Givlaari: Uses, Dosage & Side Effects
An RNA interference (RNAi) therapy for the treatment of acute hepatic porphyria in adults and adolescents aged 12 years and older
Givlaari (givosiran) is a first-in-class RNA interference (RNAi) therapeutic indicated for the treatment of acute hepatic porphyria (AHP) in adults and adolescents aged 12 years and older. It works by silencing the gene encoding aminolevulinic acid synthase 1 (ALAS1) in the liver, thereby reducing the accumulation of the neurotoxic heme intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG) that drive the debilitating symptoms of AHP. Administered as a once-monthly subcutaneous injection at a weight-based dose of 2.5 mg/kg, Givlaari has been shown in clinical trials to significantly reduce the rate of porphyria attacks requiring hospitalization, urgent healthcare visits, or intravenous hemin administration. It represents a transformative advance for patients with this rare and serious genetic disorder.
Quick Facts: Givlaari
Key Takeaways
- Givlaari (givosiran) is the first RNA interference therapy approved for acute hepatic porphyria (AHP), targeting the root cause of the disease by silencing ALAS1 messenger RNA in the liver to reduce neurotoxic ALA and PBG accumulation.
- Administered once monthly as a subcutaneous injection at 2.5 mg/kg body weight by a healthcare professional, Givlaari significantly reduced porphyria attack rates by 74% compared to placebo in the pivotal ENVISION clinical trial.
- Liver function must be monitored before and during treatment, as transaminase elevations have been reported, typically occurring 3 to 5 months after treatment initiation; dose modifications or discontinuation may be necessary.
- Givlaari can affect several CYP450 liver enzymes (CYP1A2, CYP2D6, CYP2C19, CYP3A4, CYP2E1), potentially increasing blood levels and effects of concomitant medications metabolized by these pathways.
- The most common side effects are nausea, injection site reactions, skin rashes, fatigue, and changes in liver and kidney function markers; homocysteine levels should also be monitored during treatment.
What Is Givlaari and What Is It Used For?
Givlaari contains the active substance givosiran, a synthetic double-stranded small interfering RNA (siRNA) that has been chemically modified for enhanced stability and conjugated with N-acetylgalactosamine (GalNAc) residues. GalNAc serves as a targeting ligand that binds specifically to asialoglycoprotein receptors (ASGPR) on the surface of hepatocytes (liver cells), enabling precise and efficient delivery of the siRNA to its site of action. Once inside the hepatocyte, givosiran utilizes the cell's natural RNA interference machinery to selectively degrade the messenger RNA (mRNA) encoding aminolevulinic acid synthase 1 (ALAS1), the rate-limiting enzyme in the heme biosynthesis pathway in the liver.
This targeted approach addresses the fundamental biochemical abnormality underlying acute hepatic porphyria. AHP encompasses a group of rare genetic metabolic disorders—including acute intermittent porphyria (AIP, the most common subtype), variegate porphyria (VP), hereditary coproporphyria (HCP), and ALAD-deficiency porphyria—in which inherited enzymatic defects in the heme biosynthesis pathway lead to a compensatory upregulation of ALAS1 activity. This upregulation results in the overproduction and accumulation of the neurotoxic heme precursors aminolevulinic acid (ALA) and porphobilinogen (PBG). These intermediates are directly responsible for the severe clinical manifestations of AHP, which can include excruciating abdominal pain, nausea, vomiting, tachycardia, hypertension, muscle weakness, seizures, and psychiatric disturbances.
AHP is estimated to affect approximately 1 in 100,000 people worldwide, though the prevalence of symptomatic disease is likely underestimated due to diagnostic challenges and the variable penetrance of the underlying genetic mutations. The condition disproportionately affects women of reproductive age, with hormonal fluctuations being a well-recognized trigger for acute attacks. Other common triggers include fasting, certain medications, alcohol, stress, and infections. Between acute attacks, many patients experience chronic symptoms such as ongoing pain, fatigue, nausea, and neuropathy, significantly impacting quality of life. Long-term complications of AHP include chronic kidney disease, liver disease (including an increased risk of hepatocellular carcinoma), and systemic arterial hypertension.
