11 DESCRIPTION Cannabidiol is a cannabinoid designated chemically as 2-[(1R,6R)-3-Methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol (IUPAC/CAS). Its empirical formula is C21H30O2 and its molecular weight is 314.46. The chemical structure is: Cannabidiol, the active ingredient in EPIDIOLEX, is a cannabinoid that naturally occurs inthe Cannabis sativa L.plant. Cannabidiol is awhite to pale yellow crystalline solid. It is insoluble in water and is soluble in organic solvents. EPIDIOLEX(cannabidiol)oral solution is a clear, colorless to yellow liquid containing cannabidiol at a concentration of 100mg/mL.Inactive ingredients includedehydrated alcohol, sesame seed oil, strawberry flavor, and sucralose.EPIDIOLEX contains no ingredient made from a gluten-containing grain (wheat, barley, or rye).
SPL MEDGUIDE SECTION.
MEDICATION GUIDE EPIDIOLEX ( EH-peh-DYE-oh-lex ) ( cannabidiol ) o ral s olution Read this Medication Guide before you start taking EPIDIOLEX and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. What is the most important information I should know about EPIDIOLEX? EPIDIOLEX can cause serious side effects, including: 1. EPIDIOLEX may cause liver problems. Your healthcare provider may order blood tests to check your liver before you start taking EPIDIOLEX and during treatment. In some cases, EPIDIOLEX treatment may need to be stopped. Call your healthcare provider right away if you develop any of these signs and symptoms of liver problems during treatment with EPIDIOLEX: loss of appetite, nausea, vomiting itching fever, feeling unwell, unusual tiredness unusual darkening of the urine yellowing of the skin or the whites of the eyes (jaundice right upper stomach area pain or discomfort 2. EPIDIOLEX may cause you to feel sleepy, which may get better over time. Other medicines (e.g., clobazam) or alcohol may increase sleepiness. Do not drive, operate heavy machinery, or do other dangerous activities until you know how EPIDIOLEX affects you. 3. Like other antiepileptic drugs, EPIDIOLEX may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying trouble sleeping (insomnia) attempt to commit suicide new or worse irritability new or worse depression acting aggressive, being angry, or violent new or worse anxiety acting on dangerous impulses feeling agitated or restless an extreme increase in activity and talking (mania) panic attacks other unusual changes in behavior or mood How can I watch for early symptoms of suicidal thoughts and actions? Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled. 4. Do not stop taking EPIDIOLEX without first talking to your healthcare provider. Stopping a seizure medicine such as EPIDIOLEX suddenly can cause you to have seizures more often or seizures that do not stop (status epilepticus). Call your healthcare provider between visits as needed, especially if you are worried about symptoms. What is EPIDIOLEX? EPIDIOLEX is a prescription medicine that is used to treat seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in people 2 years of age and older. It is not known if EPIDIOLEX is safe and effective in children under 2 years of age. Who should not take EPIDIOLEX? Do not take EPIDIOLEX if you are allergic to cannabidiol or any of the ingredients in EPIDIOLEX. See the end of this Medication Guide for a complete list of ingredients in EPIDIOLEX. Before taking EPIDIOLEX, tell your healthcare provider about all of your medical conditions, including if you: have or have had depression, mood problems or suicidal thoughts or behavior. have liver problems. have abused or been dependent on prescription medicines, street drugs or alcohol. are pregnant or plan to become pregnant. Tell your healthcare provider right away if you become pregnant while taking EPIDIOLEX. You and your healthcare provider will decide if you should take EPIDIOLEX while you are pregnant. If you become pregnant while taking EPIDIOLEX, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic medicines during pregnancy. are breastfeeding or plan to breastfeed. It is not known if EPIDIOLEX passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking EPIDIOLEX. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, herbal supplements, and any cannabis-based products. EPIDIOLEX may affect the way other medicines work, and other medicines may affect how EPIDIOLEX works. Do not start or stop taking other medicines without talking to your healthcare provider. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. Tell your healthcare provider if you are planning to have a cannabis drug screen because EPIDIOLEX may affect your test results. Tell the person giving the drug test that you are taking EPIDIOLEX. How should I take EPIDIOLEX? Read the Instructions for Use at the end of this Medication Guide for information on the right way to use EPIDIOLEX. Take EPIDIOLEX exactly as your healthcare provider tells you. Your healthcare provider will tell you how much EPIDIOLEX to take and when to take it. Measure each dose of EPIDIOLEX using the bottle adapter and 5 mL dosing syringes that come with EPIDIOLEX. If your dose of EPIDIOLEX is less than 1 mL, your pharmacist will provide you with 1 mL syringes to take your medicine. Use a dry syringe each time you take EPIDIOLEX. If water is inside the syringe, it could cause the oil based medicine to look cloudy. What should I avoid while taking EPIDIOLEX? Do not drive, operate heavy machinery, or do other dangerous activities until you know how EPIDIOLEX affects you. EPIDIOLEX may cause you to feel sleepy. What are the possible side effects of EPIDIOLEX? EPIDIOLEX can cause serious side effects, including: See What is the most important information I should know about EPIDIOLEX? The most common side effects of EPIDIOLEX include: sleepiness feeling very tired and weak decreased appetite rash diarrhea sleep problems increase in liver enzymes infections These are not all of the possible side effects of EPIDIOLEX. For more information ask your healthcare provider or pharmacist. Tell your healthcare provider about any side effect that bothers you or that does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also contact Greenwich Biosciences at 1-833-424-6724 (1-833-GBIOSCI). How should I store EPIDIOLEX? Store EPIDIOLEX at room temperature between 68F to 77F (20C to 25C). Always store EPIDIOLEX in an upright position. Do not freeze. Keep the child-resistant cap tightly closed. Use EPIDIOLEX within 12 weeks of first opening the bottle. Throw away (dispose of) any unused medicine after 12weeks. Keep EPIDIOLEX and all medicines out of the reach of children. General Information about the safe and effective use of EPIDIOLEX . Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use EPIDIOLEX for a condition for which it was not prescribed. Do not give EPIDIOLEX to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about EPIDIOLEX that is written for health professionals. What are the ingredients in EPIDIOLEX? Active ingredient: cannabidiol Inactive ingredients: dehydrated alcohol, sesame seed oil, strawberry flavor, and sucralose EPIDIOLEX does not contain gluten (wheat, barley or rye). Marketed by Greenwich Biosciences, Inc., Carlsbad, CA 92008 USA For more information, go to www.EPIDIOLEX.com or call 1-833-424-6724 (1-833-GBIOSCI). 2020 Greenwich Biosciences, Inc. All rights reserved. This Medication Guide has been approved by the U.S. Food and Drug Administration Issued: 04/2020
DOSAGE FORMS & STRENGTHS SECTION.
