Naltrexone HCl and Bupropion HCl Extended-Release Tablets

CONTRAVE is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of:

• 30 kg/m² or greater (obese) or
• 27 kg/m² or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia).

Limitations Of Use

• The effect of CONTRAVE on cardiovascular morbidity and mortality has not been established.
• The safety and effectiveness of CONTRAVE in combination with other products intended for weight loss, including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established.

The following adverse reactions are discussed in other sections of the labeling:

• Suicidal Behavior and Ideation [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
• Neuropsychiatric Adverse Events [see WARNINGS AND PRECAUTIONS]
• Seizures [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS]
• Increase in Blood Pressure and Heart Rate [see WARNINGS AND PRECAUTIONS]
• Allergic Reactions [see WARNINGS AND PRECAUTIONS]
• Angle-Closure Glaucoma [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the 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.

CONTRAVE was evaluated for safety in five double-blind placebo controlled trials in 4,754 overweight or obese patients (3,239 patients treated with CONTRAVE and 1,515 patients treated with placebo) for a treatment period up to 56 weeks. The majority of patients were treated with CONTRAVE 32 mg/360 mg total daily dose. In addition, some patients were treated with other combination daily doses including naltrexone up to 50 mg and bupropion up to 400 mg. All subjects received study drug in addition to diet and exercise counseling. One trial (N=793) evaluated patients participating in an intensive behavioral modification program and another trial (N= 505) evaluated patients with type 2 diabetes. In these randomized, placebo-controlled trials, 2,545 patients received CONTRAVE 32 mg/360 mg for a mean treatment duration of 36 weeks (median, 56 weeks). Baseline patient characteristics included a mean age of 46 years, 82% women, 78% white, 25% with hypertension, 13% with type 2 diabetes, 56% with dyslipidemia, 25% with BMI greater than 40 kg/m², and less than 2% with coronary artery disease. Dosing was initiated and increased weekly to reach the maintenance dose within 4 weeks.

In CONTRAVE clinical trials, 24% of subjects receiving CONTRAVE and 12% of subjects receiving placebo discontinued treatment because of an adverse event. The most frequent adverse reactions leading to discontinuation with CONTRAVE were nausea (6.3%), headache (1.7%) and vomiting (1.1%).

Common Adverse Reactions

Adverse reactions that were reported by greater than or equal to 2% of patients, and were more frequently reported by patients treated with CONTRAVE compared to placebo, are summarized in Table 3.

Table 3: Adverse Reactions Reported by Obese or Overweight Patients With an Incidence (%) of at Least 2% Among Patients Treated with CONTRAVE and More Common than with Placebo

Adverse Reaction	CONTRAVE 32 mg/360 mg N=2545 %	Placebo N=1515 %
Nausea	32.5	6.7
Constipation	19.2	7.2
Headache	17.6	10.4
Vomiting	10.7	2.9
Dizziness	9.9	3.4
Insomnia	9.2	5.9
Dry mouth	8.1	2.3
Diarrhea	7.1	5.2
Anxiety	4.2	2.8
Hot flush	4.2	1.2
Fatigue	4.0	3.4
Tremor	4.0	0.7
Upper abdominal pain	3.5	1.3
Viral gastroenteritis	3.5	2.6
Influenza	3.4	3.2
Tinnitus	3.3	0.6
Urinary tract infection	3.3	2.8
Hypertension	3.2	2.2
Abdominal pain	2.8	1.4
Hyperhidrosis	2.6	0.6
Irritability	2.6	1.8
Blood pressure increased	2.4	1.5
Dysgeusia	2.4	0.7
Rash	2.4	2.0
Muscle strain	2.2	1.7
Palpitations	2.1	0.9

Other Adverse Reactions

The following additional adverse reactions were reported in less than 2% of patients treated with CONTRAVE but with an incidence at least twice that of placebo:

Cardiac Disorders: tachycardia, myocardial infarction

Ear and Labyrinth Disorders: vertigo, motion sickness

Gastrointestinal Disorders: lower abdominal pain, eructation, lip swelling, hematochezia, hernia

General Disorders and Administration Site Conditions: feeling jittery, feeling abnormal, asthenia, thirst, feeling hot

Hepatobiliary Disorders: cholecystitis

Infections and Infestations: pneumonia, staphylococcal infection, kidney infection

Investigations: increased blood creatinine, increased hepatic enzymes, decreased hematocrit

Metabolism and Nutrition Disorders: dehydration

Musculoskeletal and Connective Tissue Disorders: intervertebral disc protrusion, jaw pain

Nervous System Disorders: disturbance in attention, lethargy, intention tremor, balance disorder, memory impairment, amnesia, mental impairment, presyncope

Psychiatric Disorders: abnormal dreams, nervousness, dissociation (feeling spacey), tension, agitation, mood swings

Renal and Urinary Disorders: micturition urgency

Reproductive System and Breast Disorders: vaginal hemorrhage, irregular menstruation, erectile dysfunction, vulvovaginal dryness

Skin and Subcutaneous Tissue Disorders: alopecia

Psychiatric And Sleep Disorders

In the one-year controlled trials of CONTRAVE, the proportion of patients reporting one or more adverse reactions related to psychiatric and sleep disorders was higher in the CONTRAVE 32/360 mg group than the placebo group (22.2% and 15.5%, respectively). These events were further categorized into sleep disorders (13.8% CONTRAVE, 8.4% placebo), depression (6.3% CONTRAVE, 5.9% placebo), and anxiety (6.1% CONTRAVE, 4.4% placebo). Patients who were 65 years or older experienced more psychiatric and sleep disorder adverse reactions in the CONTRAVE group (28.6%) compared to placebo (6.3%), although the sample size in this subgroup was small (56 CONTRAVE, 32 placebo); the majority of these events were insomnia (10.7% CONTRAVE, 3.1% placebo) and depression (7.1% CONTRAVE, 3.1% placebo).