Prior to the approval of Givlaari, the standard of care for acute AHP attacks was intravenous hemin (heme arginate or hematin), which works by replenishing the heme pool and suppressing ALAS1 activity through negative feedback. While effective for acute attacks, hemin administration requires venous access, is associated with adverse effects including thrombophlebitis and coagulopathy, and does not provide sustained suppression of the disease. For patients with recurrent attacks, prophylactic hemin infusions were sometimes used, but this approach was limited by the need for central venous access, iron overload risk, and lack of robust evidence for long-term efficacy.
The efficacy of Givlaari was established in the ENVISION trial, a randomized, double-blind, placebo-controlled, multinational phase III study that enrolled 94 patients with AHP who were aged 12 years or older. The primary endpoint was the annualized rate of porphyria attacks requiring hospitalization, an urgent healthcare visit, or intravenous hemin administration. Patients treated with Givlaari experienced a 74% reduction in the annualized attack rate compared with placebo (median annualized rate of 1.0 in the Givlaari group versus 6.5 in the placebo group, p < 0.001). Additionally, Givlaari-treated patients showed significant reductions in urinary ALA and PBG levels, hemin use, and improvement in daily worst pain scores.
Givlaari was first approved by the U.S. Food and Drug Administration (FDA) in November 2019, making it the first RNAi therapy approved for the treatment of AHP. The European Medicines Agency (EMA) granted marketing authorization in March 2020. It is now approved in more than 30 countries worldwide. Givlaari is manufactured by Alnylam Pharmaceuticals, a company specializing in RNAi therapeutics. The drug represents a paradigm shift in the management of AHP, moving from reactive treatment of acute attacks to proactive, disease-modifying therapy that addresses the underlying pathophysiology.
RNA interference is a naturally occurring biological process in which small RNA molecules silence specific genes by degrading their messenger RNA. Givlaari harnesses this mechanism to selectively reduce ALAS1 enzyme production in the liver. The GalNAc conjugation technology enables precise targeting of hepatocytes, minimizing effects on other tissues. This approach earned Andrew Fire and Craig Mello the Nobel Prize in Physiology or Medicine in 2006 for their discovery of RNAi, and Givlaari is among the first drugs to successfully translate this science into clinical therapy.
What Should You Know Before Taking Givlaari?
Contraindications
The use of Givlaari is contraindicated in patients who have experienced a serious allergic reaction (hypersensitivity) to givosiran or to any of the other ingredients in the formulation. The excipients in Givlaari include sodium hydroxide, phosphoric acid, and water for injections. If you have a known allergy to any of these substances, you must not receive Givlaari. Each milliliter of the solution contains less than 1 mmol (23 mg) of sodium, meaning it is essentially sodium-free, which is relevant for patients on sodium-restricted diets.
Although rare (occurring in up to 1 in 100 patients), serious allergic reactions including anaphylaxis have been reported with Givlaari. Signs of anaphylaxis include swelling of the lips, tongue, or throat making it difficult to swallow or breathe, wheezing, dizziness or fainting, skin rash, hives, and itching. If you experience any of these symptoms during or after your injection, your healthcare provider will immediately stop the administration and you may require additional medications to manage the reaction.
Warnings and Precautions
Givlaari can cause elevations in liver transaminases (ALT and AST). Your doctor will perform blood tests to check your liver function before starting treatment and periodically during therapy. Abnormal results, primarily occurring 3 to 5 months after treatment initiation, may require dose interruption or permanent discontinuation. Seek medical attention if you develop signs of liver injury such as yellowing of the skin or eyes, dark urine, unusual tiredness, or abdominal pain.
Before starting Givlaari, discuss the following with your healthcare provider:
- Liver problems: Givlaari can affect your liver function. Elevated levels of liver enzymes (alanine aminotransferase, ALT) have been observed in clinical trials, primarily 3 to 5 months after treatment initiation. In the ENVISION trial, ALT elevations greater than 3 times the upper limit of normal (ULN) occurred in approximately 15% of Givlaari-treated patients. Your doctor will order blood tests before you begin treatment and at regular intervals during treatment. If your liver tests show significant abnormalities, your doctor may decide to temporarily interrupt or permanently discontinue Givlaari therapy. In some cases, treatment may be restarted at a lower dose after liver enzymes have normalized.