3 DOSAGE FORMS AND STRENGTHS Cannabidiol oral solution: 100 mg/mL for oral administration. Each bottle contains 100 mL of a clear, colorless to yellow solution. Oral solution: 100mg/mL (3)
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.
PRINCIPAL DISPLAY PANEL NDC 70127-100-10 EPIDIOLEX (cannabidiol) 100 mg/mL oral solution
ADVERSE REACTIONS SECTION.
6 ADVERSE REACTIONS The following importantadverse reactions are described elsewhere in labeling: Hepatocellular Injury[see Warnings and Precautions ( 5.1 ) ] Somnolence andSedation [see Warnings and Precautions ( 5.2 ) ] Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.3 ) ] Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 )] Withdrawal of Antiepileptic Drugs [see Warnings and Precautions ( 5.5 ) ] The most common adverse reactions (10% or more for EPIDIOLEX and greater than placebo)are: somnolence; decreased appetite; diarrhea;transaminase elevations;fatigue, malaise, and asthenia; rash; insomnia, sleep disorder, and poor quality sleep; and infections. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Greenwich Biosciences at 1-833-424-6724 (1-833-GBIOSCI) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical T rials E xperience Because clinical trials are conducted under widely varying conditions, adverse reaction 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. In controlled and uncontrolled trials in patients with LGS and DS, 689patientswere treated with EPIDIOLEX, including 533 patients treatedfor more than 6 months, and 391patients treated for more than 1 year. In an expanded access program and other compassionate use programs, 161 patients with DS and LGS were treated with EPIDIOLEX, including 109 patients treated for more than 6 months, 91 patients treated for more than 1 year, and 50 patients treated for more than 2 years. In placebo-controlled trials of patients with LGS or DS (includes Studies 1, 2, 3, and a Phase 2 controlled study in DS), 323 patients received EPIDIOLEX. Adverse reactions are presented below; the durationof treatment in these trials was up to 14 weeks. Approximately 46% of patients were female, 83% were Caucasian, and the mean age was 14 years (range 2 to 48years). All patients were taking other AEDs. In controlled trials, the rate of discontinuation as a result of any adverse reaction was 2.7% for patients taking EPIDIOLEX 10 mg/kg/day, 11.8% forpatients taking EPIDIOLEX 20 mg/kg/day, and 1.3% forpatients on placebo. The most frequent cause of discontinuations was transaminase elevation. Discontinuation for transaminase elevation occurred at an incidence of 1.3%inpatients taking EPIDIOLEX 10 mg/kg/day,5.9%in patients taking EPIDIOLEX 20 mg/kg/day,and 0.4%inpatients on placebo. Somnolence, sedation, and lethargy led to discontinuation in 3% of patients taking EPIDIOLEX 20mg/kg/day compared to0% ofpatients taking EPIDIOLEX 10 mg/kg/day or on placebo. The most common adverse reactionsthat occurred in EPIDIOLEX-treated patients (incidence at least10% and greater than placebo) were somnolence; decreased appetite;diarrhea; transaminase elevations; fatigue, malaise, and asthenia; rash; insomnia, sleep disorder, and poor quality sleep; and infections. Table 3lists theadverse reactionsthat were reported in 3% of EPIDIOLEX-treated patients, and at a rate greater than those onplacebo in the placebo-controlledtrials in LGS and DS. Table 3 : Adverse Reactions in Patients Treated with EPIDIOLEX in Controlled Trials Adverse Reactions EPIDIOLEX Placebo 10 mg/kg/day 20 mg/kg/day N=75 % N=238 % N=227 % Hepatic Disorders Transaminases elevated 8 16 3 Gastrointestinal Disorders Decreased appetite 16 22 5 Diarrhea 9 20 9 Weight decreased 3 5 1 Gastroenteritis 0 4 1 Abdominal pain, discomfort 3 3 1 Nervous System Disorders Somnolence 23 25 8 Sedation 3 6 1 Lethargy 4 8 2 Fatigue, malaise, asthenia 11 12 4 Insomnia, sleep disorder, poor quality sleep 11 5 4 Irritability, agitation 9 5 2 Aggression, anger 3 5 <1 Drooling, salivary hypersecretion 1 4 <1 Gait disturbance 3 2 <1 Infections Infection, all 41 40 31 Infection, viral 7 11 6 Pneumonia 8 5 1 Infection, fungal 1 3 0 Infection, other 25 21 24 Other Rash 7 13 3 Hypoxia, respiratory failure 3 3 1 Adverse reactions were similar across LGS and DS in pediatric and adult patients. Decreased W eight EPIDIOLEX can cause weight loss. In the controlled trials of patients with LGS or DS, based on measured weights, 16% of EPIDIOLEX-treated patients had a decrease in weight of 5% from their baseline weight,compared to 8% of patients on placebo.The decrease in weight appeared to be dose-related, with 18% of patients onEPIDIOLEX20 mg/kg/day experiencing a decrease in weight 5%,compared to 9% in patients on EPIDIOLEX10 mg/kg/day.In some cases, the decreased weight was reported as an adverse event (see Table 3). Hematologic A bnormalities EPIDIOLEX can cause decreases in hemoglobin and hematocrit. Incontrolled trials of patients with LGS or DS, the mean decrease in hemoglobin from baseline to end of treatment was -0.42g/dL in EPIDIOLEX-treated patients and -0.03 g/dL in patients on placebo. A corresponding decrease in hematocrit was also observed, with a mean change of -1.5% in EPIDIOLEX-treated patients, and -0.4% in patients on placebo.There was no effect on red blood cell indices. Thirtypercent (30%) of EPIDIOLEX-treated patients developed a new laboratory-defined anemia during the course of the study (defined as a normal hemoglobin concentration at baseline, with a reported value less than the lower limit of normal at a subsequent time point), versus 13% of patientson placebo. Increases in C reatinine EPIDIOLEXcan cause elevations in serum creatinine.The mechanism has not been determined.In controlled studies in healthy adults and in patients with LGS and DS, an increase in serum creatinine of approximately 10% was observed within 2 weeksof starting EPIDIOLEX.The increase was reversible in healthy adults. Reversibility was not assessed in studies in LGS and DS.
INDICATIONS & USAGE SECTION.
1 INDICATIONS AND USAGE EPIDIOLEX is indicated for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) in patients 2 years of age and older. EPIDIOLEX isindicated for thetreatment of seizures associatedwith Lennox-Gastaut syndrome or Dravet syndromein patients 2 years of age and older(1)
DRUG ABUSE AND DEPENDENCE SECTION.
