Is it safe to take Sunosi (solriamfetol) together with modafinil?

Combining Sunosi (Solriamfetol) and Modafinil

There is no established safety data or guideline recommendation supporting the concurrent use of Sunosi (solriamfetol) and modafinil, and this combination should generally be avoided in clinical practice.

Evidence-Based Rationale

Lack of Combination Data

• Neither the American Academy of Sleep Medicine guidelines nor clinical trials have evaluated the safety or efficacy of combining solriamfetol with modafinil 1.
• All pivotal trials for both medications studied them as monotherapy compared to placebo, not in combination with other wake-promoting agents 1, 2, 3.

Overlapping Mechanisms and Risks

• Solriamfetol is a selective dopamine and norepinephrine reuptake inhibitor with dual activity at both transporters (DA IC50 = 2.9 μM; NE IC50 = 4.4 μM) 4.
• Modafinil also increases dopamine and norepinephrine levels, though through a less well-defined mechanism that differs from solriamfetol 4, 5.
• Combining two agents that both increase catecholamine activity creates additive cardiovascular risks including hypertension, tachycardia, and potential cardiac arrhythmias 1.

Common Adverse Effects That May Be Amplified

Both medications share overlapping adverse event profiles that could be potentiated when combined:

• Cardiovascular effects: Both can cause increased blood pressure and heart rate 1, 3.
• Insomnia and sleep disturbances: Reported with both agents, particularly when dosed later in the day 1, 3.
• Headache, nausea, and decreased appetite: Common to both medications 1, 3.
• Anxiety and irritability: May be exacerbated with dual therapy 1, 3.

Clinical Approach When Monotherapy Is Insufficient

Sequential Monotherapy Strategy

If a patient has inadequate response to one wake-promoting agent:

• Switch, don't add: Transition from modafinil to solriamfetol (or vice versa) rather than combining them 2, 5.
• When transitioning, most clinicians abruptly discontinue the prior wake-promoting agent (94% in real-world data) rather than tapering 2.
• Start solriamfetol at 37.5-75 mg daily and titrate to 75-150 mg based on response, typically adjusting once over approximately 14 days 2.

Alternative Combination Strategies

If monotherapy with wake-promoting agents proves insufficient:

• Consider adding sodium oxybate for narcolepsy patients, which addresses both excessive sleepiness and cataplexy through a different mechanism (GABA-B agonism) 1.
• Optimize primary OSA treatment before escalating pharmacotherapy—ensure CPAP adherence is maximized 5.
• Add-on therapy with different mechanisms: Pitolisant (histamine H3 inverse agonist) represents a mechanistically distinct option that could theoretically be combined more safely, though data remain limited 1.

Critical Safety Considerations

Cardiovascular Monitoring

• Both medications carry Schedule IV controlled substance warnings due to abuse potential 1.
• Monitor blood pressure and heart rate at baseline and after dose adjustments when using either agent 3.
• Patients with pre-existing cardiovascular disease require particularly careful assessment before initiating either medication 3.

Pregnancy and Contraception

• Both solriamfetol and modafinil may cause fetal harm based on animal data 1.
• Modafinil reduces oral contraceptive effectiveness, requiring alternative birth control methods 1, 6.
• The 2018 armodafinil/modafinil pregnancy registry showed elevated rates of major congenital anomalies 1, 6.

Common Pitfalls to Avoid

• Don't assume additive efficacy: Combining two dopaminergic agents may increase side effects without proportional therapeutic benefit 4.
• Don't overlook drug interactions: While neither medication has extensive CYP450 metabolism, modafinil is a moderate P-gp inducer that could theoretically affect other medications 1.
• Don't combine without clear documentation: If combination therapy is attempted in exceptional circumstances, document the rationale, obtain informed consent regarding off-label use, and implement intensive monitoring 3.