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Provigil Side Effects, and Drug Interactions - Modafinil

Provigil Side Effects, and Drug Interactions - Modafinil

SIDE EFFECTS

Modafinil has been evaluated for safety in over 2200 subjects, of whom more than 900 subjects with narcolepsy or narcolepsy/hypersomnia were given at least one dose of modafinil. Modafinil has been found to be generally well-tolerated. In controlled clinical trials, most adverse experiences were mild to moderate.

The most commonly observed adverse events (³5%) associated with the use of modafinil more frequently than placebo-treated patients in controlled US and foreign studies were headache, infection, nausea, nervousness, anxiety, and insomnia.

In US placebo-controlled Phase 3 clinical trials, 5% of the 369 patients who received PROVIGIL discontinued due to an adverse experience. The most frequent (³1%) reasons for discontinuation that occurred at a higher rate for PROVIGIL than placebo patients were headache (1%), nausea (1%), depression (1%) and nervousness (1%). In foreign, controlled clinical trials, reasons for discontinuation were similar to those in US trials. In a Canadian clinical trial, a 35 year old obese narcoleptic male with a prior history of syncopal episodes experienced a 9 second episode of asystole while sleeping after 27 days of modafinil treatment (300 mg/day in divided doses).

Incidence in Controlled Trials

The following table presents the adverse experiences that occurred in narcolepsy patients at a rate of 1% or more and were more frequent in PROVIGIL-treated patients than in placebo patients in US placebo-controlled clinical trials.

The prescriber should be aware that the figures provided below cannot be used to predict the frequency of adverse experiences in the course of usual medical practice, where patient characteristics and other factors may differ from those occurring during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. Review of these frequencies, however, provides prescribers with a basis to estimate the relative contribution of drug and non-drug factors to the incidence of adverse events in the population studied.

Table 2

Table 2.1-2.Incidence of Treatment-Emergent Adverse Experiences in US 9-Week
Placebo-Controlled Clinical Trials with PROVIGIL (200 mg and 400 mg) Daily.

Body System	Preferred Term	Modafinil (n = 369)	Placebo (n = 185)
Body as a Whole	Headache	50%	40%
	Chest pain	2%	1%
	Neck pain	2%	1%
	Chills	2%	0%
	Rigid Neck	1%	0%
	Fever/ Chills	1%	0%
Digestive	Nausea	13%	4%
	Diarrhea	8%	4%
	Dry mouth	5%	1%
	Anorexia	5%	1%
	Abnormal liver	3%	2%
	function 2	2%	1%
	Vomiting	1%	0%
	Mouth ulcer	1%	0%
	Gingivitis	1%	0%
	Thirst
Respiratory System	Rhinitis	11%	8%
	Pharyngitis	6%	3%
	Lung disorder	4%	2%
	Dyspnea	2%	1%
	Asthma	1%	0%
	Epistaxis	1%	0%
Nervous System	Nervousness	8%	6%
	Dizziness	5%	4%
	Depression	4%	3%
	Anxiety	4%	1%
	Cataplexy	3%	2%
	Insomnia	3%	1%
	Paresthesia	3%	1%
	Dyskinesia3	2%	0%
	Hypertonia	2%	0%
	Confusion	1%	0%
	Amnesia	1%	0%
	Emotional lability	1%	0%
	Ataxia	1%	0%
	Tremor	1%	0%
Cardio-vascular	Hypotension	2%	1%
	Hypertension	2%	0%
	Vasodilation	1%	0%
	Arrhythmia	1%	0%
	Syncope	1%	0%
Hemic / Lymphatic	Eosinophilia	2%	0%
Special Senses	Amblyopia	2%	1%
	Abnormal vision	2%	0%
Metabolic/ Nutritional	Hyperglycemia	1%	0%
	Albuminuria	1%	0%
Musculo- skeletal	Joint disorder	1%	0%
Skin / Appendages	Herpes simplex	1%	0%
	Dry skin	1%	0%
Urogenital	Abnormal urine	1%	0%
	Urinary retention	1%	0%
	Abnormal ejaculation4	1%	0%
*Notes and abbreviations are described below.