9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance EPIDIOLEX is not a controlled substance. 9.2 Abuse Animal abuse-related studies show that cannabidiol does not produce cannabinoid-like behavioral responses, including generalization to delta-9-tetrahydrocannabinol (THC) in a drug discrimination study. Cannabidiol also does not produce animal self-administration, suggesting it does not produce rewarding effects. In a human abuse potential study, acute administration of cannabidiol to non-dependent adult recreational drug users at therapeutic and supratherapeutic dosesof 750, 1500, and 4500 mg in the fasted state(equivalent respectively to 10, 20, and 60 mg/kg in a 75 kg adult) produced responses on positive subjective measures such as Drug Liking and Take Drug Againthat were within the acceptable placebo range. In contrast, 10 and 30 mg of dronabinol (synthetic THC) and 2 mg alprazolam produced large increases on positive subjective measures compared to placebo that were statistically significantly greater than those produced by cannabidiol. In other Phase 1 clinical studies conducted with cannabidiol, there were no reports of abuse-related adverse events. 9.3 Dependence In a human physical dependence study, administration of cannabidiol 1500 mg/day (750 mg twice daily) to adults for 28 days did not produce signs or symptoms of withdrawal over a 6-week assessment period beginning three days after drug discontinuation. This suggests that cannabidiol likely does not produce physical dependence.
DOSAGE & ADMINISTRATION SECTION.
2 DOSAGE AND ADMINISTRATION Obtain serum transaminases (ALT and AST) and total bilirubin levels in all patients prior to starting treatment. (2.1, 5.1) EPIDIOLEX is to be administered orally. (2.2) Therecommended starting dosage is 2.5 mg/kg taken twice daily (5mg/kg/day).After one week, the dosage can beincreasedto a maintenance dosage of 5mg/kg twice daily (10 mg/kg/day). (2.2) Based on individual clinical response and tolerability, EPIDIOLEX can be increased up to a maximum recommended maintenance dosage of 10mg/kg twice daily (20 mg/kg/day).See Full Prescribing Information for titration.(2.2) Dosage adjustment is recommendedfor patients with moderate or severe hepatic impairment. (2.5, 8.6) 2.1 Assessments Prior to Initiating EPIDIOLEX Because of the risk of hepatocellular injury, obtain serum transaminases (ALT and AST) and total bilirubin levels in all patients prior to starting treatment with EPIDIOLEX [see Warnings and Precautions ( 5.1 )]. 2. 2 Dosage Information EPIDIOLEX is to be administered orally. The starting dosage is 2.5 mg/kg twice daily (5 mg/kg/day). After one week, the dosage can be increased to a maintenance dosage of 5 mg/kg twice daily (10mg/kg/day). Patients who are tolerating EPIDIOLEX at 5 mg/kg twice daily and require further reduction of seizures may benefit from a dosage increase up to a maximum recommended maintenance dosage of 10 mg/kg twice daily (20 mg/kg/day), in weekly increments of 2.5 mg/kg twice daily (5mg/kg/day), as tolerated. For patients in whom a more rapid titration from 10 mg/kg/day to 20mg/kg/day is warranted, the dosage may be increased no more frequently than every other day.Administration of the 20 mg/kg/day dosage resulted in somewhat greater reductions in seizure rates than the recommended maintenance dosage of 10mg/kg/day, but with an increase in adverse reactions. 2. 3 Administration Instructions Food may affect EPIDIOLEX levels[see Clinical Pharmacology ( 12.3 )] . A calibrated measuring device (either 5 mL or 1 mL oral syringe) will be provided and is recommended to measure and deliver the prescribed dose accurately[see How Supplied/Storage and Handling ( 16.1 )].A household teaspoon or tablespoon is not an adequate measuring device. Discard any unused EPIDIOLEX remaining 12 weeks after first opening the bottle[see How Supplied/ Storage and Handling ( 16.2 ) ] . 2. 4 Discontinuation of EPIDIOLEX When discontinuingEPIDIOLEX, the dose should be decreased gradually. As with all antiepileptic drugs, abrupt discontinuation should be avoided when possible, to minimize the risk of increased seizure frequencyand status epilepticus[see Warnings and Precautions ( 5.5 ) ] . 2. 5 Patients with Hepatic Impairment Dose adjustment is recommended in patients with moderate (Child-Pugh B) hepatic impairment or severe (Child-Pugh C) hepatic impairment [see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.6 ), and Clinical Pharmacology ( 12.3 )]. It may be necessary to have slower dose titration in patients with moderate or severe hepatic impairment than in patients without hepatic impairment (see Table 1). EPIDIOLEX does not require dose adjustment in patients with mild (Child-Pugh A) hepatic impairment. Table 1 : Dose Adjustments in Patients with Hepatic Impairment Hepatic Impairment Starting Dosage Maintenance Dosage M aximum Recommended Dosage Mild 2.5 mg/kg twice daily (5 mg/kg/day) 5 mg/kg twice daily (10 mg/kg/day) 10 mg/kg twice daily (20 mg/kg/day) Moderate 1.25 mg/kg twice daily (2.5 mg/kg/day) 2.5 mg/kg twice daily (5 mg/kg/day) 5 mg/kg twice daily (10 mg/kg/day) Severe 0.5 mg/kg twice daily (1 mg/kg/day) 1 mg/kg twice daily (2 mg/kg/day) 2 mg/kg twice daily (4 mg/kg/day)
HOW SUPPLIED SECTION.
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied EPIDIOLEX is a strawberry flavored clear, colorless to yellow solution supplied in a 105 mL amber glass bottle with a child-resistant closure containing 100 mL of oral solution (NDC 70127-100-01). Each mL contains 100 mg of cannabidiol. EPIDIOLEX is packaged in a carton with two 5 mL calibrated oral dosing syringes and a bottle adapter (NDC70127-100-10). The pharmacy will provide 1mL calibrated oral dosing syringes when doses less than 1mL are required. 16.2 Storage and Handling Store EPIDIOLEX in an upright position at 20C to 25C (68F to 77F); excursions are permitted between 15C to 30C (59F to 86F). [See USP Controlled Room Temperature]. Do not freeze. Keep the cap tightly closed.Use within 12weeks of first opening the bottle, then discard any remainder.
SPL PATIENT PACKAGE INSERT SECTION.
