Armodafinil

Registered South African indications:

• Excessive daytime sleepiness associated with narcolepsy

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to modafinil
• Pregnancy
  - Including those who may become pregnant
• Uncontrolled moderate to severe hypertension
• Cardiac dysrhythmias

Cautions

• Breastfeeding
• Renal impairment
• Moderate to severe hepatic impairment
• Elderly
• History of psychosis, depression, or mania
• Recent history of myocardial infarction
• Recent history of unstable angina pectoris
• History of left ventricular hypertrophy
• Mitral valve prolapse syndrome when previously receiving central nervous system stimulants
• Cardiovascular disease
• History of drug and/or stimulant abuse
• Coadministration with warfarin
  (See additional prescribing points)
• Coadministration with monoamine oxidase (MAO) inhibitors
• Galactose intolerance
  - Galactosaemia
• Total lactase deficiency
• Glucose-galactose malabsorption

Forms avail. in SA and covered in this monograph: tab

Excessive daytime sleepiness associated with narcolepsy

• Oral (tab): 150-250mg, dly in the morning

Armodafinil should be used only in patients who have had a complete evaluation of their excessive sleepiness, and in whom a diagnosis of the underlying disorder of narcolepsy has been made in accordance with International Classification of Sleep Disorders (ICSD) or Diagnostic and Statistical Manual (DSM) diagnostic criteria. Such an evaluation usually consists of a complete history and physical examination, and it may be supplemented with testing in a laboratory setting

Treatment with armodafinil should be initiated and supervised by medical practitioners with appropriate experience in the treatment of narcolepsy and who have access to sleep laboratory diagnostic facilities

Armodafinil may be taken with or without food, however, administration with food may delay the onset of action and prolong the effect of the medicine. To avoid a delayed onset of action armodafinil should be taken on an empty stomach

Not established for use in children below 18 years

Pregnancy

• Contraindicated
• Armodafinil taken during pregnancy has been associated with serious foetal abnormalities such as cardiac lesions and microcephaly. In addition, intrauterine growth restriction and spontaneous abortion has been reported in association with armodafinil and modafinil in humans. A woman should not commence armodafinil until two reliable pregnancy tests have shown negative results one week apart
• Patients should be cautioned regarding the potential increased risk of pregnancy when using steroidal contraceptives with armodafinil and for two months after discontinuation of therapy. Modafinil and/or its metabolites cross the placenta in rats, but placental transfer of armodafinil per se has not been studied
• In studies of armodafinil [(R)-modafinil] and modafinil [a mixture of (R)- and (S)-modafinil] conducted in rats (armodafinil, modafinil) and rabbits (modafinil), developmental toxicity was observed at clinically relevant plasma exposures
• Oral administration of armodafinil to pregnant rats and rabbits throughout organogenesis resulted in increased incidences of foetal structural alterations and foetal toxicity at the highest dose. The highest no-effect dose for embryo foetal developmental toxicity in rats was associated with a plasma armodafinil exposure (AUC) less than that in humans at the maximum recommended human dose (MRHD) of armodafinil (250mg/day)

Breastfeeding

• Caution; not recommended 
• It is not known whether armodafinil or its metabolites are excreted in human milk. The effects of armodafinil on infants who have been breastfed have not been studied. Breastfeeding is not recommended during administration of armodafinil
• Modafinil and/or its metabolites including modafinil sulfone and modafinil acid have been found in the milk of lactating rats
• Infant growth retardation has been reported in association with armodafinil use during breastfeeding

Fertility

• The effect of armodafinil on fertility is unknown

Renal Impairment

• Caution; no dose adjustment recommended 
  There is inadequate information to determine safety and efficacy of armodafinil dosing in patients with renal impairment, mild, moderate or severe (CrCl <20ml/min)

Hepatic Impairment 

• Mild: No dose adjustment recommended 
• Moderate and severe: Caution; dose adjustment recommended 
  Reduce dose by half. There is a lack of data on dosing information for armodafinil specific to the degree of liver impairment
  Reduce dose in patients with severe (Child-Pugh class C) hepatic impairment, with or without cirrhosis

Elderly

• Caution; dose adjustment recommended 
  In elderly patients, elimination of armodafinil and its metabolites may be reduced and some elderly patients may have greater exposure to armodafinil, consideration should be given to the use of lower doses

Drugs in Sport

• Prohibited - In competition

Central Nervous System Disorders

• Headache
• Dizziness
• Disturbance in attention
• Tremor
• Migraine
• Paraesthesia
• Insomnia
• Anxiety
• Depression
• Agitation
• Nervousness
• Depressed mood
• Fatigue
• Feeling abnormal
• Irritability
• Seizures
• Hallucination
• Anger
• Aggression
• Drug abuse
• Psychotic disorder
• Suicidal ideation
• Suicide attempt
• Mania
• Persistent sleepiness
• Psychoactive and euphoric effects
• Alterations in mood, perception, thinking and feelings

Cardiovascular Disorders

• Tachycardia
• Palpitations
• Supraventricular dysrhythmias
• Myocardial infarction
• Increased blood pressure
• Myocarditis
• Chest pain

Respiratory Disorders

• Dyspnoea
• Bronchitis
• Nasopharyngitis
• Sinusitis
• Upper respiratory tract infection
• Throat tightness
• Pharyngeal oedema
• Cough

Gastrointestinal Disorders

• Upper abdominal pain
• Nausea and vomiting
• Dry mouth
• Diarrhoea
• Dyspepsia
• Constipation
• Loose stools
• Flatulence
• Oropharyngeal pain
• Mouth blistering