¹Events reported by at least 1% of PROVIGIL-treated patients and that were more frequent than in the placebo group are included; incidence is rounded to the nearest 1%. The adverse experience terminology is coded using a standard modified COSTART Dictionary. Events for which the PROVIGIL incidence was at least 1%, but equal to or less than placebo are not listed in the table. These events included the following: infection, back pain, pain, hypothermia, abdominal pain, flu syndrome, allergic reaction, fever, asthenia, accidental injury, general edema, tachycardia, palpitations, migraine, ventricular extrasystole, bradycardia, dyspepsia, tooth disorder, constipation, flatulence, increased appetite, gastroenteritis, GI disorder, ecchymosis, anemia, leukocytosis, peripheral edema, increased weight, increased SGOT, myalgia, arthritis, arthralgia, somnolence, thinking abnormality, leg cramps, sleep disorder, hallucinations, hyperkinesia, decreased libido, increased cough, sinusitis, bronchitis, pneumonia, rash, sweating, pruritus, skin disorder, psoriasis, ear pain, eye pain, ear disorder, taste perversion, dysmenorrhea , urinary tract infection, 4 pyuria, hematuria, cystitis, and disturbed menses .

²Elevated liver enzymes.

³Oro-facial dyskinesias

⁴Incidence adjusted for gender

Dose Dependency of Adverse Events

In the US Phase 3 clinical trials, the only adverse experience that was more frequent (³5% difference) in the PROVIGIL dose group of 400 mg/day than in the PROVIGIL dose group of 200 mg/day and placebo was headache.

Vital Sign Changes

There were no consistent effects or patterns of change in vital signs for PROVIGIL-treated patients enrolled in the US Phase 3 clinical trials.

Weight Changes

There were no clinically significant differences in body weight change in PROVIGIL-treated patients compared to placebo-treated patients.

Laboratory Changes

Clinical chemistry, hematology, and urinalysis parameters were monitored in US Phase 1, 2 and 3 studies. In these studies, mean plasma levels of gamma-glutamyl transferase (GGT) were found to be higher following administration of PROVIGIL, but not placebo. Few subjects (1%), however, had GGT elevations outside of the normal range. Shift of the PROVIGIL-treated population to higher, but not clinically significantly abnormal, GGT values appeared to increase with time in the 9-week US Phase 3 clinical trials. No differences were apparent in alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, total protein, albumin, or total bilirubin.

Although there were more abnormal eosinophil counts following PROVIGIL administration than placebo in US Phase 1 and 2 studies, the difference does not appear to be clinically significant. Observed shifts were from normal to high.

ECG Changes

No treatment-emergent pattern of ECG abnormalities was found in US Phase 1, 2, and 3 studies following administration of PROVIGIL.

DRUG ABUSE AND DEPENDENCE

Controlled Substance Class

Modafinil (PROVIGIL) is listed in Schedule IV of the Controlled Substances Act.

Abuse Potential and Dependence

In addition to its wakefulness-promoting effects and increased locomotor activity in animals, in humans, PROVIGIL 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. Modafinil is reinforcing, as evidenced by its self-administration in monkeys previously trained to self-administer cocaine. In some studies, Modafinil was also partially discriminated as stimulant-like. Physicians 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 behavior).

The abuse potential of modafinil (200, 400, and 800 mg) was assessed relative to methylphenidate (45 and 90 mg) in an inpatient study in individuals experienced with drugs of abuse. Results from this clincal study demonstrated that modafinil produced psychoactive and euphoric effects and feelings consistent with other scheduled CNS stimulants (methylphenidate).

Withdrawal

The effects of modafinil withdrawal were monitored following 9 weeks of modafinil use in one US Phase 3 controlled clinical trial. No specific symptoms of withdrawal were observed during 14 days of observation, although sleepiness returned in narcoleptic patients.

DRUG INTERACTIONS

CNS Active Drugs

Methylphenidate - In a single-dose study in healthy volunteers, coadministration of modafinil (200 mg) with methylphenidate (40 mg) did not cause any significant alterations in the pharmacokinetics of either drug. However, the absorption of PROVIGIL may be delayed by approximately one hour when coadministered with methylphenidate.

Clomipramine - The coadministration of a single dose of clomipramine (50 mg) on the first of three days of treatment with modafinil (200 mg/day) in healthy volunteers did not show an effect on the pharmacokinetics of either drug. However, one incident of increased levels of clomipramine and its active metabolite desmethylclomipramine has been reported in a patient with narcolepsy during treatment with modafinil (See Potential Interactions with Drugs That Inhibit or are Metabolized by Cytochrome P-450 Isoenzymes and Other Hepatic Enzymes below).

Triazolam - In a single-dose pharmacodynamic study with PROVIGIL in healthy volunteers (50, 100 or 200 mg) and triazolam (0.25 mg), no clinically important alterations in the safety profile of modafinil or triazolam were noted.

Monoamine Oxidase (MAO) Inhibitors - Interaction studies with monoamine oxidase inhibitors have not been performed. Therefore, caution should be used when concomitantly administering MAO inhibitors and modafinil.