- Kidney problems: Givlaari may affect kidney function, particularly in patients who already have existing kidney disease. Changes in serum creatinine levels and estimated glomerular filtration rate (eGFR) have been observed during treatment. The mechanism may involve reduced hepatic ALAS1 activity affecting creatine metabolism in the liver. Your doctor will monitor your kidney function during treatment, especially if you have a history of kidney disease or risk factors for renal impairment. Report any changes in urination patterns or swelling in your legs or feet to your doctor.
- Homocysteine levels: Givlaari can cause an increase in blood levels of homocysteine, a type of amino acid. Elevated homocysteine (hyperhomocysteinemia) is associated with an increased risk of cardiovascular events, although the clinical significance of Givlaari-induced homocysteine elevation has not been fully established. Your doctor will check your homocysteine levels before and during treatment. If your levels are elevated, your doctor may prescribe homocysteine-lowering therapy, typically with vitamin B6 (pyridoxine), folate (folic acid), and/or vitamin B12 (cobalamin) supplementation.
- History of allergic reactions: If you have a history of significant allergic reactions to medications or biological products, inform your doctor before starting Givlaari. Serious hypersensitivity reactions, including rare cases of anaphylaxis, have been reported.
Children and Adolescents
Givlaari is approved for use in adolescents aged 12 years and older. The safety and efficacy in this age group are supported by pharmacokinetic modeling, pharmacodynamic data, and limited clinical experience from the ENVISION trial, which included patients aged 12 and above. However, Givlaari should not be used in children under 12 years of age, as there is no clinical experience with the medication in this younger age group and the potential effects on growth and development have not been fully characterized. Healthcare providers should use clinical judgment when considering Givlaari for adolescent patients, ensuring that the benefits outweigh the potential risks.
Pregnancy and Breastfeeding
If you are pregnant, think you may be pregnant, or are planning to become pregnant, consult your doctor or pharmacist before receiving Givlaari. The effects of givosiran on human pregnancy have not been adequately studied. Animal reproductive studies have shown that givosiran can cause adverse developmental effects at doses significantly higher than the recommended human dose, including reduced fetal body weight and skeletal variations. Although the relevance of these findings to humans at the therapeutic dose is uncertain, as a precaution, Givlaari should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Women of childbearing potential should discuss contraception with their doctor during Givlaari treatment.
It is not known whether givosiran or its metabolites pass into human breast milk. Animal studies suggest that the drug and its metabolites may be present in milk. If you are breastfeeding or planning to breastfeed, consult your doctor before receiving Givlaari. Your doctor will help you decide whether to discontinue breastfeeding or to discontinue Givlaari therapy, taking into account the benefit of breastfeeding for your child and the benefit of treatment for you. As a small molecule RNA conjugate, givosiran would likely have very limited oral bioavailability if ingested by the infant, but the potential risk cannot be entirely excluded.
Driving and Operating Machinery
Givlaari is unlikely to have any effect on your ability to drive or operate machinery. No studies on the effects of givosiran on the ability to drive and use machines have been performed, but based on its pharmacological properties and the known side effect profile, no impairment of these abilities is expected. However, AHP itself can cause symptoms such as fatigue, muscle weakness, and neurological disturbances that may affect driving ability. If you experience any adverse effects that could impair your alertness or coordination, refrain from driving or operating machinery until you feel well again.
Important Information About Ingredients
Givlaari contains less than 1 mmol (23 mg) of sodium per milliliter, meaning it is essentially sodium-free. This is relevant for patients on a sodium-restricted diet. The solution contains givosiran sodium as the active ingredient, along with sodium hydroxide (for pH adjustment), phosphoric acid (for pH adjustment), and water for injections. The solution is clear and colorless to yellow. If you have any known intolerances or allergies to these components, inform your healthcare provider before starting treatment.
How Does Givlaari Interact with Other Drugs?
Unlike many biologic therapies that have minimal drug interactions, Givlaari has a clinically significant drug interaction profile that requires careful attention. Because givosiran reduces ALAS1 activity in the liver, it secondarily decreases heme availability for heme-dependent proteins, including several cytochrome P450 (CYP) enzymes that are critical for the metabolism of numerous medications. The reduction in CYP enzyme activity can lead to increased blood levels and prolonged effects of drugs metabolized by these pathways, potentially necessitating dose adjustments.