Hepatobiliary Disorders

• Increased  gamma-glutamyltransferase (GGT)
• Increased alanine aminotransferase (ALT)
• Increased aspartate aminotransferase (AST)
• Hepatitis
• Abnormal hepatic function tests

Genitourinary Disorders

• Polyuria

Endocrine and Metabolic Disorders

• Anorexia
• Decreased appetite
• Thirst

Musculoskeletal Disorders

• Pain
• Arthralgia
• Back pain

Skin and Subcutaneous Tissue Disorders

• Rash
• Contact dermatitis
• Hyperhidrosis
• Stevens-Johnson syndrome 
• Alopecia 
• Drug reaction with eosinophilia and systemic symptoms (DRESS)
• Skin blistering
• Pruritis

Immune, Blood and Lymphatic System Disorders

• Seasonal allergy
• Influenza-like illness
• Pyrexia
• Anaphylaxis
  - Swelling of face, eyes, lips, tongue or larynx
  - Difficulty in swallowing or breathing
  - Hoarseness
• Hypersensitivity reactions
  - Drug hypersensitivity
  - Dysphagia
  - Bronchospasm
• Angioedema
• Haematological abnormalities
  - Eosinophilia
  - Leukopenia
  - Thrombocytopenia
• Pancytopenia

• CYP3A4/5 substrates
• Midazolam
• Ciclosporin
• Triazolam
• Quetiapine
• Potent CYP3A4/5 inducers
• Carbamazepine
• Oxcarbazepine
• Phenobarbitone
• Phenytoin
• Rifabutin
• Rifampicin
• CYP2C19 substrates
• Diazepam
• Propranolol
• Omeprazole
• Esomeprazole
• Clomipramine
• CYP3A4/5 inhibitors
• Protease inhibitors
• Ritonavir
• Indinavir
• Nelfinavir
• Saquinavir
• Clarithromycin
• Erythromycin
• Chloramphenicol
• Ketoconazole
• Itraconazole
• Nefazodone
• Diltiazem
• Verapamil
• Steroidal contraceptives
  (See additional prescribing points)

Other interactions

• St. John’s wort

None routine. Specific cases may require

• Blood pressure
• Cardiac evaluation
  - Electrocardiogram
  - Heart rate

Additional observations

• Psychiatric symptoms
• Signs of hypersensitivity
• Drug abuse
• Levels of sleepiness
• Rash

Interactions with other medicines

• Concomitant administration of modafinil with warfarin did not produce significant changes in the pharmacokinetic profiles of (R)- and (S)-warfarin. However, since only a single dose of warfarin was tested in this study, an interaction cannot be ruled out. Therefore, more frequent monitoring of prothrombin times/INR should be considered whenever armodafinil is co-administered with warfarin

Armodafinil versus modafinil

• Armodafinil is a single enantiomer of racemic modafinil. The two enantiomers of modafinil have different pharmacokinetics. The half-life of armodafinil, the (R)-enantiomer, is approximately three times that of the (S)-enantiomer in adult humans
• The implications of the pharmacokinetic differences between the medicines on the duration of clinical action remain unelucidated. No evidence of interconversion of the (R)- and (S)-enantiomers of modafinil have been observed in vitro or in vivo. Thus, armodafinil and modafinil are not bioequivalent and therefore are not directly substitutable

Serious rash, including Stevens-Johnson Syndrome 

• Serious rash requiring hospitalisation and discontinuation of treatment has been reported in adults in association with the use of armodafinil and modafinil [the racemic mixture of (S)- and (R)-enantiomers]. Armodafinil has not been studied in paediatric patients in any setting and is not approved for use in paediatric patients

Patients (Women) using contraception

• Sexually active women of childbearing potential should be established on a contraceptive program before taking armodafinil
• The effectiveness of steroidal contraceptives may be reduced when used with armodafinil and for two months after discontinuation of therapy
• Alternative or concomitant methods of contraception are recommended for patients taking steroidal contraceptives (e.g., ethinylestradiol) when treated concomitantly with armodafinil and for two months after discontinuation of armodafinil treatment

Abuse and dependence potential

• Although the abuse potential of armodafinil has not been specifically studied, its abuse potential is likely to be similar to that of modafinil
• In humans, modafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking and feelings typical of other CNS stimulants
• In in vitro binding studies, modafinil binds to the dopamine reuptake site and causes an increase in extracellular dopamine, but no increase in dopamine release
• Medical practitioners should follow patients closely, especially those with a history of drug and/or stimulant (e.g., methylphenidate, amphetamine, or cocaine) abuse
• Patients should be observed for signs of misuse or abuse (e.g., incrementation of doses or drug-seeking behaviour)
• The abuse potential of modafinil (200, 400, and 800mg) was assessed relative to methylphenidate (45 and 90mg) in an inpatient study in individuals experienced with drugs of abuse. Results from this clinical study demonstrated that modafinil produced psychoactive and euphoric effects and feelings consistent with other scheduled CNS stimulants (methylphenidate)

The mechanism(s) through which armodafinil promotes wakefulness is unknown. Armodafinil [(R)- modafinil)] has pharmacological properties similar to those of modafinil [a mixture of (R)- and (S)- modafinil] to the extent tested in animal and in vitro studies. Armodafinil has a wake-promoting action similar to that of sympathomimetic medicines including amphetamine and methylphenidate, although their pharmacologic profile is different. Armodafinil is an indirect dopamine receptor agonist; and it binds in vitro to the dopamine transporter and inhibits dopamine reuptake.

Tablet 50mg

• Nuvigil 50mg (Teva Pharmaceuticals) originator

Tablet 150mg

• Nuvigil 150mg (Teva Pharmaceuticals) originator

Tablet 250mg

• Nuvigil 250mg (Teva Pharmaceuticals) originator