Neurocognitive Adverse Reactions

Adverse reactions involving attention, dizziness, and syncope occurred more often in individuals randomized to CONTRAVE 32/360 mg group compared to placebo (15.0% and 5.5%, respectively). The most common cognitive-related adverse reactions were attention disorders (2.5% CONTRAVE, 0.6% placebo). Adverse reactions involving dizziness and syncope were more common in patients treated with CONTRAVE (10.6%) than in placebo-treated patients (3.6%); dizziness accounted for almost all of these reported events (10.4% CONTRAVE, 3.4% placebo). Dizziness was the primary reason for discontinuation for 0.9% and 0.3% of patients in the CONTRAVE and placebo groups, respectively.

Increases In Serum Creatinine

In the one-year controlled trials of CONTRAVE, larger mean increases in serum creatinine from baseline to trial endpoint were observed in the CONTRAVE group compared with the placebo group (0.07 mg/dL and 0.01 mg/dL, respectively) as well as from baseline to the maximum value during follow-up (0.15 mg/dL and 0.07 mg/dL, respectively). Increases in serum creatinine that exceeded the upper limit of normal and were also greater than or equal to 50% higher than baseline occurred in 0.6% of subjects receiving CONTRAVE compared to 0.1% receiving placebo. An in vitro drug-drug interaction study demonstrated that bupropion and its metabolites inhibit organic cation transporter 2 (OCT2), which is involved in the tubular secretion of creatinine, suggesting that the observed increase in serum creatinine may be the result of OCT2 inhibition.

Based on in vitro results and FDA guidance for Drug Interaction Studies, the ratios of the free (unbound) Cmax and IC50 value of bupropion and hydroxybupropion were well below 0.1 suggesting a drug-drug interaction between CONTRAVE and OCT2 substrate due to bupropion and hydroxybupropion is unlikely. The ratio for the threohydrobupropion and erythrohydrobupropion metabolite mixture was 0.29, suggesting a drug-drug interaction between CONTRAVE and OCT2 due to threohydrobupropion and erythrohydrobupropion is possible.

Postmarketing Experience

Additional adverse reactions have been identified during post approval use of CONTRAVE. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Loss of consciousness, malaise

Mechanism Of Action

CONTRAVE has two components: naltrexone, an opioid antagonist, and bupropion, a relatively weak inhibitor of the neuronal reuptake of dopamine and norepinephrine. Nonclinical studies suggest that naltrexone and bupropion have effects on two separate areas of the brain involved in the regulation of food intake: the hypothalamus (appetite regulatory center) and the mesolimbic dopamine circuit (reward system). The exact neurochemical effects of CONTRAVE leading to weight loss are not fully understood.

Pharmacodynamics

Combined, bupropion and naltrexone increased the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons in vitro, which are associated with regulation of appetite. The combination of bupropion and naltrexone also reduced food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, an area associated with regulation of reward pathways.

Pharmacokinetics

Absorption

Naltrexone

Following single oral administration of CONTRAVE (two 8 mg naltrexone/90 mg bupropion tablets) to healthy subjects, mean peak naltrexone concentration (Cmax) was 1.4 ng/mL, time to peak concentration (Tmax) was 2 hours, and extent of exposure (AUC0-inf) was 8.4 ng•hr/mL.

Bupropion

Following single oral administration of CONTRAVE (two 8 mg naltrexone/90 mg bupropion tablets) to healthy subjects, mean peak bupropion concentration (Cmax) was 168 ng/mL, time to peak concentration (Tmax) was three hours, and extent of exposure (AUC0-inf) was 1,607 ng•hr/mL.

Food Effect On Absorption

When CONTRAVE was administered with a high-fat meal, the AUC and Cmax for naltrexone increased 2.1-fold and 3.7-fold, respectively, and the AUC and Cmax for bupropion increased 1.4-fold and 1.8-fold, respectively. At steady state, the food effect increased AUC and Cmax for naltrexone by 1.7-fold and 1.9-fold, respectively, and increased AUC and Cmax for bupropion by 1.1-fold and 1.3-fold, respectively. Thus, CONTRAVE should not be taken with high-fat meals because of the resulting significant increases in bupropion and naltrexone systemic exposure.

Distribution

Naltrexone

Naltrexone is 21% plasma protein bound. The mean apparent volume of distribution at steady state for naltrexone (Vss/F) is 5,697 liters.

Bupropion

Bupropion is 84% plasma protein bound. The mean apparent volume of distribution at steady state for bupropion (Vss/F) is 880 liters.

Metabolism And Excretion

Naltrexone

The major metabolite of naltrexone is 6-beta-naltrexol. The activity of naltrexone is believed to be the result of both the parent and the 6-beta-naltrexol metabolite. Though less potent, 6-beta-naltrexol is eliminated more slowly and thus circulates at much higher concentrations than naltrexone. Naltrexone and 6-beta-naltrexol are not metabolized by cytochrome P450 enzymes and in vitro studies indicate that there is no potential for inhibition or induction of important isozymes.

Naltrexone and its metabolites are excreted primarily by the kidney (53% to 79% of the dose). Urinary excretion of unchanged naltrexone accounts for less than 2% of an oral dose. Urinary excretion of unchanged and conjugated 6-beta-naltrexol accounts for 43% of an oral dose. The renal clearance for naltrexone ranges from 30 to 127 mL/min, suggesting that renal elimination is primarily by glomerular filtration. The renal clearance for 6-beta-naltrexol ranges from 230 to 369 mL/min suggesting an additional renal tubular secretory mechanism. Fecal excretion is a minor elimination pathway.

Following single oral administration of CONTRAVE tablets to healthy subjects, mean elimination half-life (T½) was approximately 5 hours for naltrexone. Following twice daily administration of CONTRAVE, naltrexone did not accumulate and its kinetics appeared linear. However, in comparison to naltrexone, 6-beta-naltrexol accumulates to a larger extent (accumulation ratio ~3).

