PRINCIPAL DISPLAY PANEL

RELEXXII**®**** 72 mg 30 count Bottle Label**

NDC 68025-084-30


WARNING: ABUSE, MISUSE, AND ADDICTION

1 INDICATIONS AND USAGE

RELEXXII is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in adults (up to the age of 65 years) and pediatric patients 6 years of age and older [see Clinical Studies (14)].

4 CONTRAINDICATIONS

RELEXXII is contraindicated in patients:

• with a known hypersensitivity to methylphenidate or other components of RELEXXII. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with other methylphenidate products [see Adverse Reactions (6.2)].
• receiving concomitant treatment with monoamine oxidase inhibitors (MAOIs), and also within 14 days following discontinuation of treatment with a MAOI, because of the risk of hypertensive crisis [see Drug Interactions (7.1)].

6 ADVERSE REACTIONS

The following are discussed in more detail in other sections of the labeling:

• Abuse, Misuse, and Addiction [see Box Warning, Warnings and Precautions (5.1), and Drug Abuse and Dependence (9.2, 9.3)]
• Known hypersensitivity to methylphenidate or other ingredients [see Contraindications (4)]
• Hypertensive crisis when used concomitantly with monoamine oxidase inhibitors [see Contraindications (4) and Drug Interactions (7.1)]
• Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions (5.2)]
• Increased Blood Pressure and Heart Rate [see Warnings and Precautions (5.3)]
• Psychiatric Adverse Reactions [see Warnings and Precautions (5.4)]
• Priapism [see Warnings and Precautions (5.5)]
• Peripheral Vasculopathy, including Raynaud’s Phenomenon [see Warnings and Precautions (5.6)]
• Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.7)]
• Potential for Gastrointestinal Obstruction [see Warnings and Precautions (5.8)]
• Acute Angle Closure Glaucoma [see Warnings and Precautions (5.9)]
• Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions (5.10)]
• Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions (5.11)]

6.1 Clinical Trials Experience

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 clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of RELEXXII for the treatment of ADHD is based on adequate and well-controlled studies of another formulation of methylphenidate hydrochloride extended-release tablets. Below is a display of adverse reactions from those adequate and well-controlled studies in ADHD.

Adults and pediatric patients 6 to 17 years with ADHD were evaluated in six controlled clinical studies and eleven open-label clinical studies (see Table 3). Safety was assessed by collecting adverse reactions, vital signs, weights, and electrocardiograms (ECGs), and by performing physical examinations and laboratory analyses. A total of 3,906 patients participated in the clinical trials.

Table 3. Exposure in Double-Blind and Open-Label Clinical Studies of Another Formulation of Methylphenidate Hydrochloride Extended-Release Tablets

• 108 mg is 1.5 times the maximum recommended dosage of RELEXXII.

The most common adverse reactions in double-blind clinical trials (>5%) were:

• Pediatric patients 6 to 17 years: abdominal pain upper (see Table 4).
• Adults: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, and hyperhidrosis (see Table 5).

The most common adverse reactions associated with discontinuation (≥1%) from either pediatric or adult clinical trials were anxiety, irritability, insomnia, and blood pressure increased.

Adverse reactions in either the pediatric or adult double-blind adverse reactions tables may be relevant for both patient populations.

Pediatric Patients 6 to 17 Years

Table 4 lists the adverse reactions reported in 1% or more of another formulation of methylphenidate hydrochloride extended-release tablet-treated pediatric patients (6 to 17 years) in four placebo-controlled, double-blind clinical trials.

Table 4. Adverse Reactions Reported by ≥1% of Pediatric Patients (6 to 17 years) Treated with Another Formulation of Methylphenidate Hydrochloride Extended-release Tablets in Four Placebo-Controlled, Double-Blind Clinical Trials

Adults

Table 5 lists the adverse reactions reported in 1% or more of adults treated with another formulation of methylphenidate hydrochloride extended-release tablets in two placebo-controlled, double-blind clinical trials.

Table 5. Adverse Reactions Reported by ≥1% of Adults Treated with Another Formulation of Methylphenidate Hydrochloride Extended-release Tablets in Two Placebo-Controlled, Double-Blind Clinical Trials*****

Adverse Reactions Observed in Clinical Trials with Another Formulation of Methylphenidate Hydrochloride Extended-release Tablets

This section includes adverse reactions reported with use of another formulation of methylphenidate hydrochloride extended-release tablets in double-blind trials that do not meet the criteria specified for Table 4 or Table 5 and all adverse reactions reported by the other formulation of methylphenidate hydrochloride extended-release tablets-treated patients who participated in open-label and postmarketing clinical trials.

