AHFS Class:

• Amphetamines 28:20.04

Generic Name(s):

• Methamphetamine Hydrochloride

Methamphetamine is a CNS stimulant.1

Attention Deficit Hyperactivity Disorder

Methamphetamine is used for the treatment of attention deficit hyperactivity disorder (ADHD) in pediatric patients 6 years of age and older.1

Use of methamphetamine for the treatment of ADHD is rare due to the overall risks versus benefits of its use.2 No published clinical trial data are available.2 There is a high potential for abuse that can lead to the development of a substance use disorder.1 Long-term abuse of methamphetamine leads to neurodegenerative changes in the brain.2

The American Academy of Pediatrics (AAP) has developed guidelines for children and adolescents with ADHD.3 For pediatric patients 6-12 years of age with ADHD, the provider should prescribe FDA-approved medications, in addition to parent training in behavior management (PTBM) and/or behavioral classroom interventions.3 For the choice of medication, evidence is stated as particularly strong for stimulant medications (e.g., methylphenidate).3 Evidence is stated as sufficient but not as strong for atomoxetine, extended-release guanfacine, and extended-release clonidine.3 For adolescents 12-18 years of age with ADHD, the provider should prescribe FDA-approved medications with the assent of the adolescent.3 The provider is also encouraged to prescribe behavioral and other evidence-based training interventions if available.3 Doses of medications should be titrated to achieve maximum benefit with tolerable side effects.3 Methamphetamine is not included in these guidelines.3

General

Pretreatment Screening

• Evaluate patients for risk of abuse, misuse, and addiction prior to initiation of CNS stimulant therapy.1
• Children, adolescents, and adults being considered for stimulant therapy should undergo a thorough medical history review (including evaluation for a family history of sudden death or ventricular arrhythmia) and physical examination to detect the presence of cardiac disease.1
• Prior to initiating stimulant therapy, screen patients with attention deficit hyperactivity disorder (ADHD) carefully to determine if they are at risk for developing a manic episode; such screening should include a detailed psychiatric history (e.g., current or prior depressive symptoms; family history of suicide, bipolar disorder, or depression).1
• Prior to initiation of therapy, screen patients for motor or verbal tics or Tourette's syndrome.1

Patient Monitoring

• Routinely monitor for the emergence or worsening of tics or Tourette's syndrome.1
• Monitor growth (weight and height) closely in pediatric patients receiving stimulant therapy.1
• Throughout treatment, reassess each patient's risk of abuse, misuse, and addiction.1 Frequently monitor for signs of abuse, misuse, and addiction during treatment.1
• Monitor for hypertension and tachycardia during stimulant therapy.1

Dispensing and Administration Precautions

Handling and Disposal

• Methamphetamine should be disposed of by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site when it is no longer needed.1 If there is no take-back program or authorized DEA collection site available, the drug can be mixed with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds and disposed of in a sealed plastic bag in the household trash.1

Administration

Methamphetamine hydrochloride is administered orally.1 Because of the potential for insomnia, administration of methamphetamine in the late evening should be avoided.1

Methamphetamine hydrochloride preparations should be stored in tight, light-resistant, child-resistant containers at 20-25°C.1

Dosage

Dosage and potency of methamphetamine hydrochloride are expressed in terms of the hydrochloride.1

Dosage of methamphetamine hydrochloride should be adjusted according to individual response and tolerance; the smallest dose required to produce the desired response should always be used.1

When possible, interrupt therapy occasionally to determine if there is recurrence of behavioral symptoms sufficient to require continued treatment.1

Pediatric Patients

Attention Deficit Hyperactivity Disorder

For the treatment of ADHD in children ≥6 years of age, the usual initial dosage of methamphetamine hydrochloride is 5 mg once or twice daily.1 Daily dosage may be increased by 5 mg at weekly intervals until an optimum clinical response is achieved.1 The usual recommended dosage is 20-25 mg daily.1 The total daily dose may be given once daily or in 2 divided doses.1

Special Populations

Hepatic Impairment

The manufacturer does not provide specific dosage recommendations for patients with hepatic impairment.1

Renal Impairment

The manufacturer does not provide specific dosage recommendations for patients with renal impairment.1

Geriatric Patients

The manufacturer does not provide specific dosage recommendations for geriatric patients.1 Due to the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease or drug therapy, dosage selection for geriatric patients should be cautious, usually starting at the low end of the dosage range.1

Contraindications

• Concomitant or recent (within 14 days) administration of monoamine oxidase inhibitors (MAOIs), since hypertensive crisis could result.1
• Known hypersensitivity to amphetamine, or any ingredient in methamphetamine hydrochloride tablets.1 Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported in patients taking other amphetamine products.1