Bupropion

Bupropion is extensively metabolized with three active metabolites: hydroxybupropion, threohydrobupropion and erythrohydrobupropion. The metabolites have longer elimination half-lives than bupropion and accumulate to a greater extent. Following bupropion administration, more than 90% of the exposure is a result of metabolites. In vitro findings suggest that CYP2B6 is the principal isozyme involved in the formation of hydroxybupropion whereas cytochrome P450 isozymes are not involved in the formation of the other active metabolites. Bupropion and its metabolites inhibit CYP2D6. Plasma protein binding of hydroxybupropion is similar to that of bupropion (84%) whereas the other two metabolites have approximately half the binding.

Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. The fraction of the oral dose of bupropion excreted unchanged was 0.5%, a finding consistent with the extensive metabolism of bupropion.

Following single oral administration of CONTRAVE tablets to healthy subjects, mean elimination half-life (T½) was approximately 21 hours for bupropion. Following twice daily administration of CONTRAVE, metabolites of bupropion, and to a lesser extent unchanged bupropion, accumulate and reach steady-state concentrations in approximately one week.

Specific Populations

Gender

Pooled analysis of CONTRAVE data suggested no clinically meaningful differences in the pharmacokinetic parameters of bupropion or naltrexone based on gender.

Race

Pooled analysis of CONTRAVE data suggested no clinically meaningful differences in the pharmacokinetic parameters of bupropion or naltrexone based on race.

Elderly

The pharmacokinetics of CONTRAVE have not been evaluated in the geriatric population. The effects of age on the pharmacokinetics of naltrexone or bupropion and their metabolites have not been fully characterized. An exploration of steady-state bupropion concentrations from several depression efficacy studies involving patients dosed in a range of 300 to 750 mg/day, on a three times daily schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of bupropion. A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects. These data suggest there is no prominent effect of age on bupropion concentration; however, another pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites [see Use in Specific Populations].

Smokers

Pooled analysis of CONTRAVE data revealed no meaningful differences in the plasma concentrations of bupropion or naltrexone in smokers compared with nonsmokers. The effects of cigarette smoking on the pharmacokinetics of bupropion were studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17 were nonsmokers. Following oral administration of a single 150 mg dose of bupropion, there was no statistically significant difference in Cmax, half-life, Tmax, AUC, or clearance of bupropion or its active metabolites between smokers and nonsmokers.

Hepatic Impairment

Pharmacokinetic data are not available with CONTRAVE in patients with hepatic impairment. The following information is available for individual constituents:

Naltrexone

An increase in naltrexone AUC of approximately 5-and 10-fold in patients with compensated and decompensated liver cirrhosis, respectively, compared with subjects with normal liver function, has been reported. These data also suggest that alterations in naltrexone bioavailability are related to liver disease severity.

Bupropion

The effect of hepatic impairment on the pharmacokinetics of bupropion was characterized in two single-dose trials, one trial in patients with alcoholic liver disease and a second trial in patients with mild-to-severe cirrhosis.

The first trial showed that the half-life of hydroxybupropion was significantly longer in eight patients with alcoholic liver disease than in eight healthy volunteers (32±14 hours vs 21±5 hours, respectively). Although not statistically significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be greater (by 53% to 57%) in patients with alcoholic liver disease. The differences in half-life for bupropion and the other metabolites in the two patient groups were minimal.

The second trial demonstrated no statistically significant differences in the pharmacokinetics of bupropion and its active metabolites in nine subjects with mild-to-moderate hepatic cirrhosis compared with eight healthy volunteers. However, more variability was observed in some of the pharmacokinetic parameters for bupropion (AUC, Cmax, and Tmax) and its active metabolites (t½) in subjects with mild-to-moderate hepatic cirrhosis. In subjects with severe hepatic cirrhosis, significant alterations in the pharmacokinetics of bupropion and its metabolites were seen (Table 4).

Table 4: Pharmacokinetics of Bupropion and Metabolites in Patients With Severe Hepatic Cirrhosis: Ratio Relative to Healthy Matched Controls

	Cmax	AUC	t½	Tmax*
Bupropion	1.69	3.12	1.43	0.5 h
Hydroxybupropion	0.31	1.28	3.88	19 h
Threo/erythrohydrobupropion amino alcohol	0.69	2.48	1.96	20 h
* = Difference

The dose of CONTRAVE should be reduced in patients with hepatic impairment [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].

Renal Impairment

A dedicated pharmacokinetic study has not been conducted for CONTRAVE in subjects with renal impairment. The following information is available for the individual constituents:

Naltrexone

Limited information is available for naltrexone in patients with moderate to severe renal impairment. In a study of seven patients with end-stage renal disease requiring dialysis, peak plasma concentrations of naltrexone were elevated at least 6-fold compared to healthy subjects.

Bupropion

Limited information is available for bupropion in patients with moderate to severe renal impairment. An inter-trial comparison between normal subjects and patients with end-stage renal failure demonstrated that the bupropion Cmax and AUC values were comparable in the two groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3-and 2.8-fold increase, respectively, in AUC for patients with end-stage renal failure. A second trial, comparing normal subjects and patients with moderate-to-severe renal impairment (GFR 30.9 ± 10.8 mL/min) showed that exposure after a single 150 mg dose of sustained-release bupropion was approximately 2-fold higher in patients with impaired renal function while levels of the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the two groups. The elimination of bupropion and/or the major metabolites of bupropion may be reduced by impaired renal function.

The dose of CONTRAVE should be reduced in patients with moderate or severe renal impairment. CONTRAVE is not recommended for use in patients with end-stage renal disease [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].

Drug Interactions

In Vitro Assessment of Drug Interactions

At therapeutically relevant concentrations, naltrexone and 6-beta-naltrexol are not major inhibitors of CYP isoforms CYP1A2, CYP2B6, CYP2C8, CYP2E1, CYP2C9, CYP2C19, CYP2D6 or CYP3A4. Both naltrexone and 6-beta-naltrexol are not major inducers of CYP isoforms CYP1A2, CYP2B6, or CYP3A4.

Bupropion and its metabolites (hydroxybupropion, erythrohydrobupropion, threohydrobupropion) are inhibitors of CYP2D6.

