METHAMPHETAMINE: 8,626 Adverse Event Reports & Safety Profile

11.

Description

Methamphetamine hydrochloride tablets, USP contain methamphetamine, a central nervous system stimulant, in the form of hydrochloride salt. Methamphetamine hydrochloride is chemically known as (S) N,α dimethylbenzeneethanamine hydrochloride with molecular formula of C10H15N.HCl and molecular weight of 185.73 g/mol It has the following structural formula: Methamphetamine hydrochloride tablets, USP contain 5 mg of methamphetamine hydrochloride, USP for oral administration.

Inactive

Ingredients: Corn starch, lactose monohydrate, stearic acid and talc.

INDICATIONS AND USAGE Attention Deficit Disorder with Hyperactivity Methamphetamine hydrochloride tablets are indicated as an integral part of a total treatment program which typically includes other remedial measures (psychological, educational, social) for a stabilizing effect in children over 6 years of age with a behavioral syndrome characterized by the following group of developmentally inappropriate symptoms: moderate to severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity. The diagnosis of this syndrome should not be made with finality when these symptoms are only of comparatively recent origin. Nonlocalizing (soft) neurological signs, learning disability, and abnormal EEG may or may not be present, and a diagnosis of central nervous system dysfunction may or may not be warranted.

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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span> .

CONTRAINDICATIONS In patients known to be hypersensitive to amphetamine, or other components of methamphetamine hydrochloride tablets. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with other amphetamine products (see ADVERSE REACTIONS ). Patients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of stopping MAOIs (including MAOIs such as linezolid or intravenous methylene blue), because of an increased risk of hypertensive crisis (see WARNINGS and DRUG INTERACTIONS ). It is also contraindicated in patients with glaucoma, advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism or known hypersensitivity or idiosyncrasy to sympathomimetic amines. Methamphetamine should not be given to patients who are in an agitated state or who have a history of drug abuse.

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.

AND PRECAUTIONS

• Risks to Patients with Serious Cardiac Disease: Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease. ( 5.2 )
• Increased Blood Pressure and Heart Rate: Monitor blood pressure and pulse. ( 5.3 )
• Psychiatric Adverse Reactions: Prior to initiating methamphetamine hydrochloride tablets, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing methamphetamine hydrochloride tablets. ( 5.4 )
• Long-Term Suppression of Growth in Pediatric Patients: Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. ( 5.5 )
• Peripheral Vasculopathy, including Raynaud’s Phenomenon: Careful observation for digital changes is necessary during methamphetamine hydrochloride tablets treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy. ( 5.6 )
• Seizures: May lower the convulsive threshold. If a seizure occurs, discontinue methamphetamine hydrochloride tablets. ( 5.7 )
• Serotonin Syndrome: Increased risk when coadministered with serotonergic agents (e.g., SSRIs, SNRIs, triptans), but also during overdosage situations. If it occurs, discontinue methamphetamine hydrochloride tablets and initiate supportive treatment. ( 5.8 )
• Motor and Verbal Tics, and Worsening of Tourette’s Syndrome: Before initiating methamphetamine hydrochloride tablets, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome. Discontinue treatment if clinically appropriate. ( 5.9 )

5.1 Abuse, Misuse, and Addiction Methamphetamine hydrochloride tablets have a high potential for abuse and misuse. The use of methamphetamine hydrochloride tablets exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Methamphetamine hydrochloride tablets can be diverted for non-medical use into illicit channels or distribution <span class="opacity-50 text-xs">[see Drug Abuse and Dependence ( 9.2 , 9.3 )]</span> . Misuse and abuse of CNS stimulants, including methamphetamine hydrochloride tablets, can result in overdose and death <span class="opacity-50 text-xs">[see Overdosage ( 10 )]</span> , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing methamphetamine hydrochloride tablets, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store methamphetamine hydrochloride tablets in a safe place, preferably locked, and instruct patients to not give methamphetamine hydrochloride tablets to anyone else. Throughout methamphetamine treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

5.2 Risks to Patients with Serious Cardiac Disease Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosages. Avoid methamphetamine use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia, coronary artery disease, or other serious heart problems.

5.3 Increased Blood Pressure and Heart Rate CNS stimulants cause an increase in blood pressure (mean increase about 2 to 4 mm Hg) and heart rate (mean increase about 3 to 6 bpm). Some patients may have larger increases. Monitor all methamphetamine hydrochloride tablets-treated patients for potential tachycardia and hypertension <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 )]</span> .