I NSTRUCTIONS FOR USE EPIDIOLEX ( EH-peh-DYE-oh-lex ) (cannabidiol) oral solution 100 mg/mL Be sure that you read, understand and follow these instructions carefully to ensure proper dosing of the oral solution. Important: Follow your healthcare providers instructions for the dose of EPIDIOLEX to take or give. Ask your healthcare provider or pharmacist if you are not sure how to prepare, take, or give the prescribed dose of EPIDIOLEX. Always use the oral syringe provided with EPIDIOLEX to make sure you measure the right amount of EPIDIOLEX. Do not use EPIDIOLEXafter the expiration date on the package and each bottle. Use EPIDIOLEX within 12 weeks of first opening the bottle. After 12 weeks, safely throw away (dispose of) any EPIDIOLEX that has not been used. Each package contains: Child-resistant cap Bottle adapter 1 bottle of EPIDIOLEX oral solution (100 mg/mL) 2reusable 5 mL oral syringes: 1 syringe to take or give the dose of EPIDIOLEX 1 extra syringe (included as a spare if needed) Supplies not included in the package: If you r dose of EPIDIOLEX is less than 1 mL, your pharmacist will provide you with 1mL syringes to take your medicine. Call your pharmacist right away if your dose of EPIDIOLEX is less than 1 mL and you do not receive 1 mL syringes with your medicine. Note: If you lose or damage an oral syringe, or cannot read the markings, use the spare syringe. Prepare T he Bottle - to use EPIDIOLEX for the first time 1. Remove the child-resistant cap by pushing down while turning the cap to the left (counter-clockwise). 2. Push the bottle adapter firmly into the bottle. Make sure the bottle adapter is fully inserted.If not fully inserted, small parts such as the bottle adapter may become a choking hazard for children and pets. Note: Do not remove the bottle adapter from the bottle after it is inserted. Prepare The Dose Your healthcare provider will tell you how much EPIDIOLEX to take or give. 3. Use this table to measure the total dose of EPIDIOLEX to be given. Dose How to measure 5 mL or less Use the oral syringe 1 time More than 5 mL Use the oral syringe more than 1 time 4. Push the plunger all the way down and insert the tip of the oral syringe fully into the bottle adapter.With the oral syringe in place, turn the bottle upside down. 5.Slowly pull the plunger of the oral syringe to withdraw the dose of EPIDIOLEX needed. See Step 3 for how to measure the total dose of EPIDIOLEX. Line up the end of the plunger with the marking for your dose of EPIDIOLEX. What to do if you see air bubbles: If there are air bubbles in the oral syringe, keep the bottle upside down and push the plunger so thatall of the liquid flows back into the bottle.Repeat Step 5 until the air bubblesare gone. 6. When you have measured the correct dose of EPIDIOLEX, leave the oral syringe in the bottle adapter and turn the bottle right side up. 7. Carefully remove the oral syringe from the bottle adapter. Give EPIDIOLEX 8. Place the tip of the oral syringe against the inside of the cheek and gently push the plunger untilall the EPIDIOLEX in the syringe is given. Do not forcefully push on the plunger. Do not direct the medicine to the back of the mouth or throat. This may cause choking. If the dose of EPIDIOLEX prescribed by the healthcare provider is more than 5 mL, repeat steps 4 through 8to complete the dose. For example: If your dose of EPIDIOLEX is 8 mL, withdraw 5 mL of medicine into the syringe and give the medicine.Insert the tip of the oral syringe back into the bottle adapter and withdraw 3 mL of medicine. Give the medicine to receive a total dose of 8 mL. Clean Up 9. Screw the child-resistant cap back on the bottle tightly by turning the cap to the right (clockwise). Do not remove the bottle adapter. The cap will fit over it. 10. Fill a cup with warm soapy water and clean the oral syringe by drawing water in and out of the syringe using the plunger. 11.Remove the plunger from the barrel of the oral syringe and rinse both parts under tap water. Do not wash the oral syringe in the dishwasher. 12.Shake off any extra water from the plunger and oral syringe barrel, and allow them to air dry until next use. Make sure the oral syringe is completely dry before the next use. If water is inside the syringe, it could cause the oil based medicine to look cloudy. Do not throw away the oral syringe. How should I store EPIDIOLEX? Store EPIDIOLEXat room temperature between 68F to 77F (20C to 25C). Always store EPIDIOLEX in an upright position. Do not freeze. Keep the child-resistant cap tightly closed. Use EPIDIOLEX within 12 weeks of first opening the bottle. Dispose of any unused EPIDIOLEXafter 12 weeks. Keep EPIDIOLEX and all medicines out of the reach of children. Helpline Details For additional assistance, call the toll-free helpline at 1-833-426-4243 (1-833-GBNGAGE). Hours: Monday-Friday 08:00am 08:00pm EST Frequently Asked Questions Q: What if there are air bubble s in the oral syringe? A: Push the liquid back into the bottle and repeat Step 5 until the air bubblesare gone. Q: What should I do if the liquid in the bottle has turned cloudy? A: The liquid in the bottle may turn cloudy if water gets in the bottle. This does not change the safety or how well the medicine works. Continue to use the cloudy liquid as prescribed by your healthcare provider. Always make sure the oral syringes are completely dry before each use. Q: What should I do if the oral syringe is not completely dry before use? A: If the oral syringe is not completely dry, use the spare syringe provided in the pack. Marketed by Greenwich Biosciences, Inc., Carlsbad, CA 92008 USA 2020 Greenwich Biosciences, Inc. All rights reserved. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 04/2020
WARNINGS AND PRECAUTIONS SECTION.