In vitro studies suggest that paroxetine, sertraline, norfluoxetine, fluvoxamine, and nelfinavir inhibit the hydroxylation of bupropion.

Bupropion (IC50 9.3 mcM) and its metabolites, hydroxybupropion (IC50 82 mcM) and threohydrobupropion and erythrohydrobupropion (1:1 mixture; IC50 7.8 mcM), inhibited the renal organic transporter OCT2 to a clinically relevant level. The systemic concentrations of substrate drugs transported by OCT2 are likely to increase as a result of reduced renal clearance when coadministered with CONTRAVE.

Effects of Naltrexone/Bupropion on the Pharmacokinetics of Other Drugs

Drug interaction between CONTRAVE and CYP2D6 substrates (metoprolol) or other drugs (atorvastatin, glyburide, lisinopril, nifedipine, valsartan) has been evaluated. In addition, drug interaction between bupropion, a component of CONTRAVE, and CYP2D6 substrates (desipramine) or other drugs (citalopram, lamotrigine) has also been evaluated.

Table 5: Effect of Naltrexone/Bupropion Coadministration on Systemic Exposure of Other Drugs

Naltrexone/Bupropion Dosage	Coadministered Drug
	Name and Dose Regimens	Change in Systemic Exposure
Initiate the following drugs at the lower end of the dose range during concomitant use with CONTRAVE [see DRUG INTERACTIONS]:
Bupropion 150 mg twice daily for 10 days	Desipramine 50 mg single dose	↑5-fold AUC, ↑2-fold Cmax
Bupropion 300 mg (as XL) once daily for 14 days	Citalopram 40 mg once daily for 14 days	↑40% AUC, ↑30% Cmax
Naltrexone/Bupropion 16 mg/180 mg twice daily for 7 days	Metoprolol 50 mg single dose	↑4-fold AUC, ↑2-fold Cmax
No dose adjustment needed for the following drugs during concomitant use with CONTRAVE:
Naltrexone/Bupropion 16 mg/180 mg single dose	Atorvastatin 80 mg single dose	No Effect
Naltrexone/Bupropion 16 mg/180 mg single dose	Glyburide 6 mg single dose	No Effect
Naltrexone/Bupropion 16 mg/180 mg single dose	Lisinopril 40 mg single dose	No Effect
Naltrexone/Bupropion 16 mg/180 mg single dose	Nifedipine 90 mg single dose	No Effect
Naltrexone/Bupropion 16 mg/180 mg single dose	Valsartan 320 mg single dose	No Effect
Bupropion 150 mg twice daily for 12 days	Lamotrigine 100 mg single dose	No Effect

Digoxin: Literature data showed that digoxin exposure was decreased when a single oral dose of 0.5 mg digoxin was administered 24 hours after a single oral dose of extended-release 150 mg bupropion in healthy volunteers.

Effects of Other Drugs on the Pharmacokinetics of Naltrexone/Bupropion

Drug interactions between CYP2B6 inhibitors (ticlopidine, clopidogrel, prasugrel), CYP2B6 inducers (ritonavir, lopinavir) and bupropion (one of the CONTRAVE components), or between other drugs (atorvastatin, glyburide, metoprolol, lisinopril, nifedipine, valsartan) and CONTRAVE have been evaluated. While not systematically studied, carbamazepine, phenobarbital, or phenytoin may induce the metabolism of bupropion.

Table 6: Effect of Coadministered Drugs on Systemic Exposure of Naltrexone/Bupropion

Name and Dose Regimens	Coadministered Drug
	CONTRAVE Components	Change in Systemic Exposure
Do not exceed one tablet twice daily dose of CONTRAVE with the following drugs:
Ticlopidine 250 mg twice daily for 4 days	Bupropion	↑85% AUC, ↑38% Cmax
	Hydroxybupropion	↓84% AUC, ↓78% Cmax
Clopidogrel 75 mg once daily for 4 days	Bupropion	↑60% AUC, ↑40% Cmax
	Hydroxybupropion	↓52% AUC, ↓50% Cmax
No dose adjustment needed for CONTRAVE with the following drugs:
Atorvastatin 80 mg single dose	Naltrexone	No Effect
	6-beta naltrexol	No Effect
	Bupropion	No Effect
	Hydroxybupropion	No Effect
	Threohydrobupropion	No Effect
	Erythrohydrobupropion	No Effect
Lisinopril 40 mg single dose	Naltrexone	No Effect
	6-beta naltrexol	No Effect
	Bupropion	No Effect
	Hydroxybupropion	No Effect
	Threohydrobupropion	No Effect
	Erythrohydrobupropion	No Effect
Valsartan 320 mg single dose	Naltrexone	No Effect
	6-beta naltrexol	No Effect
	Bupropion	No Effect
	Hydroxybupropion	↓14% AUC, No Effect on Cmax
	Threohydrobupropion	No Effect
	Erythrohydrobupropion	No Effect
Cimetidine 800 mg single dose	Bupropion	No Effect
	Hydroxybupropion	No Effect
	Threo/Erythrohydrobupropion	↑16% AUC, ↑32% Cmax
Citalopram 40 mg once daily for 14 days	Bupropion	No Effect
	Hydroxybupropion	No Effect
	Threohydrobupropion	No Effect
	Erythrohydrobupropion	No Effect
Metoprolol 50 mg single dose	Naltrexone	↓25% AUC, ↓29% Cmax
	6-beta naltrexol	No Effect
	Bupropion	No Effect
	Hydroxybupropion	No Effect
	Threohydrobupropion	No Effect
	Erythrohydrobupropion	No Effect
Nifedipine 90 mg single dose	Naltrexone	↑24% AUC, ↑58% Cmax
	6-beta naltrexol	No Effect
	Bupropion	No Effect on AUC, ↑22% Cmax
	Hydroxybupropion	No Effect
	Threohydrobupropion	No Effect
	Erythrohydrobupropion	No Effect
Prasugrel 10 mg once daily for 6 days	Bupropion	↑18% AUC, ↑14% Cmax
	Hydroxybupropion	↓24%AUC, ↓32% Cmax
Use CONTRAVE with caution with the following drugs:
Glyburide 6 mg single dose*	Naltrexone	↑2-fold AUC, ↑2-fold Cmax
	6-beta naltrexol	No Effect
	Bupropion	↑36% AUC, ↑18% Cmax
	Hydroxybupropion	↑22% AUC, ↑21% Cmax
	Threohydrobupropion	No Effect on AUC, ↑15% Cmax
	Erythrohydrobupropion	No Effect
Avoid concomitant use of CONTRAVE with following drugs:
Ritonavir 100 mg twice daily for 17 days	Bupropion	↓22% AUC, ↓21 % Cmax
	Hydroxybupropion	↓23% AUC, No Effect on Cmax
	Threohydrobupropion	↓38% AUC, ↓39 % Cmax
	Erythrohydrobupropion	↓48% AUC, ↓28 % Cmax
600 mg twice daily for 8 days	Bupropion	↓66% AUC, ↓62% Cmax
	Hydroxybupropion	↓78% AUC, ↓42 % Cmax
	Threohydrobupropion	↓50% AUC, ↓58% Cmax
	Erythrohydrobupropion	↓68% AUC, ↓48 % Cmax
Lopinavir/Ritonavir 400 mg/100 mg twice daily for 14 days	Bupropion	↓57% AUC, ↓57% Cmax
	Hydroxybupropion	↓50% AUC, ↓31% Cmax
Efavirenz 600 mg once daily for 2 weeks	Bupropion	↓55% AUC, ↓34% Cmax
	Hydroxybupropion	—55% AUC, —34% No Effect on AUC, ↑50% Cmax
*Results were confounded by the food-effect due to oral glucose coadministered with the treatment.