5.4 Psychiatric Adverse Reactions Exacerbation of Pre-Existing Psychosis CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Illness CNS stimulants may induce a mixed or manic episode in patients with bipolar disorder. Prior to initiating methamphetamine hydrochloride tablets treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or has a history of depressive symptoms or a family history of suicide, bipolar disorder, or depression).

New

Psychotic or Manic Symptoms CNS stimulants, at recommended doses, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in 0.1% of CNS stimulant-treated patients compared to 0% in placebo-treated patients. If such symptoms occur, consider discontinuing methamphetamine hydrochloride tablets.

5.5 Long-Term Suppression of Growth in Pediatric Patients CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Closely monitor growth (weight and height) in methamphetamine-treated pediatric patients treated with CNS stimulants. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

5.6 Peripheral Vasculopathy, including Raynaud’s Phenomenon CNS stimulants, including methamphetamine hydrochloride tablets, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of CNS stimulant. Careful observation for digital changes is necessary during methamphetamine treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for methamphetamine-treated patients who develop signs or symptoms of peripheral vasculopathy.

5.7 Seizures Methamphetamine hydrochloride tablets may lower the convulsive threshold in patients with prior history of seizure, in patients with prior EEG abnormalities in the absence of seizures, and in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, methamphetamine hydrochloride tablets should be discontinued.

5.8 Serotonin Syndrome Serotonin syndrome, a potentially life-threatening reaction, may occur when amphetamines are used in combination with other drugs that affect the serotonergic neurotransmitter systems such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span> . The coadministration with cytochrome P450 2D6 (CYP2D6) inhibitors may also increase the risk with increased exposure to methamphetamine hydrochloride tablets. In these situations, consider an alternative nonserotonergic drug or an alternative drug that does not inhibit CYP2D6 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span> . Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and 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 gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Concomitant use of methamphetamine hydrochloride tablets with MAOI drugs is contraindicated <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . Discontinue treatment with methamphetamine hydrochloride tablets and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of methamphetamine hydrochloride tablets with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted, initiate methamphetamine hydrochloride tablets with lower doses, monitor patients for the emergence of serotonin syndrome during drug initiation or titration, and inform patients of the increased risk for serotonin syndrome.

5.9 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome CNS stimulants, including amphetamine, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 )]</span> . Before initiating methamphetamine hydrochloride tablets, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor methamphetamine hydrochloride tablets-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if clinically appropriate.

PRECAUTIONS General Methamphetamine hydrochloride tablets should be used with caution in patients with even mild hypertension. Methamphetamine should not be used to combat fatigue or to replace rest in normal persons. Prescribing and dispensing of methamphetamine should be limited to the smallest amount that is feasible at one time in order to minimize the possibility of overdosage. Information for Patients The patient should be informed that methamphetamine may impair the ability to engage in potentially hazardous activities, such as, operating machinery or driving a motor vehicle. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud's phenomenon] Instruct patients beginning treatment with methamphetamine 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 methamphetamine hydrochloride tablets. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. The patient should be cautioned not to increase dosage, except on advice of the physician. Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with methamphetamine and should counsel them in its appropriate use. A patient Medication Guide is available for methamphetamine hydrochloride tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.

Drug Interactions

Insulin requirements in diabetes mellitus may be altered in association with the use of methamphetamine and the concomitant dietary regimen. Methamphetamine may decrease the hypotensive effect of guanethidine . Methamphetamine hydrochloride tablets should not be used concurrently with monoamine oxidase inhibitors (see CONTRAINDICATIONS ). Concurrent administration of tricyclic antidepressants and indirect-acting sympathomimetic amines such as the amphetamines, should be closely supervised and dosage carefully adjusted. Phenothiazines are reported in the literature to antagonize the CNS stimulant action of the amphetamines.

Drug/Laboratory

Test Interactions Literature reports suggest that amphetamines may be associated with significant elevation of plasma corticosteroids. This should be considered if determination of plasma corticosteroid levels is desired in a person receiving amphetamines.

Acidifying Agents

Lower blood levels and efficacy of amphetamines. Increase dose based on clinical response. Examples of acidifying agents include gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid) and urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts).

Alkalinizing Agents

Increase blood levels and potentiate the action of amphetamine. Co-administration of methamphetamine hydrochloride tablets and gastrointestinal alkalinizing agents should be avoided. Examples of alkalinizing agents include gastrointestinal alkalinizing agents (e.g., sodium bicarbonate) and urinary alkalinizing agents (e.g., acetazolamide, some thiazides).