Blood and Lymphatic System Disorders: Leukopenia

Eye Disorders: Accommodation disorder, Dry eye

Vascular Disorders: Hot flush

Gastrointestinal Disorders: Abdominal discomfort, Abdominal pain, Diarrhea

General Disorders and Administrative Site Conditions: Asthenia, Fatigue, Feeling jittery, Thirst

Infections and Infestations: Sinusitis

Investigations: Alanine aminotransferase increased, Blood pressure increased, Cardiac murmur, Heart rate increased

Musculoskeletal and Connective Tissue Disorders: Muscle spasms

Nervous System Disorders: Lethargy, Psychomotor hyperactivity, Somnolence

Psychiatric Disorders: Anger, Hypervigilance, Mood altered, Mood swings, Panic attack, Sleep disorder, Tearfulness, Tic

Reproductive System and Breast Disorders: Erectile dysfunction

Respiratory, Thoracic and Mediastinal Disorders: Dyspnea

Skin and Subcutaneous Tissue Disorders: Rash, Rash macular

Vascular Disorders: Hypertension

Discontinuation Due to Adverse Reactions

Adverse reactions in the four placebo-controlled studies of pediatric patients (6 to 17 years) leading to discontinuation occurred in 2 patients (0.6%) treated with another formulation of methylphenidate hydrochloride extended- release tablets including depressed mood (1, 0.3%) and headache and insomnia (1, 0.3%), and 6 placebo patients (1.9%) including headache and insomnia (1, 0.3%), irritability (2, 0.6%), headache (1, 0.3%), psychomotor hyperactivity (1, 0.3%), and tic (1, 0.3%).

In the two placebo-controlled studies of adults, 25 patients (6.0%) treated with another formulation of methylphenidate hydrochloride extended-release tablets and 6 placebo patients (2.8%) discontinued due to an adverse reaction. Incidence of >0.5% in patients treated with another formulation of methylphenidate hydrochloride extended-release tablets included anxiety (1.7%), irritability (1.4%), blood pressure increased (1.0%), and nervousness (0.7%). In placebo patients, blood pressure increased and depressed mood had an incidence of >0.5% (0.9%).

In the eleven open-label studies of pediatric patients and adults, 266 patients (7.0%) treated with another formulation of methylphenidate hydrochloride extended-release tablets discontinued due to an adverse reaction. Incidence of >0.5% included insomnia (1.2%), irritability (0.8%), anxiety (0.7%), decreased appetite (0.7%), and tic (0.6%).

Tics

In a long-term uncontrolled study (n=432 pediatric patients 6 to 12 years), the cumulative incidence of new onset of tics was 9% after 27 months of treatment with another formulation of methylphenidate hydrochloride extended- release tablets.

In a second uncontrolled study (n=682 pediatric patients 6 to 12 years) the cumulative incidence of new-onset tics was 1% (9/682). The treatment period was up to 9 months with mean treatment duration of 7.2 months.

Blood Pressure and Heart Rate Increases

In the laboratory classroom clinical trials in pediatric patients 6 to 12 years (Studies 1 and 2), both another formulation of methylphenidate hydrochloride extended-release tablets once daily and methylphenidate three times daily increased resting pulse by an average of 2 to 6 bpm and produced average increases of systolic and diastolic blood pressure of roughly 1 to 4 mm Hg during the day, relative to placebo. In the placebo-controlled trial in pediatric patients 13 to 17 years (Study 4), mean increases from baseline in resting pulse rate were observed with another formulation of methylphenidate hydrochloride extended-release tablets and placebo at the end of the double- blind phase (5 and 3 beats/minute, respectively). Mean increases from baseline in blood pressure at the end of the double-blind phase for another formulation of methylphenidate hydrochloride extended-release tablets and placebo-treated patients were 0.7 and 0.7 mm Hg (systolic) and 2.6 and 1.4 mm Hg (diastolic), respectively. In one placebo-controlled study in adults (Study 6), dose- dependent mean increases of 3.9 to 9.8 bpm from baseline in standing pulse rate were observed with another formulation of methylphenidate hydrochloride extended-release tablets at the end of the double-blind treatment vs. an increase of 2.7 beats/minute with placebo. Mean changes from baseline in standing blood pressure at the end of double-blind treatment ranged from 0.1 to 2.2 mm Hg (systolic) and -0.7 to 2.2 mm Hg (diastolic) for another formulation of methylphenidate hydrochloride extended-release tablets and was 1.1 mm Hg (systolic) and -1.8 mm Hg (diastolic) for placebo. In a second placebo-controlled study in adults (Study 5), mean changes from baseline in resting pulse rate were observed for another formulation of methylphenidate hydrochloride extended-release tablets and placebo at the end of the double- blind treatment (3.6 and –1.6 beats/minute, respectively). Mean changes from baseline in blood pressure at the end of the double–blind treatment for another formulation of methylphenidate hydrochloride extended-release tablets and placebo-treated patients were –1.2 and –0.5 mm Hg (systolic) and 1.1 and 0.4 mm Hg (diastolic), respectively [see Warnings and Precautions (5.3)].