Clinical Studies

The effects of CONTRAVE on weight loss in conjunction with reduced caloric intake and increased physical activity was studied in double-blind, placebo-controlled trials (BMI range 27 to 45 kg/m²) with study durations of 16 to 56 weeks randomized to naltrexone (16 to 50 mg/day) and/or bupropion (300 to 400 mg/day) or placebo.

Effect On Weight Loss And Weight Maintenance

Four 56-week multicenter, double-blind, placebo-controlled obesity trials (CONTRAVE Obesity Research, or COR-I, COR-II, COR-BMOD, and COR-Diabetes) were conducted to evaluate the effect of CONTRAVE in conjunction with lifestyle modification in 4,536 patients randomized to CONTRAVE or placebo. The COR-I, COR-II, and COR-BMOD trials enrolled patients with obesity (BMI 30 kg/m² or greater) or overweight (BMI 27 kg/m² or greater) and at least one comorbidity (hypertension or dyslipidemia). The COR-Diabetes trial enrolled patients with BMI greater than 27 kg/m² with type 2 diabetes with or without hypertension and/or dyslipidemia.

Treatment was initiated with a three-week dose-escalation period followed by approximately 1 year of continued therapy. Patients were instructed to take CONTRAVE with food. COR-I and COR-II included a program consisting of a reduced-calorie diet resulting in an approximate 500 kcal/day decrease in caloric intake, behavioral counseling, and increased physical activity. COR-BMOD included an intensive behavioral modification program consisting of 28 group counseling sessions over 56 weeks as well as a prescribed diet and exercise regimen. COR-Diabetes evaluated patients with type 2 diabetes not achieving glycemic goal of a HbA1c less than 7% either with oral antidiabetic agents or with diet and exercise alone. Of the overall population from these four trials, 24% had hypertension, 54% had dyslipidemia at study entry, and 10% had type 2 diabetes.

Apart from COR-Diabetes, which only enrolled patients with type 2 diabetes, the demographic characteristics of patients were similar across all four trials. For the four trial populations combined, the mean age was 46 years, 83% were female, 77% were Caucasian, 18% were black, and 5% were other races. At baseline, mean BMI was 36 kg/m² and mean waist circumference was 110 cm.

A substantial percentage of randomized patients withdrew from the trials prior to Week 56: 45% for the placebo group and 46% for the CONTRAVE group. The majority of these patients discontinued within the first 12 weeks of treatment. Approximately 24% of patients treated with CONTRAVE and 12% of patients treated with placebo discontinued treatment because of an adverse reaction [see ADVERSE REACTIONS].

The co-primary endpoints were percent change from baseline body weight and the proportion of patients achieving at least a 5% reduction in body weight. In the 56-week COR-I trial, the mean change in body weight was -5.4% among patients assigned to CONTRAVE 32 mg/360 mg compared with -1.3% among patients assigned to placebo (Intent-To-Treat [ITT] population), as shown in Table 7 and Figure 1. In this trial, the achievement of at least a 5% reduction in body weight from baseline occurred more frequently for patients treated with CONTRAVE 32 mg/360 mg compared with placebo (42% vs 17%; Table 7). Results from COR-BMOD and COR-Diabetes are shown in Table 7 and Figures 2 and 3.

Table 7: Changes in Weight in 56-Week Trials with CONTRAVE (ITT/LOCF*)

	COR-I		COR-BMOD		COR-Diabetes
	CONTRAVE 32 mg/ 360 mg	Placebo	CONTRAVE 32 mg/ 360 mg	Placebo	CONTRAVE 32 mg/ 360 mg	Placebo
N	538	536	565	196	321	166
Weight (kg)
Baseline mean (SD)	99.8 (16.1)	99.5 (14.4)	100.3 (15.5)	101.8 (15.0)	104.2 (19.1)	105.3 (16.9)
LS Mean % Change From Baseline (SE)	-5.4 (0.3)	-1.3 (0.3)	-8.1 (0.4)	-4.9 (0.6)	-3.7 (0.3)	-1.7 (0.4)
Difference from placebo (95% CI)	-4.1† (-4.9, -3.3)		-3.2† (-4.5, -1.8)		-2.0† (-3.0, -1.0)
Percentage of patients losing greater than or equal to 5% body weight	42	17	57	43	36	18
Risk difference vs placebo (95% CI)	25† (19, 30)		14† (6, 22)		18† (9, 25)
Percentage of patients losing greater than or equal to 10% body weight	21	7	35	21	15	5
Risk difference vs placebo (95% CI)	14† (10, 18)		14† (7, 21)		10‡ (4, 15)
Type 1 error was controlled across all 3 endpoints *Based on last observation carried forward (LOCF) in all randomized subjects who had a baseline body weight measurement and at least one post baseline body weight measurement during the defined treatment phase. All available body weight data during the double-blind treatment phase are included in the analysis, including data collected from subjects who discontinued study drug. †Difference from placebo, p < 0.001 ‡Difference from placebo, p < 0.01

The percentages of patients who achieved at least 5% or at least 10% body weight loss from baseline were greater among those assigned to CONTRAVE, compared with placebo, in all four obesity trials (Table 7).