5 WARNINGS AND PRECAUTIONS Hepatocellular Injury: EPIDIOLEX can cause transaminase elevations. Concomitant use of valproateand higher doses of EPIDIOLEX increase the risk of transaminase elevations.See Full Prescribing Information for serum transaminase and bilirubin monitoringrecommendations. (5.1) Somnolence andSedation:Monitor for somnolenceand sedation and advise patients not to drive or operate machinery until they have gained sufficient experience on EPIDIOLEX. (5.2) Suicidal Behavior and Ideation: Monitor patients for suicidal behavior and thoughts. (5.3) Hypersensitivity Reactions: Advise patients to seek immediate medical care. Discontinue and do not restart EPIDIOLEX if hypersensitivity occurs. (5.4) Withdrawal of Antiepileptic Drugs:EPIDIOLEXshould be gradually withdrawn to minimize the risk of increased seizure frequencyand status epilepticus.(5.5) 5. 1 Hepatocellular Injury EPIDIOLEXcausesdose-related elevations of liver transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]). In controlled studies for LGS and DS, the incidence of ALT elevations above 3 times the upper limit of normal (ULN)was13% in EPIDIOLEX-treated patients compared with 1% in patients on placebo.Less than 1% of EPIDIOLEX-treated patients had ALT or AST levels greater than 20times the ULN.There were cases of transaminase elevations associated with hospitalization in patients taking EPIDIOLEX. In clinical trials, serum transaminase elevations typically occurred in the first two months of treatment initiation; however, there were some cases observed up to 18 months after initiation of treatment, particularly in patients taking concomitant valproate. Resolution of transaminase elevations occurred with discontinuation of EPIDIOLEX or reduction of EPIDIOLEX and/or concomitant valproate in about two-thirds of the cases. In about one-third of the cases, transaminase elevations resolved during continued treatment with EPIDIOLEX, without dose reduction. Risk Factors fo r Transaminase Elevation Concomitant Valproate and Clobazam The majority of ALT elevations occurred in patients taking concomitant valproate[see Drug Interactions ( 7.3 )] .Concomitant use of clobazam also increased the incidence of transaminase elevations, although to a lesser extent than valproate[se e Drug Interactions ( 7.2 )] .In EPIDIOLEX-treated patients, the incidence of ALT elevations greater than 3 times the ULN was 30% in patients taking both concomitant valproate and clobazam,21% in patients taking concomitant valproate (without clobazam), 4% in patients taking concomitant clobazam (without valproate), and 3% in patients taking neither drug. Consider discontinuation or dose adjustment ofvalproate or clobazam if liver enzyme elevations occur. Dose Transaminase elevations are dose-related. Overall, ALT elevations greater than 3 times the ULN were reported in 17%of patients taking EPIDIOLEX20 mg/kg/day compared with 1% in patients takingEPIDIOLEX 10 mg/kg/day. Baseline T ransaminase E levations Patients with baselinetransaminase levels above the ULN had higher rates of transaminase elevationswhen taking EPIDIOLEX. In controlled trials (Studies 1, 2, and 3) in patients taking EPIDIOLEX 20 mg/kg/day,the frequency of treatment-emergent ALT elevations greater than 3 times the ULN was 30% when ALT wasabove the ULN at baseline,compared to 12% when ALT was within the normal range atbaseline.No patients taking EPIDIOLEX10mg/kg/dayexperienced ALT elevations greater than 3 times the ULN when ALT wasabove the ULN at baseline, compared with 2% of patients in whom ALT was within the normal range at baseline. Monitoring In general, transaminase elevations of greater than 3 times the ULN in the presence of elevated bilirubin without an alternative explanation are an important predictor of severe liver injury. Early identification of elevated liver enzymes may decrease the risk of a serious outcome. Patients with elevated baseline transaminase levels above 3 times the ULN, accompanied by elevations in bilirubin above 2 times the ULN, should be evaluated prior to initiation of EPIDIOLEX treatment. Prior to starting treatment with EPIDIOLEX, obtain serum transaminases (ALT and AST) and total bilirubin levels. Serum transaminases and total bilirubin levels should be obtained at 1 month, 3 months, and 6 months after initiation of treatment with EPIDIOLEX, and periodically thereafter or as clinically indicated. Serum transaminases and total bilirubin levels should also be obtained within 1 month following changes in EPIDIOLEX dosage and addition of or changes in medications that are known to impact the liver. Consider more frequent monitoring of serum transaminases and bilirubin in patients who are taking valproate or who have elevated liver enzymes at baseline. If a patient develops clinical signs or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, right upper quadrant abdominal pain, fatigue, anorexia, or jaundice and/or dark urine), promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment with EPIDIOLEX, as appropriate.Discontinue EPIDIOLEX in any patients with elevations oftransaminase levels greater than 3times the ULN and bilirubin levels greater than 2 times the ULN. Patients with sustained transaminase elevations of greater than 5 times the ULN should also have treatment discontinued. Patients with prolonged elevations of serum transaminases should be evaluated for other possible causes. Consider dosage adjustment of any co-administered medicationthat is known to affectthe liver (e.g., valproate and clobazam). 5. 2 Somnolence and Sedation EPIDIOLEXcan cause somnolence and sedation.In controlled studies for LGS and DS, the incidence of somnolence and sedation (includinglethargy) was 32% in EPIDIOLEX-treated patients, compared with 11% in patients on placebo and was dose-related (34%of patients taking EPIDIOLEX20mg/kg/day, compared with 27% in patients takingEPIDIOLEX 10 mg/kg/day).The rate was higher inpatients on concomitant clobazam(46% in EPIDIOLEX-treated patients taking clobazam compared with 16% in EPIDIOLEX-treated patients not on clobazam).In general,these effects were more common early in treatment and may diminish with continued treatment. Other CNS depressants, including alcohol, could potentiate the somnolence and sedation effect of EPIDIOLEX. Prescribers should monitor patients for somnolence and sedation and should advise patients not to drive or operate machinery until they have gained sufficient experience on EPIDIOLEXto gauge whether it adversely affects their ability to drive or operate machinery. 5.3 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including EPIDIOLEX, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with an AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12weeks, the estimated incidence rate of suicidal behavior or ideation among 27863 AED-treated patients was 0.43%, compared to 0.24% among 16029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5100 years) in the clinical trials analyzed. Table 2shows absolute and relative risk by indication for all evaluated AEDs. Table 2 : Risk of Suicidal Thoughts or Behaviors by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials in patients with epilepsy than in clinical trials in patients with psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing EPIDIOLEX or any other AED must balance the risk of suicidal thoughts or behaviors with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. 5. 4 Hypersensitivity Reactions EPIDIOLEX can cause hypersensitivity reactions. One subject in the EPIDIOLEX clinical trials had pruritus, erythema, and angioedema requiring treatment with antihistamines.Patients with known or suspected hypersensitivity to any ingredients of EPIDIOLEX were excluded from the clinical trials. If a patient develops hypersensitivity reactions after treatment with EPIDIOLEX, the drug should be discontinued. EPIDIOLEX is contraindicated in patients with a prior hypersensitivity reaction to cannabidiol or any of the ingredients in the product, which includes sesame seedoil[see Description ( 11 )] . 5. 5 Withdrawal of Antiepileptic Drugs (AEDs) As with most antiepileptic drugs, EPIDIOLEX should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus [see Dosage and Administration ( 2.4 ) and Clinical Studies ( 14 )].But if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.
DRUG INTERACTIONS SECTION.