Clinical pharmacology studies and population pharmacokinetic analyses from the Givlaari clinical program have identified significant effects on the following CYP enzymes:
| CYP Enzyme | Effect | Example Substrates | Clinical Significance |
|---|---|---|---|
| CYP1A2 | Decreased activity | Caffeine, theophylline, tizanidine, duloxetine, clozapine | Monitor closely; dose reduction may be needed |
| CYP2D6 | Decreased activity | Metoprolol, dextromethorphan, codeine, tamoxifen, venlafaxine | Monitor for increased effects or toxicity |
| CYP2C19 | Decreased activity | Omeprazole, clopidogrel, diazepam, citalopram | Dose adjustment may be required |
| CYP3A4 | Decreased activity | Midazolam, atorvastatin, amlodipine, cyclosporine | Monitor; consider dose adjustments |
| CYP2E1 | Decreased activity | Chlorzoxazone, isoflurane, acetaminophen (minor pathway) | Potential for altered metabolism |
The most clinically significant interaction is with CYP1A2 substrates. In a dedicated drug interaction study, givosiran increased the area under the curve (AUC) of caffeine (a sensitive CYP1A2 substrate) by approximately 3-fold and its maximum concentration (Cmax) by approximately 1.3-fold. This degree of CYP1A2 inhibition is considered clinically meaningful and necessitates caution when Givlaari is co-administered with drugs that are primarily metabolized by CYP1A2, particularly those with a narrow therapeutic index such as theophylline, tizanidine, and clozapine. For CYP2D6, an increase in AUC of dextromethorphan (a CYP2D6 probe substrate) of approximately 2.4-fold was observed.
It is important to note that the interaction with clopidogrel, a CYP2C19 substrate that is a prodrug requiring metabolic activation, is complex. Decreased CYP2C19 activity could potentially reduce the conversion of clopidogrel to its active metabolite, theoretically diminishing its antiplatelet effect. Patients requiring antiplatelet therapy with clopidogrel should be closely monitored, and alternative antiplatelet agents may need to be considered.
Given the breadth of potential drug interactions, it is essential that you inform your doctor, pharmacist, or nurse about all medications you are currently taking, have recently taken, or might take, including prescription drugs, over-the-counter medications, herbal supplements, and dietary supplements. Your healthcare provider may need to adjust the doses of your other medications, switch to alternative therapies, or implement more intensive monitoring when you start, change, or discontinue Givlaari treatment.
Because Givlaari affects multiple CYP450 enzymes involved in drug metabolism, it is critical that your doctor knows about ALL medications and supplements you are taking. Even over-the-counter medications like caffeine-containing products may be affected. Dose adjustments of your other medications may be necessary when starting or stopping Givlaari.
What Is the Correct Dosage of Givlaari?
Givlaari should always be administered by a healthcare professional (doctor or nurse) in a clinical setting. The medication is not intended for self-administration at home. The dose is calculated individually based on your body weight, ensuring that each patient receives the optimal therapeutic amount. Your healthcare provider will prepare the injection, selecting the appropriate volume from one or more single-use vials.
Adults and Adolescents (12 Years and Older)
| Parameter | Recommendation |
|---|---|
| Recommended dose | 2.5 mg/kg body weight |
| Frequency | Once monthly (every 4 weeks) |
| Route | Subcutaneous injection |
| Injection site | Abdomen (preferred), upper arm, or thigh |
| Maximum single injection volume | 1.5 mL per injection site |
| Administration | By healthcare professional only |
If the calculated dose requires a volume greater than 1 mL, more than one vial may be needed, and the dose should be divided into multiple subcutaneous injections. Each individual injection should not exceed 1.5 mL in volume, and when multiple injections are required, the injection sites should be at least 2 cm apart from each other. The injection should be given in the abdominal area, avoiding a 5 cm diameter circle around the navel. Alternative injection sites include the upper arm (the back or side) or the thigh. Injection sites should be rotated between administrations, and injections should not be given into scar tissue or areas that are red, inflamed, or swollen.