Figure 1: Weight Loss Over Time in Completer Population: COR-I Trial

Figure 2: Weight Loss Over Time in Completer Population: COR-BMOD Trial

Figure 3: Weight Loss Over Time in Completer Population: COR-Diabetes Trial

Effect On Cardiovascular And Metabolic Parameters

Changes in cardiovascular and metabolic parameters associated with obesity are presented for COR-I and COR-BMOD (Table 8). Changes in mean blood pressure and heart rate are further described elsewhere [see WARNINGS AND PRECAUTIONS].

Table 8: Change in Markers of Cardiovascular and Metabolic Parameters from Baseline in 56 Week Trials with CONTRAVE 32 mg/360 mg (COR-I and COR-BMOD)*

Parameter	COR-I			COR-BMOD
	CONTRAVE 32 mg/360 mg N=471	Placebo N=511	CONTRAVE minus Placebo (LS Mean)	CONTRAVE 32 mg/360 mg N=482	Placebo N=193	CONTRAVE minus Placebo (LS Mean)
Triglycerides, mg/dL
Baseline median (Q1, Q3)	113 (86, 158)	112 (78, 157)	-10.7†	110 (78, 162)	103 (76, 144)	-9.9†
Median % change	-11.6	1.7		-17.8	-7.4
HDL-C, mg/dL
Baseline mean (SD)	51.9 (13.6)	52.0 (13.6)	7.2	53.6 (13.5)	55.3 (12.9)	6.6
LS Mean % change (SE)	8.0 (0.9)	0.8 (0.9)		9.4 (1.0)	2.8 (1.6)
LDL-C, mg/dL
Baseline mean (SD)	118.8 (32.6)	119.7 (34.8)	-1.5	109.5 (27.5)	109.2 (27.3)	-2.9
LS Mean % change (SE)	-2.0 (1.0)	-0.5 (11)		7.1 (1.4)	10.0 (2.2)
Waist circumference, cm
Baseline mean (SD)	108.8 (11.3)	110.0 (12.2)	-3.8‡	109.3 (11.4)	109.0 (11.8)	-3.2‡
LS Mean change(SE)	-6.2 (0.4)	-2.5 (0.4)		-10.0 (0.5)	-6.8 (0.8)
Heart rate, bpm
Baseline mean (SD)	72.1 (8.7)	71.8 (8.0)	1.2	70.7 (8.3)	70.4 (9.0)	0.9
LS Mean change(SE)	1.0 (0.3)	-0.2 (0.3)		1.1 (0.4)	0.2 (0.5)
Systolic blood pressure, mmHg
Baseline mean (SD)	118.9 (9.8)	119.0 (9.8)	1.8	116.9 (9.9)	116.7 (10.9)	2.6
LS Mean change(SE)	-0.1 (0.4)	-1.9 (0.4)		-1.3 (0.5)	-3.9 (0.7)
Diastolic blood pressure, mmHg
Baseline mean (SD)	77.1 (7.2)	77.3 (6.6)	0.9	78.2 (7.2)	77.2 (7.4)	1.4
LS Mean change(SE)	0.0 (0.3)	-0.9 (0.3)		-1.4 (0.3)	-2.8 (0.5)
Q1: first quartile; Q3: third quartile *Based on last observation carried forward (LOCF) while on study drug †Hodges-Lehmann estimate of treatment difference ‡Statistically significant vs placebo (p < 0.001) based on the pre-specified closed testing procedure method for controlling Type I error

Effect Of CONTRAVE On Cardiometabolic Parameters And Anthropometry In Patients With Type 2 Diabetes Mellitus

Changes in glycemic control observed from baseline to Week 56 among patients with type 2 diabetes and obesity assigned to either CONTRAVE 32 mg/360 mg or placebo are shown in Table 9.

Table 9: Changes in Cardiometabolic Parameters and Waist Circumference in Patients with Type 2 Diabetes Mellitus in a 56 Week Trial with CONTRAVE 32 mg/360 mg (COR-Diabetes)

	CONTRAVE 32 mg/360 mg N=265		Placebo N=159		CONTRAVE minus Placebo (LS Mean)
	Baseline	Change from Baseline (LS Mean)	Baseline	Change from Baseline (LS Mean)
HbA1c (%)	8.0	-0.6	8.0	-0.1	-0.5*
Fasting Glucose (mg/dL)	160.0	-11.9	163.9	-4.0	-7.9
Waist Circumference (cm)	115.6	-5.0	114.3	-2.9	-2.1
Systolic blood pressure (mmHg)	125.0	0.0	124.5	-1.1	1.2
Diastolic blood pressure (mmHg)	77.5	-1.1	77.4	-1.5	0.4
Heart rate (bpm)	72.9	0.7	73.1	-0.2	0.9
	Baseline	% Change from Baseline (LS Mean)	Baseline	% Change from Baseline (LS Mean)	CONTRAVE minus Placebo (LS Mean)
Triglycerides (mg/dL)†	147 (98, 200)	-7.7	168 (114, 236)	-8.6	-3.3
HDL Cholesterol (mg/dL)	46.2	7.4	46.1	-0.2	7.6
LDL Cholesterol (mg/dL)	100.2	2.4	101.0	4.2	-1.9
Based on last observation carried forward (LOCF) while on study drug *Statistically significant vs placebo (p < 0.001) based on the pre-specified closed testing procedure method for controlling Type I error †Values are baseline median (first and third quartiles), median % change, and the Hodges-Lehmann estimate of the median treatment difference

Effect On Body Composition

In a subset of 124 patients (79 CONTRAVE, 45 placebo), body composition was measured using dual energy X-ray absorptiometry (DEXA). The DEXA assessment showed that mean total body fat mass decreased by 4.7 kg (11.7%) in the CONTRAVE group vs 1.4 kg (4.3%) in the placebo group at Week 52/LOCF (treatment difference, -3.3 kg [-7.4%], p < 0.01).