7 DRUG INTERACTIONS Moderate or strong inhibitors of CYP3A4 or CYP2C19: Consider dose reduction of EPIDIOLEX. (7.1) Strong inducer of CYP3A4 or CYP2C19: Consider dose increase of EPIDIOLEX. (7.1) Consider a dose reduction of substrates of UGT1A9, UGT2B7, CYP2C8, CYP2C9, and CYP2C19 (e.g., clobazam). (7.2) Substrates of CYP1A2 and CYP2B6 may also require dose adjustment. (7.2) 7.1 Effect of Other Drugs on EPIDIOLEX Moderate or Strong Inhibitors of CYP3A4 or CYP2C19 EPIDIOLEX is metabolized by CYP3A4 and CYP2C19. Therefore, coadministration with a moderate or strong inhibitor of CYP3A4 or CYP2C19 will increase cannabidiol plasma concentrations,which may result in agreater risk ofadverse reactions[ see Clinical Pharmacology ( 12.3 ) ] .Consider a reduction in EPIDIOLEX dosage when coadministered with a moderate or strong inhibitor of CYP3A4 or CYP2C19. Strong CYP3A4 or CYP2C19 Inducers Coadministration with a strong CYP3A4 or CYP2C19 inducer will decrease cannabidiol plasma concentrations, which may lowerthe efficacyof EPIDIOLEX[ see Clinical Pharmacology ( 12.3 ) ]. Consider an increase in EPIDIOLEX dosage (based on clinical response and tolerability) when coadministered with a strong CYP3A4 or CYP2C19 inducer. 7. 2 Effect of EPIDIOLEX on Other Drugs UGT1A9, UGT2B7, CYP1A2, CYP2B6 , CYP2C8, CYP2C9 and CYP2C19 Substrates In vitro data predict drug-drug interactions with CYP1A2 substrates (e.g., theophylline, caffeine), CYP2B6 substrates (e.g., bupropion, efavirenz), uridine 5' diphospho-glucuronosyltransferase 1A9 (UGT1A9) (e.g., diflunisal, propofol, fenofibrate), and UGT2B7 (e.g., gemfibrozil, lamotrigine, morphine, lorazepam) when coadministered with EPIDIOLEX. Coadministration of EPIDIOLEX is also predicted to cause clinically significant interactions with CYP2C8 and CYP2C9 (e.g., phenytoin) substrates. Because of potential inhibition of enzyme activity, consider a reduction in dosage of substrates of UGT1A9, UGT2B7, CYP2C8, and CYP2C9, as clinically appropriate, if adverse reactions are experienced when administered concomitantly with EPIDIOLEX.Because of potential for both induction and inhibition of enzyme activity, consider adjustingdosage of substrates of CYP1A2 and CYP2B6, as clinically appropriate. Sensitive CYP2C19 Substrates In vivo data show that coadministration of EPIDIOLEX increases plasma concentrations of drugs that are metabolized by (i.e., are substrates of) CYP2C19 (e.g., diazepam) and may increase the risk of adverse reactions with these substrates [see Clinical Pharmacology ( 12.3 )]. Consider a reduction in dosage of sensitive CYP2C19 substrates, as clinically appropriate, when coadministered with EPIDIOLEX. Clobazam Coadministration of EPIDIOLEX produces a 3-fold increase in plasma concentrations of N-desmethylclobazam, the active metabolite of clobazam(a substrate of CYP2C19) [ see Clinical Pharmacology ( 12.3 ) ].This may increase the risk of clobazam-related adverse reactions [see Warnings and Precautions ( 5.1 , 5.2 )]. Consider a reduction in dosage of clobazam if adverse reactions known to occur with clobazam are experienced when co-administered with EPIDIOLEX. 7.3 Concomitant Use of EPIDIOLEX and Valproate Concomitant use of EPIDIOLEX and valproate increases the incidence of liver enzyme elevations [see Warnings and Precautions ( 5.1 )].Discontinuation or reduction of EPIDIOLEX and/or concomitant valproateshould be considered. Insufficient data are available to assess the risk of concomitant administration of other hepatotoxic drugs and EPIDIOLEX. 7.4 CNS Depressants and Alcohol Concomitant use of EPIDIOLEX with other CNS depressants may increase the risk of sedation and somnolence[see Warnings and Precautions ( 5.2 )].
NONCLINICAL TOXICOLOGY SECTION.
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis and Mutagenesis Carcinogenesis Adequate studies of the carcinogenic potential of cannabidiol have not been conducted. Mutagenesis Cannabidiol was negative for genotoxicity in in vitro(Ames)and in vivo(rat Comet and bone marrow micronucleus) assays. Impairment of Fertility Oral administration of cannabidiol (0, 75, 150, or 250 mg/kg/day) to male and female rats, prior to and throughout mating and continuing in females during early gestation, produced no adverse effects on fertility.The highest dose tested was associated with plasma exposures approximately 60 times that in humans at the maximum recommended human dose (20 mg/kg/day).
USE IN SPECIFIC POPULATIONS SECTION.
8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm.(8.1) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposedto antiepileptic drugs (AEDs), such as EPIDIOLEX, during pregnancy. Encourage women whoare taking EPIDIOLEX during pregnancy to enroll in the North American Antiepileptic Drug(NAAED) Pregnancy Registry by calling the toll free number 1-888-233-2334 or visitinghttp://www.aedpregnancyregistry.org/. Risk Summary There are no adequate data on the developmental risks associated with the use ofEPIDIOLEX in pregnant women.Administration of cannabidiol to pregnant animals produced evidence of developmental toxicity (increased embryofetal mortality in rats and decreased fetal body weights in rabbits; decreased growth, delayed sexual maturation,long-term neurobehavioral changes, and adverse effects on the reproductive system in rat offspring) at maternal plasma exposures similar to (rabbit)or greater than (rat) that in humans at therapeutic doses( see Animal Data) .In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 24% and 1520%, respectively. The background risks of major birth defects and miscarriage for the indicated populations are unknown. Data Animal Data Oral administration of cannabidiol (0,75, 150, or 250mg/kg/day) to pregnant rats throughout the period of organogenesis resulted inembryofetal mortality at the highest dose tested. There were no other drug-related maternal or developmental effects. The highest no-effect dose for embryofetal toxicityin rats was associated with maternal plasma cannabidiol exposures (AUC) approximately 16timesthat in humans at therecommended human dose (RHD) of 20mg/kg/day. Oral administration of cannabidiol (0, 50, 80, or 125 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in decreased fetal body weights and increased fetal structural variations at the highest dose tested, which was also associated with maternal toxicity. Maternal plasma cannabidiol exposuresat the no-effect level for embryofetal developmental toxicity in rabbits wereless than that in humans at the RHD. When cannabidiol (75, 150, or 250mg/kg/day) was orally administered to rats throughout pregnancy and lactation, decreased growth, delayed sexual maturation, neurobehavioral changes (decreased activity), and adverse effects on male reproductive organ development (small testes in adult offspring) and fertilitywere observed in the offspring at the mid and high dose. These effects occurred in the absence of maternal toxicity. The no-effect dosefor pre- and postnatal developmental toxicity in rats was associated with maternal plasma cannabidiol exposures approximately 9 times that in humans at the RHD. 8.2 Lactation Risk Summary There are no data on the presence of cannabidiolor its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for EPIDIOLEX and any potential adverse effects on the breastfed infant from EPIDIOLEX or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness of EPIDIOLEX for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome have been established in patients 2 years of age and older. Safety and effectiveness of EPIDIOLEX in pediatric patients below 2 years of age have not been established. Juvenile Animal Data Administration of cannabidiol (subcutaneous doses of 0 or 15 mg/kg on Postnatal Days (PNDs) 4-6 followed by oral administration of 0, 100, 150, or 250 mg/kg on PNDs 7-77) to juvenile rats for 10 weeks resulted in increased body weight, delayed male sexual maturation, neurobehavioral effects (decreased locomotor activity and auditory startle habituation),increased bone mineral density, and liver hepatocyte vacuolation. A no-effect dose was not established. The lowest dose causing developmental toxicity in juvenile rats (15 sc/100 po mg/kg) was associated with cannabidiol exposures approximately 30times thatin humans at the recommended dose of 20 mg/kg/day. 8.5 Geriatric Use Clinical trials of EPIDIOLEX in the treatment of LGS and DS did not include any patients aged above 55years to determine whether or not they respond differently from 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[see Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.1 ) , and Clinical Pharmacology ( 12.3 ) ]. 8. 6 Hepatic Impairment Because of an increase in exposure to EPIDIOLEX, dosage adjustments are necessary in patients with moderate or severe hepatic impairment [see Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.1 ), and Clinical Pharmacology ( 12.3 )]. EPIDIOLEX does not require dosageadjustments in patients with mild hepatic impairment.