Warnings/Precautions

Warnings

Abuse, Misuse, and Addiction

A boxed warning is included in the prescribing information for methamphetamine concerning the high potential for abuse and misuse.1 The use of methamphetamine products exposes patients to the risks of abuse and misuse, which can lead to the development of substance use disorder (including addiction).1 Abuse of CNS stimulants such as methamphetamine can result in overdose or death.1 This risk is further increased with higher dosages or unapproved routes of administration (i.e., snorting, injection).1 The potential for abuse, misuse, and addiction should be assessed prior to initiation of CNS stimulant therapy, and patients should be monitored for signs of abuse, misuse, and addiction frequently during therapy.1

In addition, tolerance can develop during amphetamine therapy, which is characterized by a reduced response to the drug after repeated administration.1 In patients who are physically dependent on CNS stimulants, abrupt cessation of therapy, rapid dosage reduction, or administration of an antagonist may result in a withdrawal syndrome characterized by dysphoric mood, depression, fatigue, vivid and unpleasant dreams, insomnia or hypersomnia, increased appetite, and psychomotor retardation or agitation.1

Patients and/or their caregivers should be advised that methamphetamine can be abused and can result in dependence; they should be advised that methamphetamine should not be shared with others and should be stored in a safe (preferably locked) location to prevent misuse and abuse.1 Methamphetamine should be disposed of by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site when it is no longer needed.1 If there is no take-back program or authorized DEA collection site available, the drug can be mixed with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds and disposed of in a sealed plastic bag in the household trash.1

Other Warnings/Precautions

Risks to Patients with Serious Cardiac Disease

Sudden, unexplained death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease receiving usual dosages of CNS stimulants for the treatment of ADHD.1

Patients who are being considered for stimulant therapy should undergo a thorough medical history review (including evaluation for a family history of sudden death or ventricular arrhythmia) and physical examination to detect the presence of cardiac disease.1 In general, CNS stimulants should not be used in patients with known serious structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.1

Increased Blood Pressure and Heart Rate

Stimulants cause modest increases in average blood pressure (i.e., by about 2-4 mm Hg) and heart rate (i.e., by about 3-6 beats/minute); larger increases may occur in some patients.1 All patients should be monitored for hypertension and tachycardia.1

Psychiatric Adverse Reactions

Stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder.1

Stimulants have the potential to precipitate mixed or manic episodes in patients with comorbid bipolar disorder.1 Prior to initiating stimulant therapy, patients with ADHD should be carefully screened to determine if they are at risk for developing a manic episode; such screening should include a detailed psychiatric history (e.g., current or prior depressive symptoms; family history of suicide, bipolar disorder, or depression).1

Psychotic or manic symptoms (e.g., hallucinations, delusional thinking, mania) also have been reported in patients without a history of psychotic illness or mania who received usual dosages of stimulants.1 In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% of patients receiving stimulants compared with 0% of those receiving placebo.1 If psychotic or manic symptoms occur during stimulant therapy, discontinuance of therapy should be considered.1

Long-term Suppression of Growth in Pediatric Patients

Administration of stimulants in children with ADHD has been associated with growth suppression (height and weight).1 Therefore, the manufacturer states that growth should be monitored during therapy with stimulants, and children who are not growing or gaining height or weight as expected may require temporary discontinuance of therapy.1

Seizures

Some evidence suggests that stimulants may lower the seizure threshold in patients with a history of seizures, in those with prior electroencephalography (EEG) abnormalities without seizures, and rarely, in patients without prior seizures or EEG abnormalities.1 If seizures occur in a patient receiving methamphetamine, the drug should be discontinued.1

Peripheral Vasculopathy Including Raynaud's Phenomenon

Stimulants used to treat ADHD, including methamphetamine, are associated with peripheral vascular disorders, including Raynaud's phenomenon.1 Manifestations usually are intermittent and mild, but ulceration of the digits and/or breakdown of soft tissue may occur rarely.1 Peripheral vascular disorders, including Raynaud's phenomenon, have been reported during postmarketing experience in patients in all age groups receiving stimulants at therapeutic dosages and at various times throughout the treatment course.1 Manifestations generally improve following dosage reduction or drug discontinuance.1 Careful observation for digital changes is warranted during ADHD stimulant therapy, and further clinical evaluation (e.g., referral to a rheumatologist) may be appropriate for patients with signs or symptoms of peripheral vasculopathy.1

Serotonin Syndrome

Potentially fatal serotonin syndrome can occur when amphetamines are used in conjunction with other medications that affect serotonergic neurotransmitters, such as MAOIs, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort ( Hypericum perforatum ).1 Symptoms of serotonin syndrome can include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1 Amphetamines and amphetamine derivatives are metabolized to some extent by cytochrome P-450 (CYP) isoenzyme 2D6, and to a minor extent, inhibit CYP2D6 metabolism.1 Therefore, there is a potential pharmacokinetic interaction when amphetamines are used concomitantly with CYP2D6 inhibitors.1 In patients receiving concomitant CYP2D6 inhibitors, an alternative nonserotonergic drug, or drug that does not also inhibit CYP2D6, should be considered.1