CONTRAVE®
(CON-trayv)
(naltrexone HCl and bupropion HCl) Extended-release Tablets

What is the most important information I should know about CONTRAVE?

CONTRAVE can cause serious side effects, including:

• Suicidal thoughts or actions. One of the ingredients in CONTRAVE is bupropion. Bupropion has caused some people to have suicidal thoughts or actions or unusual changes in behavior, whether or not they are taking medicines used to treat depression.

Bupropion may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.

If you already have depression or other mental illnesses, taking bupropion may cause it to get worse, especially within the first few months of treatment.

Stop taking CONTRAVE and call a healthcare provider right away if you, or your family member, have any of the following symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying
• new or worse irritability
• attempts to commit suicide
• acting aggressive, being angry, or violent
• new or worse depression
• acting on dangerous impulses
• new or worse anxiety
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood
• feeling very agitated or restless
• panic attacks
• trouble sleeping (insomnia)

While taking CONTRAVE, you or your family members should:

• Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when you start taking CONTRAVE or when your dose changes.
• Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms.

CONTRAVE has not been studied in and is not approved for use in children under the age of 18.

What is CONTRAVE?

CONTRAVE is a prescription medicine which contains 2 medicines (naltrexone and bupropion) that may help some obese or overweight adults, who also have weight related medical problems, lose weight and keep the weight off. CONTRAVE should be used with a reduced calorie diet and increased physical activity.

It is not known if CONTRAVE changes your risk of heart problems or stroke or of death due to heart problems or stroke.

It is not known if CONTRAVE is safe and effective when taken with other prescription, over-the-counter, or herbal weight loss products.

It is not known if CONTRAVE is safe and effective in children under 18 years of age.

CONTRAVE is not approved to treat depression or other mental illnesses, or to help people quit smoking (smoking cessation). One of the ingredients in CONTRAVE, bupropion, is the same ingredient in some other medicines used to treat depression and to help people quit smoking.

Do not take CONTRAVE if you:

• have uncontrolled hypertension.
• have or have had seizures.
• use other medicines that contain bupropion such as WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, APLENZIN and ZYBAN.
• have or have had an eating disorder called anorexia (eating very little) or bulimia (eating too much and vomiting to avoid gaining weight).
• are dependent on opioid pain medicines or use medicines to help stop taking opioids such as methadone or buprenorphine, or are in opiate withdrawal.
• drink a lot of alcohol and abruptly stop drinking, or use medicines called sedatives (these make you sleepy), benzodiazepines, or anti-seizure medicines and you stop using them all of a sudden.
• are taking medicines called monoamine oxidase inhibitors (MAOIs). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including linezolid. Do not start CONTRAVE until you have stopped taking your MAOI for at least 14 days.
• are allergic to naltrexone or bupropion or any of the ingredients in CONTRAVE. See the end of this Medication Guide for a complete list of ingredients in CONTRAVE.
• are pregnant or planning to become pregnant. Tell your healthcare provider right away if you become pregnant while taking CONTRAVE.

Before taking CONTRAVE, tell your healthcare provider about all of your medical conditions, including if you:

• have or have had depression or other mental illnesses (such as bipolar disorder)
• have attempted suicide in the past
• have or have had seizures
• have had a head injury
• have had a tumor or infection of your brain or spine (central nervous system)
• have had a problem with low blood sugar (hypoglycemia) or low levels of sodium in your blood (hyponatremia)
• have or have had liver problems
• have high blood pressure
• have or have had a heart attack, heart problems, or have had a stroke
• have kidney problems
• are diabetic taking insulin or other medicines to control your blood sugar
• have or have had an eating disorder
• drink a lot of alcohol
• abuse prescription medicines or street drugs
• are over the age of 65
• are breastfeeding or plan to breastfeed. CONTRAVE can pass into your breast milk and may harm your baby. You and your healthcare provider should decide if you should take CONTRAVE or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

CONTRAVE may affect the way other medicines work and other medicines may affect the way CONTRAVE works causing side effects.

Ask your healthcare provider for a list of these medicines if you are not sure.

Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.

How should I take CONTRAVE?

How to take CONTRAVE
	Morning Dose	Evening Dose
Starting: Week 1	1 tablet	None
Week 2	1 tablet	1 tablet
Week 3	2 tablets	1 tablet
Week 4 Onward	2 tablets	2 tablets

• Take CONTRAVE exactly as your healthcare provider tells you to.
• Do not change your CONTRAVE dose without talking with your healthcare provider.
• Your healthcare provider will change your dose if needed.
• Your healthcare provider should tell you to stop taking CONTRAVE if you have not lost a certain amount of weight after 16 weeks of treatment.
• Swallow CONTRAVE tablets whole. Do not cut, chew, or crush CONTRAVE tablets. Tell your healthcare provider if you cannot swallow CONTRAVE tablets whole.
• Do not take more than 2 tablets in the morning and 2 tablets in the evening.
• Do not take more than 2 tablets at the same time or more than 4 tablets in 1 day.
• Do not take CONTRAVE with high-fat meals. It may increase your risk of seizures.
• If you miss a dose of CONTRAVE, wait until your next regular time to take it. Do not take more than 1 dose of CONTRAVE at a time.
• If you take too much CONTRAVE, call your healthcare provider or go to the nearest emergency room right away.

What should I avoid while taking CONTRAVE?