INFORMATION FOR PATIENTS SECTION.
17 PATIENT COUNSELING INFORMATION Advise the caregiver or patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Administration Information Advise patients who are prescribed EPIDIOLEX to use the adapter and oral dosing syringes provided[see Dosage and Administration n ( 2.3 ) and Instructions for Use ]. Instruct patients to discard any unused EPIDIOLEX oral solution after 12 weeks of first opening the bottle [see Dosage and Administration ( 2.3 )]. Hepatocellular Injury Inform patients about the potential for elevations of liver enzymes. Discuss with the patient the importance of measuring hepatic laboratory values and having them evaluated by the healthcare provider beforetreatment with EPIDIOLEXand periodically during treatment[see Warnings and Precautions ( 5.1 ) ]. Advise patients of the clinical signs or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine) and to contact a healthcare provider promptly if these signs or symptoms occur. Somnolence and Sedation Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that EPIDIOLEX does not affect them adversely (e.g., impair judgment, thinking or motor skills) [see Warnings and Precautions ( 5.2 ) ]. Suicidal Thinking and Behavior Counsel patients, their caregivers, and their families that antiepileptic drugs, including EPIDIOLEX, may increase the risk of suicidal thoughts and behavior and advise them to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts of self-harm. Instruct patients, caregivers, and families to report behaviors of concern immediately to healthcare providers[see Warnings and Precautions ( 5.3 ) ]. Withdrawal of Antiepileptic Drugs (AEDs) Advise patients not to discontinue use of EPIDIOLEX without consulting with their healthcare provider. EPIDIOLEX should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus[see Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.4 ) ]. Pregnancy Registry Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during EPIDIOLEX therapy. Encourage women who are taking EPIDIOLEX to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant.This registry is collecting information about the safety of antiepileptic drugs during pregnancy [ s ee Use in Specific Populations ( 8.1 ) ]. Drug Testing Advise patients of the potential for positive cannabis drug screens. Marketed by Greenwich Biosciences, Inc., Carlsbad, CA 92008 USA 2020 Greenwich Biosciences, Inc. All rights reserved.
CLINICAL STUDIES SECTION.
14 CLINICAL STUDIES 14. 1 Lennox Gastaut Syndrome The effectiveness of EPIDIOLEX for the treatment of seizures associated with LGS was established in two randomized, double-blind, placebo-controlledtrials in patients aged 2 to 55 years. Study 1(N=171) compared a dose of EPIDIOLEX 20mg/kg/day with placebo.Study 2(N=225) compared a 10mg/kg/day dose and a 20mg/kg/day dose of EPIDIOLEX with placebo.In both studies, patients had a diagnosisof LGS and were inadequately controlled on at leastoneAED, with or without vagal nerve stimulation and/or ketogenic diet. Both trials had a 4-week baseline period, during which patients were required to have a minimum of 8 drop seizures (2 drop seizures per week).The baseline period was followed by a 2-week titration period and a 12-week maintenance period. InStudy 1, 94% of patients were taking at least 2concomitant AEDs. The most frequently used concomitant AEDs (>25%) in Study 1 were clobazam (49%), valproate(40%), lamotrigine (37%), levetiracetam (34%), and rufinamide (27%).In Study 2, 94% of patients were taking at least 2 concomitant AEDs. The most frequently usedconcomitant AEDs (>25%)in Study 2, wereclobazam(49%), valproate(38%), levetiracetam (31%), lamotrigine(30%), and rufinamide(29%). The primary efficacy measure in both studieswas the percent change from baseline in the frequency (per 28 days) of drop seizures (atonic, tonic, or tonic-clonic seizures)over the 14-week treatment period. Key secondary endpoints in both studies included analyses of change in total seizure frequency and changes from baseline in the Subject/Caregiver Global Impression of Change (S/CGIC) score at the last visit.For the S/CGIC, the following question was rated on a 7-point scale: Since [you/your child] started treatment, please assess the status of [your/your childs] overall condition (comparing [your/their] condition now to [your/their] condition before treatment) using the scale below. The 7-point scale was as follows: Very Much Improved (1); Much Improved (2); Slightly Improved (3); No Change (4); Slightly Worse (5); Much Worse (6); Very Much Worse (7). In Studies 1 and 2, the median percent change from baseline (reduction) in the frequency of drop seizureswas significantly greater for both dosage groups of EPIDIOLEX than for placebo (Table 4).A reduction in drop seizures was observed within 4 weeks of initiating treatment with EPIDIOLEX, and the effect remained generally consistent over the 14-week treatment period. Table 4 : Change in Drop Seizure Frequency in Lennox Gastaut Syndrome during the Treatment Period ( Stud ies 1 and 2 ) Drop Seizure Frequency (per 28 Days) Placebo EPIDIOLEX 10 mg/kg/day EPIDIOLEX 20 mg/kg/day Study 1 N =85 N/A N =86 Baseline Period Median 75 N/A 71 Median Percentage Change During Treatment -22 N/A -44 p-value compared to placebo 0.01 Study 2 N =76 N =73 N =76 Baseline Period Median 80 87 86 Median Percentage Change During Treatment -17 -37 -42 p-value compared to placebo 14. 2 Dravet Syndrome Theeffectivenessof EPIDIOLEX for the treatment of seizures associated with DS was demonstrated in a single randomized, double-blind, placebo-controlledtrial in 120 patients aged 2 to 18 years. Study 3 compared a dose of EPIDIOLEX 20 mg/kg/day with placebo. Patients had a diagnosis of treatment-resistant DS and were inadequately controlled with at least one concomitant AED, with or without vagal nerve stimulation or ketogenic diet. During the 4-week baseline period, patients were required to have at least 4convulsive seizures while on stable AED therapy. The baseline period was followed by a 2-week titration period and a 12-week maintenance period. The primary efficacy measure was the percent change from baseline in the frequency (per 28 days) of convulsive seizures(all countable atonic, tonic, clonic, and tonic-clonic seizures) over the 14-week treatment period. In Study 3, 93% of patients were taking at least2 concomitant AEDs during the trial. The most commonly used concomitant AEDs (>25%) in Study 3 were clobazam (65%), valproate (57%), stiripentol (43%), levetiracetam (28%), and topiramate (26%).The baseline median convulsive seizure frequency was 13 per 28 days for the combined groups. The median percent change from baseline (reduction) in the frequency of convulsive seizures was significantly greater for EPIDIOLEX 20mg/kg/day than for placebo (see Table 5). A reduction in convulsive seizures was observed within 4 weeks of initiating treatment with EPIDIOLEX and the effect remained generally consistent over the 14-week treatment period. Table 5 : Change in Convulsive Seizure Frequency in Dravet Syndrome during the Treatment Period ( Study 3 ) Total Convulsive Seizure Frequency (per 28 Days) Placebo EPIDIOLEX 20 mg/kg/day Study 3 N=59 N=61 Baseline Period Median 15 12 Median Percentage Change During Treatment -13 -39 p-value compared to placebo 0.01 Figure 3displays the percentage of patients by category of reduction from baseline in convulsive seizure frequency (per 28 days) during the treatment period in Study 3. Figure 3 : Proportion of Patients by Category of Seizure Response for EPIDIOLEX and Placebo in Patients with Dravet Syndrome ( Study 3 ) In Study 3, 4 of 60 (6.7%) patients treated with EPIDIOLEX 20 mg/kg/dayreported noconvulsive seizures during the maintenance period, compared to 0 patients in the placebo group.
