Methamphetamine

12.1 Mechanism of Action Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The exact mode of therapeutic action in the treatment of ADHD is not known.

1 INDICATIONS AND USAGE Methamphetamine hydrochloride tablets are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients 6 years of age and older. • Methamphetamine hydrochloride tablets are a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients 6 years of age and older. ( 1 )

2 DOSAGE AND ADMINISTRATION • Administer methamphetamine hydrochloride tablets orally once daily or in two divided doses daily. Avoid administration late in the evening due to the risk of insomnia. ( 2.2 ) • Recommended starting dosage is 5 mg once or twice daily. ( 2.3 ) • Daily dosage may be increased in 5 mg increments at weekly intervals depending on clinical response. ( 2.3 ) • The recommended dosage range is 20 mg to 25 mg daily. ( 2.3 ) 2.1 Pretreatment Screening Prior to treating patients with methamphetamine hydrochloride tablets, assess: • for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical examination) [see Warnings and Precautions ( 5.2 )] . • the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating methamphetamine hydrochloride tablets [see Warnings and Precautions ( 5.9 )] . 2.2 Important Dosing Information Administer methamphetamine hydrochloride tablets orally once daily or in two divided doses daily. Avoid taking methamphetamine hydrochloride tablets late in the evening due to the risk of insomnia. 2.3 Recommended Dosage For pediatric patients 6 years of age and older, the recommended starting dosage is 5 mg methamphetamine hydrochloride tablets once or twice daily. The daily dosage may be increased in increments of 5 mg at weekly intervals based on clinical response of the patient. The recommended dosage range is 20 mg to 25 mg daily. 2.4 Dosage Modifications Due to Drug Interactions Agents that alter urinary pH can impact excretion and alter blood levels of amphetamine. Acidifying agents (e.g., ascorbic acid) decrease blood levels, while alkalinizing agents (e.g., sodium bicarbonate) increase blood levels. Adjust methamphetamine hydrochloride tablets dosage based on clinical response [see Drug Interactions ( 7.1 )] .

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Abuse, Misuse, and Addiction [see Boxed Warning, Warnings and Precautions ( 5.1 ), Drug Abuse and Dependence ( 9.2 , 9.3 )] • Hypersensitivity to amphetamine products or other ingredients of methamphetamine hydrochloride tablets [see Contraindications ( 4 )] • Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors [see Contraindications ( 4 ), Drug Interactions ( 7.1 )] • Risks to Patient 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 )] • Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions ( 5.5 )] • Peripheral Vasculopathy, including Raynaud’s Phenomenon [see Warnings and Precautions ( 5.6 )] • Seizures [see Warnings and Precautions ( 5.7 )] • Serotonin Syndrome [see Warnings and Precautions ( 5.8 )] • Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions ( 5.9 )] The following adverse reactions associated with the use of methamphetamine hydrochloride tablets were identified in clinical trials or postmarketing reports. Because these reactions were 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. Cardiovascular: Elevation of blood pressure, tachycardia and palpitation. Fatal cardiorespiratory arrest has been reported, mostly in the context of abuse/misuse Central Nervous System: Psychotic episodes reported at recommended doses. Dizziness, dysphoria, overstimulation, euphoria, insomnia, tremor, restlessness and headache. Exacerbation of motor and verbal tics and Tourette’s syndrome Gastrointestinal: Diarrhea, constipation, dryness of mouth, unpleasant taste, intestinal ischemia, and other gastrointestinal disturbances Hypersensitivity: Urticaria Endocrine: Impotence and changes in libido; frequent or prolonged erections Musculoskeletal: Rhabdomyolysis Metabolism and Nutrition Disorders: Suppression of growth has been reported with the long-term use of stimulants in pediatric patients Skin and Subcutaneous Tissue Disorders: Alopecia The following additional adverse reactions have been identified during post approval use of amphetamines: Allergic: Rash, hypersensitivity reactions, including angioedema and anaphylaxis. Serious skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. Cardiovascular: Dyspnea, sudden death, myocardial infarction. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use Central Nervous System: dyskinesia, fatigue, aggression, anger, logorrhea, dermatillomania, and paresthesia (including formication) Eye Disorders: Mydriasis Vascular Disorders: Raynaud’s phenomenon Common adverse reactions include: palpitation, dizziness, insomnia, tremor, headache, diarrhea, dryness of mouth. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS Acidifying and Alkalinizing Agents: Agents that alter GI and urinary pH can alter blood levels of amphetamine. Acidifying agents can decrease amphetamine blood levels, while alkalinizing agents can increase amphetamine blood levels. ( 7.1 ) 7.1 Drugs Having Clinically Important Interactions with Methamphetamine Hydrochloride Tablets Table 1 presents clinically important drug interactions with methamphetamine hydrochloride tablets. Table 1: Clinically Important Drug Interactions with Methamphetamine Hydrochloride Tablets Monoamine Oxidase Inhibitors (MAOI) Clinical Impact: MAOI antidepressants slow amphetamine metabolism, increasing amphetamines effect on the release of norepinephrine and other monoamines from adrenergic nerve endings causing headaches and other signs of hypertensive crisis. Toxic neurological effects and malignant hyperpyrexia can occur, sometimes with fatal results. Intervention: Concomitant use of methamphetamine hydrochloride tablets with monoamine oxidase inhibitors (MAOIs) or within 14 days after discontinuing MAOI treatment is contraindicated [see Contraindications ( 4 )] . Serotonergic Drugs Clinical Impact: The concomitant use of amphetamines, including methamphetamine, and serotonergic drugs increases the risk of serotonin syndrome. Intervention: Initiate methamphetamine hydrochloride tablets with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during methamphetamine hydrochloride tablets initiation or dosage increase. If serotonin syndrome occurs, discontinue methamphetamine hydrochloride tablets and the concomitant serotonergic drug(s) [see Warnings and Precautions ( 5.8 )] . Alkalinizing Agents Clinical Impact: Alkalinizing agents may increase exposure to amphetamines and potentiate the action of amphetamine. Intervention: Avoid co-administration of methamphetamine hydrochloride tablets and gastrointestinal and urinary alkalinizing agents. Acidifying Agents Clinical Impact: Acidifying agents lower blood levels and efficacy of amphetamines. Intervention: Increase dose of methamphetamine hydrochloride tablets based on clinical response. Tricyclic Antidepressants Clinical Impact: May enhance the activity of tricyclic or sympathomimetic agents causing sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated. Intervention: Monitor frequently and adjust methamphetamine hydrochloride tablets dose or use alternative therapy based on clinical response. CYP2D6 Inhibitors Clinical Impact: Concomitant use of methamphetamine hydrochloride tablets and CYP2D6 inhibitors may increase the exposure of methamphetamine compared to the use of the drug alone, and increase the risk of serotonin syndrome. Intervention: Start with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during methamphetamine hydrochloride tablets initiation and after a dosage increase. If serotonin syndrome occurs, discontinue methamphetamine hydrochloride tablets and the CYP2D6 inhibitor [see Warnings and Precautions ( 5.8 )] . Gastric pH Modulators Clinical Impact: Time to maximum concentration (T max ) of amphetamine is decreased compared to when administered alone. Intervention: Monitor patients for changes in clinical effect and use alternative therapy based on clinical response. Guanethidine Clinical Impact: Methamphetamine may decrease the hypotensive effect of guanethidine . Intervention: Monitor patients and adjust therapy based on clinical response. Insulin requirements in diabetes mellitus may be altered in association with the use of methamphetamine and the concomitant dietary regimen. 7.2 Drug/Laboratory Test Interactions Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening. Amphetamines may interfere with urinary steroid determinations.