• Do not drink a lot of alcohol while taking CONTRAVE. If you drink a lot of alcohol, talk with your healthcare provider before suddenly stopping. If you suddenly stop drinking alcohol, you may increase your chance of having a seizure.

What are the possible side effects of CONTRAVE?

CONTRAVE may cause serious side effects, including:

• See “What is the most important information I should know about CONTRAVE?”
• Seizures. There is a risk of having a seizure when you take CONTRAVE. The risk of seizure is higher in people who:
  • take higher doses of CONTRAVE
  • have certain medical conditions
  • take CONTRAVE with certain other medicines

Do not take any other medicines while you are taking CONTRAVE unless your healthcare provider has said it is okay to take them.

If you have a seizure while taking CONTRAVE, stop taking CONTRAVE and call your healthcare provider right away.

You should not take CONTRAVE again if you have a seizure.

• Risk of opioid overdose. One of the ingredients in CONTRAVE (naltrexone) can increase your chance of having an opioid overdose if you take opioid medicines while taking CONTRAVE.
  You can accidentally overdose in 2 ways:
  • Naltrexone blocks the effects of opioids, such as heroin, methadone or opioid pain medicines. Do not take large amounts of opioids, including opioid-containing medicines, such as heroin or prescription pain pills, to try to overcome the opioid-blocking effects of naltrexone. This can lead to serious injury, coma, or death.
  • After you take naltrexone, its blocking effect slowly decreases and completely goes away over time. If you have used opioid street drugs or opioid-containing medicines in the past, using opioids in amounts that you used before treatment with naltrexone can lead to overdose and death. You may also be more sensitive to the effects of lower amounts of opioids:
  • after you have gone through detoxification
  • when your next dose of CONTRAVE is due
  • if you miss a dose of CONTRAVE
  • after you stop CONTRAVE treatment

It is important that you tell your family and the people closest to you of this increased sensitivity to opioids and the risk of overdose.

You or someone close to you should get emergency medical help right away if you:

• have trouble breathing
• become very drowsy with slowed breathing
• have slow, shallow breathing (little chest movement with breathing)
• feel faint, very dizzy, confused, or have unusual symptoms
• Sudden opioid withdrawal. People who take CONTRAVE must not use any type of opioid (must be opioid-free) including street drugs, prescription pain medicines (including tramadol), cough, cold, or diarrhea medicines that contain opioids, or opioid dependence treatments, buprenorphine or methadone, for at least 7 to 10 days before starting CONTRAVE. Using opioids in the 7 to 10 days before you start taking CONTRAVE may cause you to suddenly have symptoms of opioid withdrawal when you take it. Sudden opioid withdrawal can be severe, and you may need to go to the hospital. Tell your healthcare provider you are taking CONTRAVE before a medical procedure or surgery.
• Severe allergic reactions. Some people have had a severe allergic reaction to bupropion, one of the ingredients in CONTRAVE. Stop taking CONTRAVE and call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the following signs and symptoms of an allergic reaction:
  • rash
  • painful sores in your mouth or around your eyes
  • itching
  • swelling of your lips or tongue
  • hives
  • chest pain
  • fever
  • trouble breathing
  • swollen lymph glands
• Increases in blood pressure or heart rate. Some people may get high blood pressure or have a higher heart rate when taking CONTRAVE. Your healthcare provider should check your blood pressure and heart rate before you start taking, and while you take CONTRAVE.
• Liver damage or hepatitis. One of the ingredients in CONTRAVE, naltrexone can cause liver damage or hepatitis. Stop taking CONTRAVE and tell your healthcare provider if you have any of the following symptoms of liver problems:
  • stomach area pain lasting more than a few days
  • dark urine
  • yellowing of the whites of your eyes
  • tiredness
    Your healthcare provider may need to stop treating you with CONTRAVE if you get signs or symptoms of a serious liver problem.
• Manic episodes. One of the ingredients in CONTRAVE, bupropion can cause some people who were manic or depressed in the past to become manic or depressed again.
• Visual problems (angle-closure glaucoma). One of the ingredients in CONTRAVE, bupropion, can cause some people to have visual problems (angle-closure glaucoma). Signs and symptoms of angle-closure glaucoma may include:
  • eye pain
  • changes in vision
  • swelling or redness in or around the eye

Talk with your healthcare provider to find out if you are at risk for angle-closure glaucoma and to get treatment to prevent it if you are at risk.

• Increased risk of low blood sugar (hypoglycemia) in people with type 2 diabetes mellitus who also take medicines to treat their diabetes. Weight loss can cause low blood sugar in people with type 2 diabetes mellitus who also take medicines used to treat type 2 diabetes mellitus (such as insulin or sulfonylureas). You should check your blood sugar before you start taking CONTRAVE and while you take CONTRAVE.

The most common side effects of CONTRAVE include:

• nausea
• dizziness
• constipation
• trouble sleeping
• headache
• dry mouth
• vomiting
• diarrhea

These are not all of the possible side effects of CONTRAVE.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store CONTRAVE?

Store CONTRAVE at room temperature between 59oF to 86oF (15oC to 300C).

Keep CONTRAVE and all medicines out of the reach of children.

General information about the safe and effective use of CONTRAVE.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use CONTRAVE for a condition for which it was not prescribed. Do not give CONTRAVE to other people, even if they have the same symptoms that you have. It may harm them.

If you take a urine drug screening test, CONTRAVE may make the test result positive for amphetamines. If you tell the person giving you the drug screening test that you are taking CONTRAVE, they can do a more specific drug screening test that should not have this problem.

You can ask your pharmacist or healthcare provider for information about CONTRAVE that is written for health professionals.

What are the ingredients in CONTRAVE?

Active ingredient: naltrexone hydrochloride and bupropion hydrochloride

Inactive ingredients: microcrystalline cellulose, hydroxypropyl cellulose, lactose anhydrous, L-cysteine hydrochloride, crospovidone, magnesium stearate, hypromellose, edetate disodium, lactose monohydrate, colloidal silicon dioxide, Opadry II Blue and FD&C Blue #2 aluminum lake