6.2 Postmarketing Experience

The following additional adverse reactions have been identified during post- approval use of another formulation of methylphenidate hydrochloride extended- release tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: Pancytopenia, Thrombocytopenia, Thrombocytopenic purpura

Cardiac Disorders: Angina pectoris, Bradycardia, Extrasystoles, Supraventricular tachycardia, Ventricular extrasystoles

Eye Disorders: Diplopia, Increased intraocular pressure, Mydriasis, Visual impairment

General Disorders: Chest pain, Chest discomfort, Drug effect decreased, Hyperpyrexia, Therapeutic response decreased

Hepatobiliary Disorders: Hepatocellular injury, Acute hepatic failure

Immune System Disorders: Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritus NEC, Rashes, Eruptions, and Exanthemas NEC

Investigations: Blood alkaline phosphatase increased, Blood bilirubin increased, Hepatic enzyme increased, Platelet count decreased, White blood cell count abnormal

Musculoskeletal, Connective Tissue and Bone Disorders: Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis

Nervous System Disorders: Convulsion, Grand mal convulsion, Dyskinesia, Serotonin syndrome in combination with serotonergic drugs, Motor and Verbal Tics

Psychiatric Disorders: Disorientation, Hallucination, Hallucination auditory, Hallucination visual, Mania, Logorrhea, Libido changes

Reproductive System and Breast Disorders: Priapism

Skin and Subcutaneous Tissue Disorders: Alopecia, Erythema

Vascular Disorders: Raynaud's phenomenon

7 DRUG INTERACTIONS

7.1 Clinically Important Drug Interactions

Table 6 presents clinically important drug interactions with RELEXXII.

Table 6: Drugs Having Clinically Important Interactions with RELEXXII

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including RELEXXII, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388.

Risk Summary

Published studies and post-marketing reports on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the fetus associated with the use of central nervous system (CNS) stimulants during pregnancy (see Clinical Considerations).

No effects on morphological development were observed in development studies with oral administration of methylphenidate to pregnant rats at doses up to 4 times the maximum recommended human dose (MRHD) of 72 mg/day given to adults on a mg/m2 basis. However, malformations were observed in rabbits at a dose 54 times the MRHD given to adults.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

CNS stimulants, such as RELEXXII, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine‑dependent mothers.

Data

Animal Data

In development studies conducted in rats and rabbits, methylphenidate was administered at doses up to 30 and 200 mg/kg/day, respectively. Methylphenidate has been shown to cause malformations in rabbits when given in doses of 200 mg/kg/day, which is approximately 54 times the MRHD on a mg/m2 basis, respectively. A reproduction study in rats revealed no evidence of harm to the fetus at oral doses up to 30 mg/kg/day, approximately 4-fold the MRHD on a mg/m2 basis.

8.2 Lactation

Risk Summary

Limited published literature, based on breast milk sampling from five mothers, reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. However, long‑term neurodevelopmental effects on infants from CNS stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for RELEXXII and any potential adverse effects on the breastfed infant from RELEXXII or from the underlying maternal condition.

Clinical Considerations

Monitor breastfeeding infants for adverse reactions, such as agitation, anorexia, and reduced weight gain.

8.4 Pediatric Use

The safety and effectiveness of RELEXXII for the treatment of ADHD have been established in pediatric patients 6 to 17 years.

The safety and effectiveness of RELEXXII in pediatric patients less than 6 years have not been established.

The long-term efficacy of methylphenidate in pediatric patients have not been established.

Long Term Suppression of Growth

Growth should be monitored during treatment with stimulants, including RELEXXII. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.7) and Adverse Reactions (6.1)].

Juvenile Animal Toxicity Data

In the study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal day 7) and continuing through sexual maturity (postnatal week 10). When these animals were tested as adults (postnatal weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the MRHD of 54 mg/day given to children on a mg/m2 basis) or greater, and a deficit in the acquisition of a specific learning task was observed in females exposed to the highest dose (9 times the MRHD given to children on a mg/m2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (equal to the MRHD given to children on a mg/m2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

8.5 Geriatric Use

RELEXXII has not been studied in patients greater than 65 years of age.

RECENT MAJOR CHANGES

Boxed Warning 10/2023

Dosage and Administration (2.1, 2.3) 10/2023

Warnings and Precautions (5.1, 5.2, 5.9, 5.10, 5.11) 10/2023

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Methylphenidate HCl is a CNS stimulant. The mode of therapeutic action in ADHD is not known.

12.2 Pharmacodynamics

Methylphenidate is a racemic mixture comprised of the d- and l-threo entantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.

12.3 Pharmacokinetics

In a relative bioavailability study in healthy adults under fasted conditions, plasma exposures of 72 mg RELEXXII and 72 mg (2 x 36 mg) methylphenidate extended-release tablets were compared. The peak plasma concentration (Cmax) of RELEXXII and methylphenidate extended-release tablets is 19.7 ng/mL and 19.3 ng/mL, respectively. The area under the plasma concentration-time curve (AUC0-inf) of RELEXXII and methylphenidate extended-release tablets is 206.1 ng∙h/mL and 200.9 ng∙h/mL, respectively.

