Cannabis (Cannabis sativa)
Drug Approval Package: Epidiolex (Cannabidiol) CSV JSON

U.S. Food and Drug Administration
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210365Orig1s000TOC.cfm

Cannabis (Cannabis sativa)

FDA: 210365 Orig 1

1 . CBD effect on CLB and N-desmethylclobazam (id=NPDI-kJ7mIQ)

In Vivo Interaction Study

Increased systemic exposure was detected.

clobazam

cannabidiol (cbd)

Study GWEP1543

Results

Clobazam exposure was increased slightly (~20%) by co-administration with CBD while exposure to the n-desmethylclobazam metabolite was increased by 3.4 fold as a result of concommitant CBD.

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

Fixed-sequence
Parallel
Multiple dosing

Population

Females
Healthy volunteers
Males

12

Arm 1, Group 1

Drug or Natural Product Administration

Object Administration — clobazam

Oral

Not specified

10 mg

5 mg BID

14 days

Precipitant Administration — cannabidiol (cbd)

Oral

Solution

1500 mg

750 mg BID

14 days

Natural Product Characteristics

Not specified

2 . CBD Effect on N-desmethylclobazam Concentrations (id=NPDI-_jX3DQ)

In Vivo Interaction Study

Increased systemic exposure was detected.

n-desmethylclobazam

cannabidiol (cbd)

From page 109 of "Clinical Pharmacology Biopharmaceutics Review"

Results

From page 109

Units for these values are NOT means but are instead a ratio of day 33 values:day 1 values

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

Double-blind
Placebo-controlled
Randomized crossover
Multiple dosing

Population

Females
Males
Patients

CYP2C19 intermediate metabolizer
CYP2C19 rapid metabolizer
CYP2C19 ultra-rapid metabolizer

20

"A total of 20 patients were randomized to receive 20 mg/kg/day of CBD or placebo on a 4:1 basis."

Pharmacokinetic (PK) Sampling Information

Predose; postdose: 15 and 30 m, 1, 1.5, 2, 4, 6, 12 and 24 h

Drug or Natural Product Administration

Object Administration — n-desmethylclobazam

Oral

Not stated

Not stated

Not stated

31 d

Precipitant Administration — cannabidiol (cbd)

Oral

Solution

20 mg/kg

BID

31 d

Natural Product Characteristics

Not stated

10-day titration, 21 days at maintenance dose of 20 mg/kg/day

3 . CBD Effect on Stiripentol Concentrations (id=NPDI-8_xKYg)

In Vivo Interaction Study

Increased systemic exposure was detected.

stiripentol

cannabidiol (cbd)

Study GWEP1543

Results

When CBD was combined with stiripentol there was a minor increase in Cmax and AUCtau; 1.28 and 1.55-fold, respectively.

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

Fixed-sequence
Parallel
Multiple dosing

Population

Females
Healthy volunteers
Males

12

Arm 1, Group 3

Drug or Natural Product Administration

Object Administration — stiripentol

Oral

Not stated

1500 mg

750 mg BID

14 days

Precipitant Administration — cannabidiol (cbd)

Oral

Solution

1500 mg

750 mg BID

14 days

Natural Product Characteristics

Not specified

4 . Clobazam Effect on 6-OH-CBD (id=NPDI-z3MwKw)

In Vivo Interaction Study

No Effect (based on bioequivalence limits) was detected.

6α-oh-cannabidiol

clobazam

Study GWEP1543

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

Fixed-sequence
Parallel
Multiple dosing

Population

Females
Healthy volunteers
Males

16

Arm 2, Group 2

Drug or Natural Product Administration

Object Administration — 6α-oh-cannabidiol

Oral

Solution

1500 mg

750 mg BID

21 days

Precipitant Administration — clobazam

Oral

Not specified

10 mg

5 mg BID

21 days

Natural Product Characteristics

Not specified

5 . Clobazam Effect on 7-COOH-CBD (id=NPDI-ZM5Pkw)

In Vivo Interaction Study

No Effect (based on bioequivalence limits) was detected.