Children Under 12 Years
Givlaari should not be used in children under 12 years of age. There is no clinical experience with the drug in this age group, and the safety and efficacy have not been established. The developing liver and metabolic pathways in younger children may respond differently to ALAS1 silencing, and the long-term effects on growth, development, and heme-dependent processes have not been studied.
Elderly Patients
No dose adjustment is required for elderly patients. Limited data are available from elderly patients in clinical trials, but the pharmacokinetics and pharmacodynamics of givosiran are not expected to be significantly different in older adults compared with younger adults. As with any medication in elderly patients, careful clinical monitoring is advisable, particularly regarding liver and kidney function, as older patients may have reduced hepatic and renal reserve.
Renal and Hepatic Impairment
No dose adjustment is needed for patients with mild hepatic impairment (Child-Pugh class A) or mild to moderate renal impairment. Givlaari has not been studied in patients with moderate or severe hepatic impairment (Child-Pugh class B or C), or in patients with severe renal impairment or end-stage renal disease. Since Givlaari is primarily metabolized by nucleases and its metabolites are excreted renally, patients with significant kidney disease may have altered drug exposure. Your doctor will consider these factors when deciding whether Givlaari is appropriate for you and will monitor your liver and kidney function closely during treatment.
Dose Adjustments for Liver Function Abnormalities
If blood tests reveal clinically significant elevations in your liver enzymes during treatment, your doctor may need to modify or interrupt your Givlaari therapy. The specific approach depends on the severity and persistence of the transaminase elevations. If treatment is interrupted and your liver enzymes return to acceptable levels, your doctor may consider restarting Givlaari at a reduced dose, with continued close monitoring. If significant liver enzyme elevations recur after restarting at a lower dose, permanent discontinuation may be necessary.
Missed Dose
If you miss your scheduled injection appointment, contact your doctor or nurse as soon as possible to arrange an alternative time. There is no need for a double dose. After receiving the missed dose, resume your regular once-monthly dosing schedule based on the date of the most recent injection. Using a calendar or mobile phone reminders can help you keep track of your monthly injection schedule.
Overdose
In the unlikely event that you receive more Givlaari than prescribed, your healthcare provider will monitor you for adverse effects. There is no specific antidote for givosiran overdose. In clinical trials, single doses higher than the recommended dose were administered without dose-limiting toxicity, but the potential for increased adverse effects with overdose exists, particularly regarding liver function. Treatment of overdose is supportive, with monitoring of liver function tests, kidney function, and clinical status. Given that givosiran has a sustained pharmacodynamic effect despite a short plasma half-life, monitoring should continue for an appropriate duration.
What Are the Side Effects of Givlaari?
Like all medicines, Givlaari can cause side effects, although not everybody gets them. The side effects observed in clinical trials and post-marketing surveillance are described below, organized by frequency. Most side effects are mild to moderate in severity and manageable with appropriate monitoring and clinical care. However, some side effects, particularly liver enzyme elevations and allergic reactions, require prompt medical attention.
Very Common
May affect more than 1 in 10 people
- Nausea – feeling sick to the stomach, which may occur around the time of injection
- Elevated transaminases – blood tests showing increased liver enzymes (ALT/AST), a sign of possible liver inflammation
- Skin rashes – including red, itchy, or dry skin, eczema, or hives (urticaria)
- Elevated creatinine / decreased eGFR – blood tests showing changes in kidney function markers
- Injection site reactions – redness, pain, itching, or swelling at the injection site
- Fatigue – feeling unusually tired or lacking energy
Common
May affect up to 1 in 10 people
- Hypersensitivity reactions – allergic reactions with symptoms such as hives, rash, swollen eyes, mouth or face, difficulty breathing, itching
- Pancreatitis – inflammation of the pancreas, which may cause severe abdominal pain, nausea, and vomiting
- Elevated homocysteine – blood tests showing an increase in homocysteine, a type of amino acid
Rare
May affect up to 1 in 1,000 people
- Anaphylaxis – severe, life-threatening allergic reaction with swelling (especially lips, tongue, or throat), breathing difficulties, wheezing, dizziness, fainting, skin rash, hives, and itching
The liver enzyme elevations (transaminase increases) observed with Givlaari are of particular clinical importance. In the ENVISION trial, ALT elevations greater than 3 times the upper limit of normal occurred in approximately 15% of patients treated with Givlaari, compared with 2% in the placebo group. Most elevations occurred between 3 and 5 months after treatment initiation and were reversible with dose interruption or discontinuation. In some cases, transaminase elevations occurred in the context of identified triggers such as intercurrent illness or concomitant hepatotoxic medications. Your doctor will perform regular liver function tests to detect any abnormalities early.