Absorption

Methylphenidate is readily absorbed. Following oral administration of RELEXXII plasma methylphenidate concentrations increase rapidly, reaching an initial maximum at about 1.5 hour, followed by gradual ascending concentrations over the next 5 to 6 hours, after which a gradual decrease begins. Mean time to reach peak plasma concentrations of RELEXXII occurs at 5.5 hours.

Methylphenidate hydrochloride extended-release tablets once daily minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily. Figure 1 displays mean plasma exposures of methylphenidate hydrochloride extended-release tablets once daily and methylphenidate three times daily (administered every 4 hours) in adults.

Figure 1: Mean Methylphenidate Plasma Concentration-Time Profiles


The mean single-dose pharmacokinetic parameters in 36 healthy adults following the administration of methylphenidate hydrochloride extended-release tablets 18 mg once daily and methylphenidate 5 mg three times daily are summarized in Table 7.

Table 7. Methylphenidate Pharmacokinetic Parameters (Mean ± SD) After Single Dose in Healthy Adults

The pharmacokinetics of methylphenidate hydrochloride extended-release tablets were evaluated in healthy adults following single- and multiple-dose administration (steady state) of doses up to 144 mg per day (2 times the maximum recommended daily dosage of methylphenidate hydrochloride extended- release tablets). The mean half-life was about 3.6 hours. No differences in the pharmacokinetics of methylphenidate hydrochloride extended-release tablets were noted following single and repeated once-daily dosing, indicating no significant drug accumulation. The AUC and t1/2 following repeated once-daily dosing are similar to those following the first dose of methylphenidate hydrochloride extended-release tablets in a dose range of 18 mg to 144 mg.

Effect of Food

There were no differences in either the pharmacokinetics or the pharmacodynamic performance of methylphenidate hydrochloride extended-release tablets when administered after a high-fat breakfast. There is no evidence of dose dumping in the presence or absence of food.

Effect of Alcohol

In-vitro studies were conducted to explore the effect of alcohol on the release characteristics of methylphenidate from RELEXXII. At alcohol concentrations up to 40%, there was no increased release of methylphenidate in the first two hours.

Dose Proportionality

Following administration methylphenidate hydrochloride extended-release tablets in single doses of 18 mg, 36 mg, and 54 mg per day to healthy adults, Cmax and AUC (0–inf) of d-methylphenidate were proportional to dose, whereas l-methylphenidate Cmax and AUC (0–inf) increased disproportionately with respect to dose. Following administration of methylphenidate hydrochloride extended-release tablets, plasma concentrations of the l-isomer were approximately 1/40 the plasma concentrations of the d-isomer.

In healthy adults, single and multiple dosing of once-daily methylphenidate hydrochloride extended-release tablets doses from 54 mg to 144 mg per day resulted in linear and dose-proportional increases in Cmax and AUCinf for total methylphenidate (MPH) and its major metabolite, α-phenyl-piperidine acetic acid (PPAA). There was no time dependency in the pharmacokinetics of methylphenidate. The ratio of metabolite (PPAA) to parent drug (MPH) was constant across doses from 54 mg to 144 mg per day, both after single dose and upon multiple dosing.

In a multiple-dose study in ADHD with pediatric patients 13 to 16 years administered their prescribed dose (18 mg to 72 mg per day) of methylphenidate hydrochloride extended-release tablets, mean Cmax and AUCTAU of d- and total methylphenidate increased proportionally with respect to dose.

Distribution

Plasma methylphenidate concentrations in adults and pediatric patients 13 to 17 years decline biexponentially following oral administration. The half-life of methylphenidate in adults and adolescents following oral administration of methylphenidate hydrochloride extended-release tablets was approximately 3.5 hours.

Elimination

Metabolism

In humans, methylphenidate is metabolized primarily by de-esterification to PPAA, which has little or no pharmacologic activity. In adults the metabolism of methylphenidate hydrochloride extended-release tablets once daily as evaluated by metabolism to PPAA is similar to that of methylphenidate three times daily. The metabolism of single and repeated once-daily doses of methylphenidate hydrochloride extended-release tablets is similar.

Excretion

After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPAA, accounting for approximately 80% of the dose.

Specific Populations

Male and Female Patients

In healthy adults, the mean dose-adjusted AUC (0–inf) values for methylphenidate hydrochloride extended-release tablets were 36.7 ng∙h/mL in men and 37.1 ng∙h/mL in women, with no differences noted between the two groups.

Racial or Ethnic Groups

In adults receiving methylphenidate hydrochloride extended-release tablets, dose-adjusted AUC (0–inf) was consistent across ethnic groups; however, the sample size may have been insufficient to detect ethnic variations in pharmacokinetics.

