Givlaari Drug Interactions: What to Avoid and What to Tell Your Doctor

Givlaari (givosiran) has an unusual and important drug interaction profile. Unlike most medications that are themselves metabolized by liver enzymes, Givlaari changes the activity of those liver enzymes — specifically CYP1A2 and CYP2D6. This means that many other medications you take may be affected once you start Givlaari.

Before starting Givlaari, your doctor should review every medication, supplement, and herbal product you take. This guide explains how these interactions work, which drugs are most concerning, and how to discuss your medication list with your healthcare team.

Why Does Givlaari Cause Drug Interactions?

Givlaari works by reducing ALAS1 enzyme activity in liver cells. Because heme is a critical component of cytochrome P450 (CYP) enzymes — which the liver uses to metabolize most drugs — lowering ALAS1 also reduces the overall activity of certain CYP enzymes, particularly CYP1A2 and CYP2D6.

When these enzymes are less active, they break down other medications more slowly. This causes levels of those medications to build up higher in your blood than expected — potentially to toxic levels. This is known as enzyme inhibition, and it's why the FDA requires a careful medication review before starting Givlaari.

CYP1A2 Interactions: How Large Is the Effect?

In drug interaction studies, one dose of Givlaari increased the AUC (overall blood exposure) of caffeine — a sensitive CYP1A2 substrate — by 3.1-fold, and peak concentration (Cmax) by 1.3-fold. This is a significant interaction. Applied to actual medications, this means drugs processed by CYP1A2 could accumulate to 3x their intended levels in your bloodstream.

Examples of sensitive CYP1A2 substrates to avoid or use with extreme caution:

• Theophylline (used for asthma/COPD) — serious risk of toxicity
• Clozapine (antipsychotic) — increased risk of seizures and agranulocytosis
• Olanzapine (antipsychotic) — increased sedation and metabolic side effects
• Alosetron (for IBS-D) — increased exposure risk
• Tizanidine (muscle relaxant) — risk of severe hypotension
• Fezolinetant (for menopause vasomotor symptoms) — contraindicated with Givlaari

CYP2D6 Interactions: Also Significant

Givlaari increased the AUC of dextromethorphan (a sensitive CYP2D6 substrate) by 2.4-fold and Cmax by 2-fold. CYP2D6 metabolizes a wide range of medications including:

• Aripiprazole (Abilify) — antipsychotic; increased exposure risk
• Brexpiprazole (Rexulti) — antipsychotic; dose reduction may be needed
• Atomoxetine (Strattera) — ADHD medication; increased cardiovascular risk
• Amitriptyline and other tricyclic antidepressants — cardiac risk at elevated levels
• Codeine and tramadol — altered conversion to morphine; unpredictable analgesic effects or toxicity

What About AHP Triggers? A Note on Medication Choice

Patients with AHP also face a separate category of medication concern: drugs that are known to trigger porphyria attacks (distinct from CYP interaction concerns). These attack-triggering medications include:

• Barbiturates (e.g., phenobarbital)
• Sulfonamide antibiotics (e.g., sulfamethoxazole)
• Most anti-epileptic drugs (phenytoin, carbamazepine, valproate)
• Rifampin (antibiotic)
• Exogenous hormones in high doses

The American Porphyria Foundation maintains an up-to-date drug list at porphyriafoundation.org. Always check this resource before starting any new medication. This list is separate from the CYP interaction concern with Givlaari itself.

What to Tell Your Doctor and Pharmacist

Before starting Givlaari, give your prescribing specialist and pharmacist a complete list of everything you take — including:

• All prescription medications
• Over-the-counter medications (including pain relievers, cold medicines with dextromethorphan, sleep aids)
• Vitamins and supplements
• Herbal products (St. John's Wort, for example, can affect liver enzymes)

Your doctor or clinical pharmacist can run a formal drug interaction check and determine whether dose adjustments are needed for any medications that are CYP1A2 or CYP2D6 substrates before you start Givlaari.

The Scope of the Problem

Givosiran has clinically meaningful interactions with at least 87 other drugs when serious interactions are counted. For patients with complex medication regimens — which is not uncommon in AHP patients who have been through years of symptomatic management — this requires careful clinical coordination. Your AHP specialist, primary care physician, and pharmacist all need to be on the same page. For more on Givlaari's safety profile, see our Givlaari side effects guide.

If you're navigating Givlaari access alongside managing complex care, medfinder can help you find specialty pharmacies and clinical sites that can administer your monthly injection.