If clinically feasible, consider initiating methamphetamine therapy at a lower dosage and monitoring patients for the emergence of serotonin syndrome during therapy initiation or titration.1 Patients should be informed of the risk of serotonin syndrome.1 If symptoms of serotonin syndrome occur, methamphetamine and any concomitant serotonergic agents should be immediately discontinued, and supportive care initiated.1

Motor and Verbal Tics and Worsening of Tourette's Syndrome

Onset or exacerbation of motor or verbal tics and worsening of Tourette's syndrome have been reported with CNS stimulants.1

Prior to initiation of therapy, patients should be screened for a family history and clinically evaluated for motor or verbal tics or Tourette's syndrome.1 Patients receiving stimulant therapy should be routinely monitored for the emergence or worsening of tics or Tourette's syndrome, and treatment discontinued if clinically needed.1

Specific Populations

Pregnancy

The National Pregnancy Registry for ADHD Medications monitors pregnancy outcomes in women exposed to ADHD medications during pregnancy.1 Clinicians are encouraged to register women who become pregnant while receiving methamphetamine by calling 866-961-2388 or visiting [Web].1

Methamphetamine has been shown to have teratogenic and embryocidal effects in mammals receiving doses exceeding the usual therapeutic human dosage.1 There are no adequate and controlled studies to date in pregnant women.1 Methamphetamine should not be used during pregnancy unless the potential benefits justify the possible risks to the fetus.1

Infants born to women dependent on amphetamines have an increased risk of premature delivery and low birth weight.1 Infants born to mothers receiving amphetamines during pregnancy may also experience symptoms of withdrawal such as dysphoria, agitation, and significant lassitude.1

Lactation

Amphetamines are distributed into human milk.1 Breastfeeding should be avoided during therapy with amphetamines.1

Pediatric Use

The safety and efficacy of methamphetamine for ADHD have not been established in children <6 years of age.1

Long-term therapy with CNS stimulants may be associated with suppression of growth in children.1

Geriatric Use

Clinical studies of methamphetamine did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.1 While other reported clinical experience has not revealed age-related differences in response, dosage selection for geriatric patients should be cautious, usually starting at the low end of the dosage range.1 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease or drug therapy observed in this population also should be considered.1

Hepatic Impairment

Methamphetamine has not been specifically studied in hepatic impairment.1

Renal Impairment

Methamphetamine has not been specifically studied in renal impairment.1

Common Adverse Effects

Adverse effects reported with the use of methamphetamine include blood pressure elevations, tachycardia/heart palpitations, and fatal cardiopulmonary arrest in the context of drug abuse/misuse.1 Additionally, psychotic episodes, dizziness, dysphoria, overstimulation, euphoria, insomnia, tremor, restlessness, headache, exacerbation of motor and verbal tics and Tourette's syndrome, diarrhea, constipation, dry mouth, unpleasant taste, intestinal ischemia, and other GI disturbances have been reported.1 Urticaria, impotence and libido changes, frequent or prolonged erections, rhabdomyolysis, suppression of growth in children with long-term use, and alopecia have also been reported.1

Amphetamines and amphetamine derivatives are metabolized to some extent by cytochrome P-450 (CYP) isoenzyme 2D6, and to a minor extent, inhibit CYP2D6 metabolism.1

CYP2D6 Inhibitors

Concomitant use of methamphetamine and inhibitors of CYP2D6 (e.g., fluoxetine, paroxetine, quinidine, ritonavir) may increase the exposure of amphetamine and increase the risk of serotonin syndrome.1

Dosage of methamphetamine should be initiated at lower dosages when used concomitantly with inhibitors of CYP2D6.1 Patients should be monitored for emergence of serotonin syndrome during initiation and dosage titration of methamphetamine.1 If serotonin syndrome occurs, discontinue the CYP2D6 inhibitor and methamphetamine.1

Acidifying Agents

Concomitant use of GI (e.g., guanethidine, reserpine, glutamic acid, ascorbic acid) and urinary (e.g., ammonium chloride, sodium acid phosphate, methenamine) acidifying agents lowers plasma levels and reduces the efficacy of amphetamines.1 If concomitant GI or urinary acidifying agents are used, the methamphetamine dosage should be increased based on clinical response.1

Alkalinizing Agents

Concomitant use of GI (e.g., sodium bicarbonate) and urinary (e.g., acetazolamide, some thiazides) alkalinizing agents increases plasma levels of amphetamines and potentiates activity.1 Concomitant use of methamphetamine and GI alkalinizing agents should be avoided.1

