Tadalafil (Generic) and Pregabalin Interaction: What Patients and Clinicians Need to Know

Is there a known interaction between tadalafil and pregabalin?

Neither label's interaction section names the other drug, so what exists is the handling of each drug on its own, and that is where the question is mostly settled. Generic tadalafil tablets follow the Cialis indications [5], so the tadalafil figures below come from the Cialis label.

The Lyrica label states that pregabalin is predominantly excreted unchanged in the urine, that less than 2% of a dose is recovered as metabolites, and that it does not bind plasma proteins. Its conclusion is that pregabalin's pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or protein-binding displacement [1]. Pregabalin is at least 90% bioavailable regardless of dose and has an elimination half-life of about 6 hours [1].

The Cialis label states that tadalafil is a substrate of and is predominantly metabolized by CYP3A4, and that tadalafil does not inhibit or induce CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 [2]. The interaction that label quantifies is with a strong CYP3A4 inhibitor: ketoconazole 400 mg daily raised tadalafil 20 mg exposure (AUC) by 312% [2]. Pregabalin at concentrations about 10 times those reached in clinical trials did not inhibit CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4, and did not induce CYP1A2 or CYP3A4 [1].

Could the pair add to dizziness or low blood pressure?

This is the realistic overlap, and both sets of numbers come from trials of one drug at a time.

Pregabalin's adult controlled trials reported dizziness in 30% versus 8% on placebo and somnolence in 23% versus 8% [1]. In the diabetic-neuropathy trials the dizziness rate rose with dose: 8% at 75 mg a day, 9% at 150 mg, 23% at 300 mg and 29% at 600 mg, against 5% on placebo [1]. The label also warns that pregabalin may impair the ability to drive or operate machinery [1].

Tadalafil is a mild vasodilator. In a clinical pharmacology study, 20 mg produced a mean maximal fall in supine blood pressure, relative to placebo, of 1.6/0.8 mm Hg in healthy subjects [2]. In the three 12-week studies of tadalafil 5 mg once daily for BPH or for ED with BPH (placebo n=576, tadalafil n=581), dizziness was reported by 1.0% on tadalafil versus 0.5% on placebo, and headache by 4.1% versus 2.3% [2].

The Cialis label warns that alpha-blockers, antihypertensives and substantial alcohol (5 units or more) can add to tadalafil's blood-pressure lowering, and it contraindicates nitrates [2].

Does the pregabalin breathing warning apply to tadalafil?

The Lyrica label's respiratory warning is specific about company. There is evidence from case reports, human studies and animal studies associating pregabalin with serious, life-threatening or fatal respiratory depression when it is co-administered with CNS depressants, including opioids, or in people with underlying respiratory impairment; the label asks for monitoring and consideration of a low starting dose [1]. The FDA's December 19, 2019 safety communication named opioids and other CNS depressants, conditions such as COPD that reduce lung function, and older age as the risk factors. It listed confusion, unusual dizziness, extreme sleepiness, slowed or shallow breathing, unresponsiveness and bluish skin as symptoms needing immediate medical attention [3].

In the Lyrica label's own interaction studies, multiple doses given with oxycodone, lorazepam or ethanol produced no pharmacokinetic interaction but additive effects on cognitive and gross motor function, and no clinically important effect on respiration was seen in those studies [1]. Tadalafil's most common labeled adverse reactions are headache, dyspepsia, back pain, myalgia, nasal congestion, flushing and pain in limb [2].

If pregabalin is taken with an opioid or another CNS depressant such as a benzodiazepine, the label's respiratory-depression warning applies, especially with respiratory impairment [1][3]. With ethanol, the label reported additive effects on thinking and movement but no clinically important respiratory effect in that study [1].

What about alcohol?

Both labels address alcohol. Pregabalin given with ethanol showed no pharmacokinetic interaction but additive effects on thinking and movement [1]. For tadalafil, both alcohol and tadalafil are mild vasodilators, and substantial alcohol (5 units or more) can increase orthostatic signs and symptoms: higher heart rate, lower standing blood pressure, dizziness and headache. Tadalafil did not change alcohol plasma concentrations and alcohol did not change tadalafil concentrations [2].

Does kidney function matter for either drug?

The Lyrica label's doses (150 mg a day to start, up to 300 mg for diabetic nerve pain, up to 450 mg for fibromyalgia, up to 600 mg for spinal cord injury pain, adult seizures and, after 2 to 4 weeks in selected patients, postherpetic neuralgia) apply to a creatinine clearance of at least 60 mL/min, and the label adjusts them downward from there. Its own example: a patient starting postherpetic neuralgia treatment at 150 mg a day with a clearance of 50 mL/min would receive 75 mg a day in two or three divided doses; for hemodialysis, a supplemental dose follows each 4-hour session [1].

Tadalafil has its own creatinine-clearance limits in the Cialis label. For as-needed use at a clearance of 30 to 50 mL/min, the starting dose is 5 mg with a maximum of 10 mg no more often than every 48 hours. Below 30 mL/min or on hemodialysis, the maximum is 5 mg no more often than every 72 hours, and once-daily use is not recommended. For BPH or ED with BPH at 30 to 50 mL/min, the label starts at 2.5 mg [2]. The Adcirca label reports that exposure is about doubled in mild or moderate renal impairment after single 5 to 10 mg doses [4]. The Cialis label reports exposure about 25% higher in healthy men aged 65 and older [2].

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