7-cooh-cbd

clobazam

Study GWEP1543

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

Fixed-sequence
Parallel
Multiple dosing

Population

Females
Healthy volunteers
Males

16

Arm 2, Group 2

Drug or Natural Product Administration

Object Administration — 7-cooh-cbd

Oral

Solution

1500 mg

750 mg BID

21 days

Precipitant Administration — clobazam

Oral

Not specified

10 mg

5 mg BID

21 days

Natural Product Characteristics

Not specified

6 . Clobazam Effect on 7-OH-CBD (id=NPDI-9oyo4g)

In Vivo Interaction Study

No Effect (based on bioequivalence limits) was detected.

7-hydroxycannabidiol

clobazam

Study GWEP1543

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

Fixed-sequence
Parallel
Multiple dosing

Population

Females
Healthy volunteers
Males

16

Arm 2, Group 2

Drug or Natural Product Administration

Object Administration — 7-hydroxycannabidiol

Oral

Solution

1500 mg

750 mg BID

21 days

Precipitant Administration — clobazam

Oral

Not specified

10 mg

5 mg BID

21 days

Natural Product Characteristics

Not specified

7 . Clobazam Effect on CBD (id=NPDI-4EVwQw)

In Vivo Interaction Study

No Effect (based on bioequivalence limits) was detected.

cannabidiol (cbd)

clobazam

Study GWEP1543

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

Fixed-sequence
Parallel
Multiple dosing

Population

Females
Healthy volunteers
Males

16

Arm 2, Group 2

Drug or Natural Product Administration

Object Administration — cannabidiol (cbd)

Oral

Solution

1500 mg

750 mg BID

21 days

Precipitant Administration — clobazam

Oral

Not specified

10 mg

5 mg BID

21 days

Natural Product Characteristics

Not specified

8 . Stiripentol Effect on CBD, 6-OH-CBD, and 7-COOH-CBD (id=NPDI-2TMzVA)

In Vivo Interaction Study

No Effect (based on bioequivalence limits) was detected.

cannabidiol (cbd)

stiripentol

Study GWEP1543

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

Fixed-sequence
Parallel
Multiple dosing

Population

Females
Healthy volunteers
Males

12

Arm 2, Group 4

Drug or Natural Product Administration

Object Administration — cannabidiol (cbd)

Oral

Solution

1500 mg

750 mg BID

4 days

Precipitant Administration — stiripentol

Oral

Not specified

1500 mg

750 mg BID

4 days

Natural Product Characteristics

Not specified

9 . Valproic Acid Effect on Cannabidiol Metabolites (id=NPDI-AEDMtg)

In Vivo Interaction Study

No Effect (based on bioequivalence limits) was detected.

cannabidiol (cbd)

valproic acid

Study GWEP1543

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

Fixed-sequence
Parallel
Multiple dosing

Population

Females
Healthy volunteers
Males

14

Arm 2, Group 6

Drug or Natural Product Administration

Object Administration — cannabidiol (cbd)

Oral

Solution

1500 mg

750 mg BID

9 days

Precipitant Administration — valproic acid

Oral

Not specified

1000 mg

500 mg BID

9 days

Natural Product Characteristics

Not specified

10 . CBD Effect on clobazam and N-desmethylclobazam (id=NPDI-Y9U8Tw)

In Vivo Interaction Study

No Effect (based on bioequivalence limits) was detected.

clobazam

cannabidiol (cbd)

Study GWEP1428 (p 106)

Results

Test ratios indicate the Day33:Day 1 ratio for individuals allocated to active drug.
Control ratios indicate the Day 33:Day ratio for individuals allocated to placebo.

CBD did not alter Cmax or AUC of clobazam but did increase exposure to the N-desmethylclobazam metabolite.

Data from page 109

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

Double-blind
Placebo-controlled
Randomized crossover
Multiple dosing

Population

Females
Males
Patients

CYP2C19 intermediate metabolizer
CYP2C19 rapid metabolizer
CYP2C19 ultra-rapid metabolizer

20

"A total of 20 patients were randomized to receive 20 mg/kg/day of CBD or placebo on a 4:1 basis."

