Provigil and Tadalafil Interaction: What You Need to Know

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What happens when modafinil and tadalafil are taken together?

Provigil (modafinil) is a wakefulness drug approved for excessive sleepiness in narcolepsy, obstructive sleep apnea and shift work disorder, and it is a Schedule IV controlled prescription drug [1]. Tadalafil (Cialis) is a PDE5 inhibitor approved for erectile dysfunction, the signs and symptoms of benign prostatic hyperplasia (BPH), and both conditions together [2].

The two drugs meet at one liver enzyme. The Provigil label says modafinil can increase the clearance of CYP3A4/5 substrates by inducing metabolic enzymes, which lowers their systemic exposure, and that dose adjustment of those drugs should be considered [1]. The Cialis label says tadalafil is a substrate of, and predominantly metabolized by, CYP3A4 [2].

Induction pushes tadalafil levels down, not up. For CYP3A4 inducers, the Cialis label says no dose adjustment is warranted, but lower exposure can be anticipated to decrease the efficacy of once-daily Cialis, by an unknown amount [2].

How large could the drop be?

The Cialis label reports numbers for one inducer, rifampin: 600 mg daily reduced single-dose tadalafil 10 mg exposure (AUC) by 88% and peak concentration (Cmax) by 46% [2]. These figures are for rifampin, not modafinil, and show what one CYP3A4 inducer did to tadalafil.

Neither interaction section names the other drug. The Cialis label names rifampin, carbamazepine, phenytoin and phenobarbital as inducers, and the Provigil label names steroidal contraceptives, cyclosporine, midazolam and triazolam as CYP3A4/5 substrates [1][2].

Once-daily Cialis versus as-needed Cialis

The Cialis label notes that once-daily use provides continuous plasma tadalafil levels and that physicians should consider this when evaluating interactions with other medicines [2]. As-needed Cialis starts at 10 mg and can go to 20 mg or down to 5 mg, no more than once a day. Once-daily doses are 2.5 mg or 5 mg for ED and 5 mg for BPH [2]. Tadalafil's mean terminal half-life is 17.5 hours in healthy subjects, and once-daily dosing reaches steady state within 5 days at about 1.6 times the exposure of a single dose [2].

Adcirca (tadalafil for PAH) is a separate product

Adcirca is tadalafil 20 mg tablets taken as 40 mg once daily for pulmonary arterial hypertension. It is a different product and strength from Cialis. The Adcirca label says to avoid other PDE5 inhibitors, including Cialis, and to avoid use in people chronically taking potent inducers such as rifampin [3].

Nitrates: the rule that does not depend on modafinil

Any form of organic nitrate, taken regularly or intermittently, is contraindicated with Cialis, which was shown to potentiate the blood-pressure-lowering effect of nitrates [2]. The label says that where a nitrate is medically necessary in a life-threatening situation, at least 48 hours should elapse after the last Cialis dose before a nitrate is considered, and then only under close medical supervision with hemodynamic monitoring [2]. This is an emergency rule, not permission to combine them.

A crossover study of 150 men given tadalafil 20 mg or placebo daily for 7 days, then sublingual nitroglycerin 0.4 mg, found standing systolic pressure fell below 85 mm Hg in more tadalafil-treated men at 4, 8 and 24 hours, with no difference at 48, 72 and 96 hours [4]. The authors concluded the interaction lasted 24 hours and was not seen at 48 hours [4].

Cialis side effects to know about

In the eight 12-week placebo-controlled trials of as-needed Cialis for ED, headache occurred in 15% of men on 20 mg versus 5% on placebo, and dyspepsia in 10% versus 1% [2]. The label says back pain or myalgia usually began 12 to 24 hours after dosing and typically resolved within 48 hours [2]. It also says an erection lasting more than 4 hours, painful or not, needs emergency care, and that patients should stop Cialis and seek medical attention for sudden vision loss in one or both eyes or sudden decrease or loss of hearing [2].