CLINICAL PHARMACOLOGY SECTION.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The precise mechanisms by which EPIDIOLEX exerts its anticonvulsant effect in humans areunknown. Cannabidiol does not appear to exert its anticonvulsant effects through interaction with cannabinoid receptors. 12.2 Pharmacodynamics There are no relevantdataon the pharmacodynamic effects of cannabidiol. 12.3 Pharmacokinetics Cannabidiol demonstrated an increase in exposure that was less than dose-proportional over the range of 5to 20mg/kg/day in patients. Absorption Cannabidiol has a time to maximum plasma concentration (Tmax) of 2.5 to 5hours at steady state (Css). Effect of Food Coadministration of EPIDIOLEXwith a high-fat/high-calorie meal increased Cmaxby 5-fold, AUC by 4-fold, and reduced the total variability, compared with the fasted state in healthy volunteers[see Dosage and Administration ( 2.2 )]. Distribution The apparent volume of distribution in healthy volunteers was20963L to 42849L. Protein binding of the cannabidiol and its metabolites was >94% in vitro. Elimination The half-life of cannabidiol in plasma was 56 to 61 hours after twice-daily dosing for 7 days in healthy volunteers. The plasma clearance of cannabidiol following a single EPIDIOLEX 1500 mg dose (1.1 times the maximum recommended daily dosage) is 1111 L/h. Metabolism Cannabidiol is metabolized in the liver and the gut (primarily inthe liver)by CYP2C19 and CYP3A4 enzymes, and UGT1A7, UGT1A9, and UGT2B7 isoforms. After repeat dosing,the active metabolite of cannabidiol,7-OH-CBD,has a38% lower AUC thanthe parent drug.The 7-OH-CBD metabolite is converted to 7-COOH-CBD, which has an approximately 40-fold higherAUC thanthe parent drug. Based on preclinical models of seizure, the 7-OH-CBD metabolite is active; however, the 7-COOH-CBD metabolite is not active. Excretion EPIDIOLEX is excreted in feces, with minor renal clearance. S pecific Populations Patients with Hepatic Impairment No effects on the exposures of cannabidiol or metabolite exposures were observed following administration of a single dose of EPIDIOLEX 200 mg in patients with mild (Child-Pugh A) hepatic impairment. Patientswith moderate(Child-Pugh B)or severe(Child-Pugh C) hepatic impairment had an approximately 2.5 to 5.2-fold higher AUC, compared with healthy volunteerswith normal hepatic function [ see Dos ag e and Administration ( 2.5 ), Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.6 )] . Drug Interaction Studies In Vitro Assessment of Drug Interactions Drug Metabolizing Enzymes [see Drug Interactions ( 7.1 , 7.2 )] Cannabidiol is a substrate for cytochrome p450 (CYP) enzymes CYP3A4 and CYP2C19. Cannabidiol has the potential to inhibit CYP2C8, CYP2C9, and CYP2C19 at clinically relevant concentrations. Cannabidiol may induce or inhibitCYP1A2 and CYP2B6 at clinically relevant concentrations. Cannabidiol inhibits uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes UGT1A9 and UGT2B7, but does not inhibit the UGT1A1, UGT1A3, UGT1A4, UGT1A6, or UGT2B17 isoforms. Transporters Cannabidiol and the cannabidiol metabolite, 7-OH-CBD, are not anticipated to interact with BCRP, BSEP, MDR1/P-pg, OAT1, OAT3, OCT1, OCT2, MATE1, MATE2-K, OATP1B1, or OATP1B3. The cannabidiol metabolite, 7-COOH-CBD,is not a substrate of BCRP, OATP1B1, OATP1B3, or OCT1. However, 7-COOH-CBD is a substrate for P-gp.7-COOH-CBDis an inhibitor of transport mediated via BCRP and BSEP at clinically relevant concentrations. In Vivo Assessment of Drug Interactions Drug Interaction Studies with AEDs Clobazam and Valproate The interaction potential with other AEDs (clobazam and valproate) was evaluated in dedicated clinical studies following coadministration of EPIDIOLEX (750 mg twice daily in healthy volunteers and 20 mg/kg/day in patients). Coadministration with clobazam in healthy volunteers increased the cannabidiol active metabolite 7-OH CBD mean Cmax by 73% and AUC by 47%; and increased the clobazam active metabolite, N-desmethylclobazam, Cmax and AUC by approximately 3-fold [see Drug Interactions ( 7.2 )]. When EPIDIOLEX was coadministered with valproate, there was no effect on valproate exposure. Effect of EPIDIOLEX on Midazolam Coadministration of EPIDIOLEX with midazolam (a sensitive CYP3A4 substrate) did not result in changes in plasma concentrations of midazolam compared to midazolam administered alone.
4 CONTRAINDICATIONS EPIDIOLEX is contraindicated in patientswith a history of hypersensitivity tocannabidiolor any of the ingredients in the product[see Description ( 11 ) and Warnings and Precautions ( 5.4 ) ] . Hypersensitivity to cannabidiol or any of the ingredients in EPIDIOLEX(4)