Pediatric Patients

Increase in age resulted in increased apparent oral clearance (CL/F) (58% increase in pediatric patients 13 to 17 years compared to pediatric patients 6 to 12 years). Some of these differences could be explained by body-weight differences among these populations. This suggests that subjects with higher body weight may have lower exposures of total methylphenidate at similar doses.

The pharmacokinetics of methylphenidate hydrochloride extended-release tablets have not been studied in pediatric patients less than 6 years of age.

Patients with Renal Impairment

There is no experience with the use of methylphenidate hydrochloride extended- release tablets in patients with renal insufficiency. After oral administration of radiolabeled methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of PPAA. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of methylphenidate hydrochloride extended-release tablets.

Patients with Hepatic Impairment

There is no experience with the use of methylphenidate hydrochloride extended- release tablets in patients with hepatic insufficiency.

3 DOSAGE FORMS AND STRENGTHS

RELEXXII (methylphenidate hydrochloride extended-release tablets) are available in the following strengths:

• 18 mg: yellow with “TL706” imprinted in black ink
• 27 mg: gray with “TL707” imprinted in black ink
• 36 mg: white with “TL708” imprinted in black ink
• 45 mg: pink with “TL711” imprinted in black ink
• 54 mg: pink with “TL709” imprinted in black ink
• 63 mg: orange with “TL700” imprinted in black ink and
• 72 mg: blue with “TL710” imprinted in black ink.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

RELEXXII contains methylphenidate, a Schedule II controlled substance.

9.2 Abuse

RELEXXII has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions (5.1)]. RELEXXII can be diverted for non-medical use into illicit channels or distribution.

Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of methylphenidate may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including RELEXXII, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration such as snorting or injection.

In two placebo-controlled human abuse potential studies, single oral doses of another formulation of methylphenidate hydrochloride extended-release tablets were compared to single oral doses of immediate-release methylphenidate (IR MPH) and placebo in subjects with a history of recreational stimulant use to assess relative abuse potential. For the purpose of this assessment, the response for each of the subjective measures was defined as the maximum effect within the first 8 hours after dose administration.

In one study (n=40), both the other formulation of methylphenidate hydrochloride extended-release tablets (108 mg, which is 1.5 times the maximum recommended dosage of methylphenidate hydrochloride extended-release tablets) and 60 mg IR MPH compared to placebo produced statistically significantly greater responses on the five subjective measures suggestive of abuse potential. In comparisons between the two active treatments, however, the other formulation of methylphenidate hydrochloride extended-release tablets (108 mg) produced variable responses on positive subjective measures that were either statistically indistinguishable from (Abuse Potential, Drug Liking, Amphetamine, and Morphine Benzedrine Group [Euphoria]) or statistically less than (Stimulation – Euphoria) responses produced by 60 mg IR MPH.

In another study (n=49), both doses of another formulation of methylphenidate hydrochloride extended-release tablets (54 mg and 108 mg) and both doses of IR MPH (50 mg and 90 mg) produced statistically significantly greater responses compared to placebo on the two primary scales used in the study (Drug Liking, Euphoria). When doses of the other methylphenidate hydrochloride extended- release tablets (54 mg and 108 mg) were compared to IR MPH (50 mg and 90 mg), respectively, methylphenidate hydrochloride extended-release tablets produced statistically significantly lower subjective responses on these two scales than IR MPH. Methylphenidate hydrochloride extended-release tablets (108 mg) produced responses that were statistically indistinguishable from the responses on these two scales produced by IR MPH (50 mg). Differences in subjective responses to the respective doses should be considered in the context that only 18% of the total amount of methylphenidate in RELEXXII is available for immediate release from the drug overcoat.

Although these findings reveal a relatively lower response to another formulation of methylphenidate hydrochloride extended-release tablets on subjective measures suggestive of abuse potential compared to IR MPH at roughly equivalent total MPH doses, the relevance of these findings to the abuse potential of RELEXXII in the community is unknown.

9.3 Dependence

Physical Dependence

RELEXXII may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants including RELEXXII include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

Tolerance

RELEXXII may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained by a lower dose).

10 OVERDOSAGE

Clinical Effects of Overdose

Overdose of CNS stimulants is characterized by the following sympathomimetic effects:

• Cardiovascular effects including tachyarrhythmias, and hypertension or hypotension. Vasospasm, myocardial infarction, or aortic dissection may precipitate sudden cardiac death. Takotsubo cardiomyopathy may develop.
• CNS effects including psychomotor agitation, confusion, and hallucinations. Serotonin syndrome, seizures, cerebral vascular accidents, and coma may occur.
• Life-threatening hyperthermia (temperatures greater than 104°F) and rhabdomyolysis may develop.