Pharmacokinetic (PK) Sampling Information

Predose; post-dose: 15 and 30 m, 1, 1.5, 2, 4, 6, 12, 24 hr

Drug or Natural Product Administration

Object Administration — clobazam

Oral

Not stated

Not stated

Not stated

31 d

Precipitant Administration — cannabidiol (cbd)

Oral

Solution

20 mg/kg

BID

31 d

Natural Product Characteristics

Not stated

10-day titration, 21 days maintenance of 20 mg/kg/day; CBD/placebo was taken twice daily immediately after patients' clobazam dose

11 . CBD Effect on Midazolam (id=NPDI-d2rDLg)

In Vivo Interaction Study

No Effect (based on bioequivalence limits) was detected.

midazolam 708298

cannabidiol (cbd)

Systemic exposure to midazolam was relatively unaffected by concomitant administration of CBD indicating lack of inhibition or induction of CYP3A4. The increased exposure to 1'-hydroxymidazolam may be due to downstream inhibition of glucuronidation by UGT2B7. Further details can be found in "Clinical Pharmacology Biopharmaceutics Review(s)"

Results

C estimated from Fig 8; page 111

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

Fixed-sequence
Single dosing

Population

Females
Healthy volunteers
Males

16

Pharmacokinetic (PK) Sampling Information

Predose; 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 14, 18, 24 h

Drug or Natural Product Administration

Object Administration — midazolam

Oral

Solution

2.5 mg

Once

Once

Precipitant Administration — cannabidiol (cbd)

Oral

Solution

escalating dosing until 750 mg

BID

25 days

Natural Product Characteristics

Not stated

Information from Study GWEP17028 (starting page 109)

Subjects received a single 2.5 mg oral midazolam dose on Day -1 (reference). Subjects then recieved "escalating doses of CBD from Day 1 (250 mg once daily) to Day 11 (750 mg twice daily), followed by 14 days of 750 mg CBD b.i.d. (Days 12-25). On Day 25, subjects received a 2.5 mg oral dose of midazolam concurrently with the morning dose of CBD (test)"

12 . CBD Effect on Valproic Acid Concentrations (id=NPDI-wM7_CQ)

In Vivo Interaction Study

No Effect (based on bioequivalence limits) was detected.

valproic acid

cannabidiol (cbd)

Study GWEP1543

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

Fixed-sequence
Parallel
Multiple dosing

Population

Females
Healthy volunteers
Males

12

Arm 1, Group 5

Drug or Natural Product Administration

Object Administration — valproic acid

Oral

Not stated

1000 mg

500 mg BID

14 days

Precipitant Administration — cannabidiol (cbd)

Oral

Solution

1500 mg

750 mg BID

14 days

Natural Product Characteristics

Not specified

13 . Stiripentol Effect on 7-OH-CBD (id=NPDI-a9Sh7Q)

In Vivo Interaction Study

Decreased systemic exposure was detected.

7-hydroxycannabidiol

stiripentol

Study GWEP1543

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

Fixed-sequence
Parallel
Multiple dosing

Population

Females
Healthy volunteers
Males

12

Arm 2, Group 4

Drug or Natural Product Administration

Object Administration — 7-hydroxycannabidiol

Oral

Solution

1500 mg

750 mg BID

4 days

Precipitant Administration — stiripentol

Oral

Not specified

1500 mg

750 mg BID

4 days

Natural Product Characteristics

Not specified

14 . Valproic Acid Effect on CBD (id=NPDI-AWv-_A)

In Vivo Interaction Study

Decreased systemic exposure was detected.

cannabidiol (cbd)

valproic acid

Study GWEP1543

Results

Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

Fixed-sequence
Parallel
Multiple dosing

Population

Females
Healthy volunteers
Males

14

Arm 2, Group 6

Drug or Natural Product Administration

Object Administration — cannabidiol (cbd)

Oral

Solution

1500 mg

750 mg BID

9 days

Precipitant Administration — valproic acid

Oral

Not specified

1000 mg

500 mg BID

9 days

Natural Product Characteristics

Not specified