Monoamine Oxidase Inhibitors

Use of methamphetamine concomitantly with monoamine oxidase inhibitors (MAOIs, e.g., selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue) can cause hypertensive crisis.1 Potential outcomes can include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure.1 Methamphetamine is therefore contraindicated during or within 14 days of administration of MAOIs.1

Phenothiazines

Phenothiazines reportedly antagonize the CNS stimulant effect of amphetamines.1

Proton Pump Inhibitors

The rate of absorption of amphetamine is increased when used concomitantly with proton pump inhibitors (e.g., omeprazole).1 Patients should be monitored for changes in clinical effects and therapy adjusted based on clinical response.1

Serotonergic Drugs

Concomitant use of methamphetamine and serotonergic drugs (e.g., selective serotonin reuptake inhibitors [SSRIs], serotonin norepinephrine reuptake inhibitors [SNRIs], triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort [ Hypericum perforatum ]) increases the risk of serotonin syndrome.1

Concomitant use of tricyclic antidepressants can also cause significant increases in d-amphetamine in the brain and can potentiate the cardiovascular effects of amphetamines.1 If a tricyclic antidepressant is used concomitantly, monitor patients frequently and adjust or use alternate drug therapy based on clinical response.1

Initiate methamphetamine at lower doses and monitor for emergence of serotonin syndrome during initiation and dosage titration of methamphetamine.1 If serotonin syndrome occurs, discontinue methamphetamine and the serotonergic drug.1

Description

Methamphetamine is a sympathomimetic amine with CNS stimulant activity; it also causes elevations in systolic and diastolic blood pressure, weak bronchodilation, and respiratory stimulation.1 The exact mechanism by which methamphetamine produces beneficial changes in hyperkinetic children is not known.1

Methamphetamine is readily absorbed from the GI tract.1 Methamphetamine is primarily metabolized in the liver by aromatic hydroxylation, N-dealkylation, and deamination; at least 7 metabolites have been identified in urine.1 The biologic half-life of methamphetamine reportedly is 4-5 hours.1 Methamphetamine is eliminated principally in urine.1 Urinary excretion of the drug is pH dependent, and excretion is enhanced in acidic urine.1 Following oral administration of methamphetamine hydrochloride, approximately 62% of the administered dose is excreted in urine within the first 24 hours, with metabolites and unchanged drug accounting for about two-thirds and one-third, respectively, of the recovered drug.1

Advice to Patients

• Provide the patient or caregiver with a copy of the manufacturer's patient information (medication guide).1
• Risk of abuse, misuse, and addiction, which can lead to overdose and death.1 Advise patients not to share methamphetamine with others and store the drug in a safe (preferably locked) location to prevent abuse.1 Advise patient or caregiver on proper disposal of any remaining unused or expired drug.1
• Potential risks to patients with serious cardiac disease, including sudden death.1 Advise patients to inform their clinicians immediately of any adverse cardiovascular effects (e.g., chest pain, shortness of breath, or fainting).1
• Inform patients that methamphetamine may impair the ability to operate machinery or drive a motor vehicle.1
• Advise patients or caregivers that methamphetamine can elevate blood pressure and pulse rate.1
• Advise patients that recommended dosages of methamphetamine may cause psychotic or manic symptoms, even in patients without a history of psychotic symptoms or mania.1
• Inform patients or caregivers about the risk of peripheral vascular disorders, including Raynaud's phenomenon, and the associated signs and symptoms (e.g., feelings of numbness, coolness, or pain in fingers or toes; changes in color from pale to blue to red).1 Advise patients to report any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes to their clinician and to immediately contact their clinician if any signs of unexplained wounds appear on fingers or toes; further clinical evaluation may be appropriate.1
• Advise patients that methamphetamine may slow growth and cause weight loss in children.1
• Inform patients that motor and verbal tics and worsening of Tourette's syndrome can occur during stimulant therapy.1 Advise patients to notify their clinician if they experience new or worsening tics or Tourette's syndrome.1
• Advise patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed.1 Inform patients about the existence of a pregnancy registry for ADHD medications.1
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses/conditions (e.g., cardiac/cardiovascular disease, mental/psychiatric disorder, suicidal ideation or behaviors, history of substance abuse).1
• Advise patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Only references cited for selected revisions after 1984 are available electronically.

1. Hikma Pharmaceuticals. Methamphetamine hydrochloride tablets prescribing information. Greenville, NC; 2023 Oct.

2. Hodgkins P, Shaw M, McCarthy S, Sallee FR. The pharmacology and clinical outcomes of amphetamines to treat ADHD: does composition matter?. CNS Drugs. 2012;26(3):245-268.

3. Wolraich ML, Hagan JF Jr, Allan C et al. Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2019; 144(4):e20192528.