Overdose Management

Consider the possibility of multiple drug ingestion. The pharmacokinetic profile of RELEXXII should be considered when treating patients with overdose. Because methylphenidate has a large volume of distribution and is rapidly metabolized, dialysis is not useful. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

11 DESCRIPTION

RELEXXII contains methylphenidate, a CNS stimulant, present as methylphenidate hydrochloride salt. Chemically, methylphenidate hydrochloride is d,l (racemic) methyl α-phenyl-2-piperidineacetate hydrochloride. Its empirical formula is C14H19NO2•HCl. Its structural formula is:


Methylphenidate hydrochloride is a white, odorless crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. It has a pKa of 8.71 (at 21.5°C). Its molecular weight is 269.77.

RELEXXII is for oral administration and is available in the following strengths: 18 mg, 27 mg, 36 mg, 45 mg, 54 mg, 63 mg, and 72 mg containing methylphenidate hydrochloride (equivalent to 15.6 mg, 23.4 mg, 31.1 mg, 38.9 mg, 46.7 mg, 54.5 mg, and 62.3 mg methylphenidate respectively).

RELEXXII contains the following inactive ingredients: cellulose acetate, colloidal silicon dioxide, ferrosoferric oxide, hypromellose, iron oxide black, lactose monohydrate, magnesium stearate, phosphoric acid, polyethylene glycol, polyethylene oxide, sodium chloride, succinic acid, titanium dioxide, triacetin.

RELEXXII also contains the following color additives:

27 mg: FD&C Yellow #6 Aluminum Lake, FD&C Blue #2 Aluminum Lake, FD&C Red #40 Aluminum Lake

45 mg: FD&C Red #40 Aluminum Lake

54 mg: FD&C Yellow #6 Aluminum Lake, FD&C Red #40 Aluminum Lake, FD&C Blue #2 Aluminum Lake

63 mg: iron oxide red, iron oxide yellow

72 mg: FD&C Blue #1 Aluminum Lake

System Components and Performance

RELEXXII uses osmotic pressure to deliver methylphenidate hydrochloride at a controlled rate. The system, which resembles a conventional tablet in appearance, comprises an osmotically active bilayer core surrounded by a semipermeable membrane with an immediate-release drug overcoat. The bilayer core is composed of a drug layer containing the drug and excipients, and a push layer containing osmotically active components. There is a precision- laser drilled orifice on the drug-layer end of the tablet. In an aqueous environment, such as the gastrointestinal tract, the drug overcoat dissolves within one hour, providing an initial dose of methylphenidate. Water permeates through the membrane into the tablet core. As the osmotically active polymer excipients expand, methylphenidate is released through the orifice. The membrane controls the rate at which water enters the tablet core, which in turn controls drug delivery. Furthermore, the drug release rate from the system increases with time over a period of 6 to 7 hours due to the drug- concentration gradient incorporated into the two drug layers of core of RELEXXII. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the stool as a tablet shell along with insoluble core components. It is possible that RELEXXII may be visible on abdominal x-rays under certain circumstances, especially when digital enhancing techniques are utilized.

14 CLINICAL STUDIES

The efficacy of RELEXXII for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients (6 to 17 years) and adult patients is based upon adequate and well-controlled studies of another formulation of methylphenidate hydrochloride extended-release tablets (referred to as “methylphenidate hydrochloride extended-release tablets” in the section below). The results of these adequate and well-controlled studies are presented below.

Methylphenidate hydrochloride extended-release tablets was demonstrated to be effective in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in four randomized, double-blind, placebo-controlled studies in pediatric patients 6 to 17 years and two double-blind placebo-controlled studies in adults who met the Diagnostic and Statistical Manual 4th edition (DSM-IV) criteria for ADHD.

Pediatric Patients 6 to 12 Years

Three double-blind, active- and placebo-controlled studies were conducted in 416 pediatric patients 6 to 12 years. The controlled studies compared methylphenidate hydrochloride extended-release tablets given once daily (18 mg, 36 mg, or 54 mg), methylphenidate given three times daily over 12 hours (15 mg, 30 mg, or 45 mg total daily dose), and placebo in two single-center, 3-week crossover studies (Studies 1 and 2) and in a multicenter, 4-week, parallel-group comparison (Study 3). The primary comparison of interest in all three trials was methylphenidate hydrochloride extended-release tablets versus placebo.

Symptoms of ADHD were evaluated by community schoolteachers using the Inattention/Overactivity with Aggression (IOWA) Conners scale. Statistically significant reduction in the Inattention/Overactivity subscale versus placebo was shown consistently across all three controlled studies for methylphenidate hydrochloride extended-release tablets. Studies 1 and 2 involved a 3-way crossover of 1 week per treatment arm. Study 3 involved 4 weeks of parallel- group treatments with a Last Observation Carried Forward analysis at Week 4.

The scores for methylphenidate hydrochloride extended-release tablets and placebo for the three studies are presented in Figure 2. Error bars represent the mean plus standard error of the mean.