Tricyclic Antidepressants

May enhance the activity of tricyclic or sympathomimetic agents causing striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated. Monitor frequently and adjust or use alternative therapy based on clinical response. Examples of tricyclic antidepressants include desipramine, Protriptyline. CYP2D6 Inhibitors The concomitant use of methamphetamine hydrochloride tablets and CYP2D6 inhibitors may increase the exposure of methamphetamine hydrochloride tablets compared to the use of the drug alone and increase the risk of serotonin syndrome. Initiate 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 , OVERDOSAGE ). Examples of CYP2D6 Inhibitors include paroxetine and fluoxetine (also serotonergic drugs), quinidine, ritonavir.

Serotonergic Drugs

The concomitant use of methamphetamine hydrochloride tablets and serotonergic drugs increases the risk of serotonin syndrome. Initiate 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 ). Examples of serotonergic drugs include selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort.

Mao

Inhibitors Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure. Do not administer methamphetamine hydrochloride tablets concomitantly or within 14 days after discontinuing MAOI (see CONTRAINDICATIONS and WARNINGS ). Examples of MAOIs include selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue.

Proton Pump Inhibitors

Time to maximum concentration (Tmax) of amphetamine is decreased compared to when administered alone. Monitor patients for changes in clinical effect and adjust therapy based on clinical response. An example of a proton pump inhibitor is omeprazole. Carcinogenesis, Mutagenesis, Impairment of Fertility Data are not available on long-term potential for carcinogenicity, mutagenicity, or impairment of fertility.

Pregnancy

Teratogenic effects Pregnancy Category C Methamphetamine has been shown to have teratogenic and embryocidal effects in mammals given high multiples of the human dose. There are no adequate and well-controlled studies in pregnant women. Methamphetamine hydrochloride tablets should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. Nonteratogenic effects Infants born to mothers dependent on amphetamines have an increased risk of premature delivery and low birth weight. Also, these infants may experience symptoms of withdrawal as demonstrated by dysphoria, including agitation and significant lassitude. Usage in Nursing Mothers Amphetamines are excreted in human milk. Mothers taking amphetamines should be advised to refrain from nursing.

Pediatric Use

Long-term effects of methamphetamine in children have not been established (see WARNINGS ). Drug treatment is not indicated in all cases of the behavioral syndrome characterized by moderate to severe distractibility, short attention span, hyperactivity, emotional lability and impulsivity. It should be considered only in light of the complete history and evaluation of the child. The decision to prescribe methamphetamine hydrochloride tablets should depend on the physician's assessment of the chronicity and severity of the child's symptoms and their appropriateness for his/her age. Prescription should not depend solely on the presence of one or more of the behavioral characteristics. When these symptoms are associated with acute stress reactions, treatment with methamphetamine hydrochloride tablets is usually not indicated. Clinical experience suggests that in psychotic children, administration of methamphetamine hydrochloride tablets may exacerbate symptoms of behavior disturbance and thought disorder. Amphetamines have been reported to exacerbate motor and phonic tics and Tourette's syndrome. Therefore, clinical evaluation for tics and Tourette's syndrome in children and their families should precede use of stimulant medications.

Geriatric Use Clinical

Studies of methamphetamine hydrochloride tablets did not include sufficient numbers of subjects age 65 years and over to determine whether elderly subjects respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy observed in this population.

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, USP Table 1 presents clinically important drug interactions with methamphetamine hydrochloride tablets, USP .

Table

1: Clinically Important Drug Interactions with methamphetamine hydrochloride tablets, USP 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, USP 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 hydrochloride tablets, USP , and serotonergic drugs increases the risk of serotonin syndrome. Intervention: Initiate methamphetamine hydrochloride tablets, USP with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during methamphetamine hydrochloride tablets, USP initiation or dosage increase. If serotonin syndrome occurs, discontinue methamphetamine hydrochloride tablets, USP and the concomitant serotonergic drug(s) [see Warnings and Precautions 5.8]. AlkalinizingAgents Clinical Impact: Alkalinizing agents may increase exposure to amphetamines and potentiate the action of amphetamine.

Intervention

Avoid co-administration of methamphetamine hydrochloride tablets, USP 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, USP 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, USP dose or use alternative therapy based on clinical response. CYP2D6 Inhibitors Clinical Impact: Concomitant use of methamphetamine hydrochloride tablets, USP and CYP2D6 inhibitors may increase the exposure of methamphetamine hydrochloride tablets, USP 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, USP initiation and after a dosage increase. If serotonin syndrome occurs, discontinue methamphetamine hydrochloride tablets, USP and the CYP2D6 inhibitor [see Warnings and Precautions 5.8]. Gastric pH Modulators Clinical Impact: Time to maximum concentration (Tmax) 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 ofguanethidine.

Intervention

Monitor patients and adjust therapy based on clinicalresponse. 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.