinical Pharmacology (12.3)].

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