Potential Interactions with Drugs That Inhibit , Induce, or are Metabolized by Cytochrome P-450 Isoenzymes and Other Hepatic Enzymes

In a controlled study in patients with narcolepsy, chronic dosing of PROVIGIL at 400 mg/day once daily resulted in a ~20% mean decrease in modafinil plasma trough concentrations by week 9, relative to those at week 3 suggesting that chronic administration of PROVIGIL might have caused induction of its metabolism. In addition, coadministration of potent inducers of CYP3A4 (e.g., carbamazepine, phenobarbital, rifampin) or inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole) could alter the levels of modafinil due to the partial involvement of that enzyme in the metabolic elimination of the compound.

In in vitro studies using primary human hepatocyte cultures, modafinil was shown to slightly induce CYP1A2, CYP2B6 and C.P.A. in a concentration-dependent manner. Although induction results based on in vitro experiments are not necessarily predictive of response in vivo, caution needs to be exercised when PROVIGIL is coadministered with drugs that depend on these three enzymes for their clearance. Specifically, lower blood levels of such drugs could result. In the case of C.P.A. and CYP2B6, no other evidence of enzyme induction has been observed. A modest induction of C.P.A. by modafinil has been indicated by other results, hence the clearance of C.P.A. substrates such as cyclosporine or steroidal contraceptives and to a lesser degree, theophylline may be increased. One case of an interaction between modafinil and cyclosporine has been reported in a 41 year old woman who had undergone an organ transplant. After one month of administration of 200 mg/day of modafinil, cyclosporine blood levels were decreased by 50%. The interaction was postulated to be due to the increased metabolism of cyclosporine, since no other factor expected to affect the disposition of the drug had changed.

The exposure of human hepatocytes to modafinil in vitro produced an apparent concentration-related suppression of expression of CYP2C9 activity. The clinical relevance of this finding is unclear, since no other indication of CYP2C9 suppression has been observed. However, monitoring of prothrombin times is suggested as a precaution for the first several months of coadministration of PROVIGIL and warfarin, a CYP2C9 substrate, and thereafter whenever PROVIGIL dosing is changed. In addition, patients receiving PROVIGIL and phenytoin, a CYP2C9 substrate, concomitantly should be monitored for signs of phenytoin toxicity.

In vitro studies using human liver microsomes showed that modafinil has little or no capacity to inhibit the major CYP enzymes except for CYP2C19, which is reversibly inhibited at pharmacologically relevant concentrations of modafinil. Drugs that are largely eliminated via CYP2C19 metabolism, such as diazepam, propranolol, phenytoin or S-mephenytoin may have prolonged elimination upon coadministration with PROVIGIL and may require dosage reduction.

In addition, CYP2C19 provides an ancillary pathway for the metabolism of certain tricyclic antidepressants (e.g., clomipramine and desipramine) that are primarily metabolized by CYP2D6. In tricyclic-treated patients deficient in CYP2D6 (i.e., those who are p.o. metabolizers of debrisoquine; 7-10% of the Caucasian population; similar or lower in other populations), the amount of metabolism by CYP2C19 may be substantially increased. PROVIGIL may cause elevation of the levels of the tricyclics in this subset of patients. Physicians should be aware that a reduction in the dose of tricyclic agents might be needed in these patients.

Drug-Drug Interactions

Because modafinil is a reversible inhibitor of the drug-metabolizing enzyme CYP2C19, co-administration of modafinil with drugs such as diazepam, phenytoin, and propranolol, which are largely eliminated via that pathway, may increase the circulating levels of those compounds. In addition, in individuals deficient in the enzyme CYP2D6 (i.e., 7-10% of the Caucasian population; similar or lower in other populations), the levels of CYP2D6 substrates such as tricyclic antidepressants and selective serotonin reuptake inhibitors, which have ancillary routes of elimination through CYP2C19, may be increased by co-administration of modafinil. Dose adjustments may be necessary for patients being treated with these and similar medications (see PRECAUTIONS, Drug Interactions).

Chronic administration of modafinil may also cause modest induction of the metabolizing enzyme CYP3A4, thus reducing the levels of co-administered substrates for that enzyme system, such as steroidal contraceptives, cyclosporine and to a lesser degree, theophylline. Dose adjustments may be necessary for patients being treated with these and similar medications (see PRECAUTIONS, Drug Interactions).

An apparent concentration-related suppression of CYP2C9 activity was observed in human hepatocytes after exposure to modafinil in vitro. Although no other indication of CYP2C9 suppression has been observed, the in vitro results suggest that there is potential for metabolic interaction between PROVIGIL and CYP2C9 substrates, such as warfarin or phenytoin (see PRECAUTIONS, Drug Interactions).

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