Dexmethylphenidate Hydrochloride (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis

Lifetime carcinogenicity studies have not been carried out with dexmethylphenidate. In a lifetime carcinogenicity study carried out in B6C3F1 mice, racemic methylphenidate caused an increase in hepatocellular adenomas, and in males only, an increase in hepatoblastomas was seen at a daily dose of approximately 60 mg/kg/day. This dose is approximately 2 times the MRHD of 60 mg/day of racemic methylphenidate given to children on a mg/m ² basis. 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. Racemic methylphenidate did not cause any increase 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 4 times the MRHD (children) of 60 mg/day of racemic methylphenidate on a mg/m ² basis.

In a 24-week carcinogenicity study with racemic methylphenidate 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 concentrations as in the lifetime carcinogenicity study; the high-dose group was exposed to 60-74 mg/kg/day of racemic methylphenidate.

Mutagenesis

Dexmethylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vivo mouse bone marrow micronucleus test. In an in vitro assay using cultured Chinese Hamster Ovary cells treated with racemic methylphenidate, sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response.

Impairment of Fertility

No human data on the effect of methylphenidate on fertility are available.

Fertility studies have not been conducted with dexmethylphenidate. Racemic 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 of up to 160 mg/kg/day, approximately 10 times the MRHD of 60 mg/day of racemic methylphenidate given adolescents on a mg/m ² basis.

14 CLINICAL STUDIES

The efficacy of dexmethylphenidate hydrochloride tablets for the treatment of ADHD was established in two double-blind, parallel-group, placebo- controlled trials in untreated or previously treated patients (ages 6 to 17 years old) who met The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for ADHD inattentive, hyperactive-impulsive, or combined inattentive/hyperactive-impulsive subtypes. The sample was predominantly younger (ages 6 to 12 years); thus, the findings are most pertinent to this age group.

In Study 1, patients were randomized to receive either dexmethylphenidate hydrochloride tablets (5, 10, or 20 mg/day total dose), racemic methylphenidate HCl (10, 20, or 40 mg/day total dose), or placebo in a multicenter, 4-week, parallel group study in 132 pediatric patients. Patients received study medication twice daily separated by a 3.5 to 5.5 hours interval. Treatment was initiated with the lowest dose, and doses could be doubled at weekly intervals, depending on clinical response and tolerability, up to the maximum dose. The primary outcome was change from baseline to week 4 of the average score (an average of 2 ratings during the week) of the teacher’s version of the Swanson, Nolan and Pelham (SNAP)-ADHD Rating Scale. This 18 item scale measures ADHD symptoms of inattention and hyperactivity/impulsivity, rated on a scale of 0 (Not at All) to 3 (Very Much). Patients treated with dexmethylphenidate hydrochloride tablets showed a statistically significant improvement in symptom scores from baseline over patients who received placebo (Table 3).

Study 2 was a multicenter, placebo-controlled, double-blind, 2-week treatment withdrawal study in 75 children (ages 6 to 12 years) who were responders during a 6-week, open-label initial treatment period. Children took study medication twice a day separated by a 3.5 to 5.5 hour interval. The primary outcome was proportion of treatment failures at the end of the 2-week withdrawal phase, where treatment failure was defined as a rating of 6 (much worse) or 7 (very much worse) on the Investigator Clinical Global Impression — Improvement (CGI-I). Patients continued on dexmethylphenidate hydrochloride tablets showed a statistically significant lower rate of failure over patients who received placebo (Table 4).

16 HOW SUPPLIED/STORAGE AND HANDLING

Dexmethylphenidate hydrochloride tablets, 2.5 mg are blue, round, biconvex tablets debossed “A1” on one side and plain on the other side.

Bottles of 100………………. NDC 10702-0106-01

Dexmethylphenidate hydrochloride tablets, 5 mg are yellow, round, biconvex tablets debossed “A2” on one side and plain on the other side.

Bottles of 100………………. NDC 10702-0107-01

Dexmethylphenidate hydrochloride tablets, 10 mg are white, round, biconvex tablets, debossed “A3” on one side and plain on the other side.

Bottles of 100………………. NDC 10702-0108-01

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

Dispense in tight, light-resistant container (USP).

Disposal

Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired dexmethylphenidate hydrochloride tablets by a medicine takeback program or by an authorized collector registered with the Drug Enforcement Administration. If no take-back program or authorized collector is available, mix dexmethylphenidate hydrochloride tablets with an undesirable, nontoxic substance to make it less appealing to children and pets. Place the mixture in a container, such as a sealed plastic bag and discard dexmethylphenidate hydrochloride tablets in the household trash.

17 PATIENT COUNSELING INFORMATION

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

Controlled Substance Status/High Potential for Abuse and Dependence

Advise patients that dexmethylphenidate hydrochloride tablets is a controlled substance, and it can be abused and lead to dependence. Instruct patients that they should not give dexmethylphenidate hydrochloride tablets to anyone else. Advise patients to store dexmethylphenidate hydrochloride tablets in a safe place, preferably locked, to prevent abuse. Advise patients to comply with laws and regulations on drug disposal. Advise patients to dispose of remaining, unused, or expired dexmethylphenidate hydrochloride tablets by a medicine take-back program if available [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9.1, 9.2, 9.3), How Supplied/Storage and Handling (16)].

Serious Cardiovascular Risks

Advise patients that there is a potential serious cardiovascular risk, including sudden death, myocardial infarction, stroke, and hypertension with dexmethylphenidate hydrochloride tablets 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)].

Blood Pressure and Heart Rate Increases

Instruct patients that dexmethylphenidate hydrochloride tablets can cause elevations of their blood pressure and pulse rate [see Warnings and Precautions (5.3)].

Psychiatric Risks

Advise patients that dexmethylphenidate hydrochloride tablets, 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 of the possibility of painful or prolonged penile erections (priapism). Instruct them 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]

Instruct patients beginning treatment with dexmethylphenidate hydrochloride tablets 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 physician 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 dexmethylphenidate hydrochloride tablets. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see Warnings and Precautions (5.6)].

Suppression of Growth

Advise patients that dexmethylphenidate hydrochloride tablets may cause slowing of growth and weight loss [see Warnings and Precautions (5.7)].

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to ADHD medications, including dexmethylphenidate hydrochloride tablets, during pregnancy [see Use in Specific Populations (8.1)].

Manufactured by:
KVK-Tech, Inc.
110 Terry Drive
Newtown, PA 18940

Manufacturer’s code: 10702 Item ID #: 6205/04 Rev.: 01/2022