Figure 2: Mean Community School Teacher IOWA Conners Inattention/Overactivity Scores with Methylphenidate Hydrochloride Extended- Release Tablets Once Daily (18 mg, 36 mg, or 54 mg) and Placebo (Studies 1, 2, and 3)


In Studies 1 and 2, symptoms of ADHD were evaluated by laboratory schoolteachers using the Swanson, Kotkin, Agler, M-Fynn, and Pelham (SKAMP) laboratory school rating scale. The combined results from these two studies demonstrated statistically significant improvements in attention and behavior in patients treated with methylphenidate hydrochloride extended-release tablets versus placebo that were maintained through 12 hours after dosing. Figure 3 presents the laboratory schoolteacher SKAMP ratings for methylphenidate hydrochloride extended-release tablets and placebo.

Figure 3: Laboratory School Teacher SKAMP Ratings: Mean (SEM) of Combined Attention (Studies 1 and 2)


Pediatric Patients 13 to 17 years

In a randomized, double-blind, multicenter, placebo-controlled trial (Study 4) involving 177 patients, methylphenidate hydrochloride extended-release tablets was demonstrated to be effective in the treatment of ADHD in pediatric patients aged 13 to 18 years at doses up to 72 mg once daily (1.4 mg/kg/day). Of 220 patients who entered an open 4-week titration phase, 177 were titrated to an individualized dose (maximum of 72 mg once daily) based on meeting specific improvement criteria on the ADHD Rating Scale and the Global Assessment of Effectiveness with acceptable tolerability. Patients who met these criteria were then randomized to receive either their individualized dose of methylphenidate hydrochloride extended-release tablets (18 mg to 72 mg once daily, n=87) or placebo (n=90) during a two-week double-blind phase. At the end of this phase, mean scores for the investigator rating on the ADHD Rating Scale demonstrated that methylphenidate hydrochloride extended-release tablets was statistically significantly superior to placebo.

Adults

Two double-blind, placebo-controlled studies were conducted in 627 adults aged 18 to 65 years. The controlled studies compared methylphenidate hydrochloride extended-release tablets administered once daily and placebo in a multicenter, parallel-group, 7-week dose-titration study (Study 5) (36 mg to 108 mg once daily) and in a multicenter, parallel-group, 5-week, fixed-dose study (Study 6) (18 mg, 36 mg, and 72 mg once daily).

Study 5 demonstrated the effectiveness of methylphenidate hydrochloride extended-release tablets in the treatment of ADHD in adults aged 18 to 65 years at doses from 36 mg once daily to 108 mg once daily based on the change from baseline to final study visit on the Adult ADHD Investigator Rating Scale (AISRS). Of 226 patients who entered the 7-week trial, 110 were randomized to methylphenidate hydrochloride extended-release tablets and 116 were randomized to placebo. Treatment was initiated at 36 mg once daily and patients continued with incremental increases of 18 mg once daily (36 mg to 108 mg once daily) based on meeting specific improvement criteria with acceptable tolerability. At the final study visit, mean change scores (LS Mean, SEM) for the investigator rating on the AISRS demonstrated methylphenidate hydrochloride extended-release tablets was statistically significantly superior to placebo.

Study 6 was a multicenter, double-blind, randomized, placebo-controlled, parallel-group, dose-response study (5-week duration) with 3 fixed-dose groups (18 mg, 36 mg, and 72 mg). Patients were randomized to receive methylphenidate hydrochloride extended-release tablets administered at doses of 18 mg (n=101), 36 mg (n=102), 72 mg once daily (n=102), or placebo (n=96). All three doses of methylphenidate hydrochloride extended-release tablets were statistically significantly more effective than placebo in improving CAARS (Conners' Adult ADHD Rating Scale) total scores at double-blind end point in adult subjects with ADHD.

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

RELEXXII® (methylphenidate hydrochloride extended-release tablets) are available as:

• 18 mg yellow tablets with “TL706” imprinted in black ink
  • NDC 68025-095-10 in 100-count bottle
• 27 mg gray tablets with “TL707” imprinted in black ink
  • NDC 68025-096-10 in 100-count bottle
• 36 mg white tablets with “TL708” imprinted in black ink
  • NDC 68025-097-10 in 100-count bottle
• 45 mg pink tablets with “TL711” imprinted in black ink
  • NDC 68025-088-30 in 30-count bottle
• 54 mg pink tablets with “TL709” imprinted in black ink
  • NDC 68025-098-10 in 100-count bottle
• 63 mg orange tablets with “TL 700” imprinted in black ink
  • NDC 68025-089-30 in 30-count bottle
• 72 mg blue tablets with “TL710” imprinted in black ink
  • NDC 68025-084-30 in 30-count bottle

Storage and Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from humidity.

MEDICATION GUIDE

2 DOSAGE AND ADMINISTRATION

2.1 Pretreatment Screening

Prior to treating patients with RELEXXII, assess:

• for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions (5.2)].
• the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating RELEXXII [see Warnings and Precautions (5.11)].

2.2 General Administration Information

Administer RELEXXII orally once daily in the morning with or without food.

Swallow RELEXXII whole with liquid. Do not chew, divide, or crush [see Warnings and Precautions (5.8)].

2.3 Dosage Recommendations for Patients New to Methylphenidate

Table 1 includes the starting dosage and dosage recommendations for RELEXXII in pediatric patients 6 to 17 years and adults who are not currently taking methylphenidate or other stimulants.

Table 1: Dosage Recommendations for RELEXXII in Pediatric Patients 6 to 17 years and Adults

**2.4 Dosage Recommendations for Patients Currently Using

Methylphenidate**

The recommended starting dosage of RELEXXII for patients who are currently taking methylphenidate twice daily or three times daily at doses of 10 mg to 60 mg daily is provided in Table 2.

Table 2. Recommended Starting Dosage when Converting from Methylphenidate Regimens to RELEXXII

2.5 Dose Titration

Doses may be increased in 18 mg increments at weekly intervals for patients who have not achieved clinical response at a lower dose. Daily dosages above 54 mg in pediatric patients 6 to 12 years and above 72 mg in pediatric patients 13 to 17 years have not been studied and are not recommended. Daily dosages above 72 mg are not recommended in adults.

Dosage strengths of 27 mg, 45 mg, and 63 mg are available for additional titration options based on clinical response.

2.6 Dosage Reduction and Discontinuation

If paradoxical aggravation of symptoms or other adverse reaction occur, reduce the dosage, or, if necessary, discontinue RELEXXII.

If improvement is not observed after appropriate dosage adjustment over a one- month period, discontinue RELEXXII.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis

In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas at a daily dose of approximately 60 mg/kg/day. This dose is approximately 4 times the MRHD of methylphenidate hydrochloride extended-release tablets on a mg/m2 basis, respectively. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown.

Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 6 times the MRHD of methylphenidate hydrochloride extended-release tablets on a mg/m2 basis, respectively.

In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate.

Mutagenesis

Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay.

Impairment of Fertility

Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week Continuous Breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 11-fold the MRHD of methylphenidate hydrochloride extended-release tablets on a mg/m2 basis, respectively.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Abuse, Misuse, and Addiction

Educate patients and their families about the risks of abuse, misuse, and addiction of RELEXXII, which can lead to overdose and death, and proper disposal of any unused drug [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2), and Overdosage (10)].Advise patients to store RELEXXII in a safe place, preferably locked, and instruct patients to not give RELEXXII to anyone else.

Administration Instructions

Instruct patients to swallow RELEXXII whole with the aid of liquids, and not to chew, divide, or crush the tablets. Advise patients that the medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell, along with insoluble core components, is eliminated from the body; advise patients not to be concerned if they occasionally notice in their stool something that looks like a tablet [see Dosage and Administration (2.2), Warnings and Precautions (5.8)].

Risks to Patients with Serious Cardiac Disease

Advise patients that there are potential risks to patients with serious cardiac disease, including sudden death with RELEXXII use. Instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see Warnings and Precautions (5.2)].

Increased Blood Pressure and Heart Rate

Advise patients and their caregivers that RELEXXII can cause elevations of their blood pressure and pulse rate [see Warnings and Precautions (5.3)].

Psychiatric Adverse Reactions

Advise patients and their caregivers that RELEXXII, at recommended doses, can cause psychotic or manic symptoms, even in patients without prior history of psychotic symptoms or mania [see Warnings and Precautions (5.4)].

Priapism

Advise patients, caregivers, and family members of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism [see Warnings and Precautions (5.5)].

Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, including Raynaud’s Phenomenon] (see Warnings and Precautions (5.6)].

• Instruct patients beginning treatment with RELEXXII about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red.
• Instruct patients to report to their healthcare provider any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes.
• Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking RELEXXII.
• Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

Long-Term Suppression of Growth in Pediatric Patients

Advise patients, families and caregivers that RELEXXII may cause slowing of growth and weight loss [see Warnings and Precautions (5.7)].

Increased Intraocular Pressure (IOP) and Glaucoma

Advise patients that IOP and glaucoma may occur during treatment with RELEXXII [see Warnings and Precautions (5.10)].

Motor and Verbal Tics, and Worsening of Tourette’s Syndrome

Advise patients that motor and verbal tics and worsening of Tourette’s Syndrome may occur during treatment with RELEXXII. Instruct patients to notify their healthcare provider if emergence of new tics or worsening of tics or Tourette’s syndrome occurs [see Warnings and Precautions (5.11].

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to RELEXXII during pregnancy [see Use in Specific Populations (8.1)].

Distributed by:

Vertical Pharmaceuticals, LLC

Alpharetta, GA 30005

1-800-444-5164

www.verticalpharma.com

200438-6

Patent numbers:

US 9,855,258

US 9,827,234

US 9,707,217

US 10,265,308

US 10,695,336