Injection site reactions were reported in a significant proportion of patients but were generally mild. Reactions included redness, pain, pruritus (itching), and swelling at the injection site. These reactions typically resolved within a few days. Rotating the injection site between administrations can help minimize these reactions.
The increase in serum creatinine and decrease in eGFR observed with Givlaari may be related to a pharmacological effect on creatine biosynthesis in the liver, as ALAS1 silencing can secondarily affect metabolic pathways involving creatine precursors. This effect should be distinguished from true renal impairment, and your doctor will interpret kidney function markers in the context of your overall clinical picture. Patients with pre-existing kidney disease may be at higher risk and require closer monitoring.
Pancreatitis (inflammation of the pancreas) was reported as a common side effect. Symptoms of pancreatitis include severe abdominal pain that may radiate to the back, nausea, vomiting, and elevated pancreatic enzyme levels. If you experience sudden severe abdominal pain, seek immediate medical attention. Your doctor may check blood levels of pancreatic enzymes (amylase and lipase) if pancreatitis is suspected.
Contact your doctor or seek emergency medical care immediately if you experience: signs of a severe allergic reaction (swelling of face, lips, tongue, or throat; difficulty breathing; severe rash); sudden severe abdominal pain (possible pancreatitis); yellowing of skin or eyes, dark urine, or unusual fatigue (possible liver injury); or significant changes in urination patterns.
How Should You Store Givlaari?
Proper storage of Givlaari is essential to ensure the medication remains effective and safe. Although Givlaari is typically stored and handled by healthcare professionals in clinical settings rather than by patients at home, it is important to understand the storage requirements:
- Temperature: Store at or below 25°C (77°F). Do not freeze. If the medication has been frozen, do not use it.
- Light protection: Keep the vial in the original outer carton to protect from light. Prolonged exposure to light may degrade the active substance.
- Single use: Each vial is intended for single use only. Once the vial has been opened and the required dose drawn up, any remaining solution in the vial should be discarded. Do not save leftover medication for later use.
- Use immediately after opening: Once the product has been opened, it should be used immediately. Prepared syringes should be administered promptly.
- Expiration date: Do not use Givlaari after the expiration date (EXP) printed on the outer carton and the vial. The expiration date refers to the last day of the stated month.
- Keep out of reach of children: Store this medicine out of the sight and reach of children.
- Disposal: Do not dispose of Givlaari through household waste or wastewater. Your healthcare provider will dispose of any unused medication in accordance with local regulations to protect the environment.
The solution should appear clear and colorless to yellow. Before administration, your healthcare provider will visually inspect the solution. If the solution appears cloudy, discolored, or contains visible particles, it should not be used. Each 1 mL vial contains givosiran sodium equivalent to 189 mg of givosiran.
What Does Givlaari Contain?
Active Ingredient
The active substance in Givlaari is givosiran, present as givosiran sodium. Each milliliter of solution for injection contains givosiran sodium equivalent to 189 mg of givosiran. Givosiran is a synthetic double-stranded small interfering RNA (siRNA) molecule with enhanced stabilization chemistry (ESC). It is covalently linked to a triantennary N-acetylgalactosamine (GalNAc) ligand at the 3’ end of the sense strand, which facilitates specific uptake by hepatocytes via asialoglycoprotein receptors. The molecular weight of givosiran sodium is approximately 16,300 Daltons.
Other Ingredients (Excipients)
| Component | Function |
|---|---|
| Givosiran sodium | Active ingredient (189 mg/mL as givosiran) |
| Sodium hydroxide | pH adjustment |
| Phosphoric acid | pH adjustment / buffering |
| Water for injections | Solvent |
The formulation is intentionally simple, containing only the active ingredient, pH-adjusting agents, and water. This minimalist formulation reduces the risk of allergic reactions to excipients. The solution has a pH range that ensures stability and tolerability upon subcutaneous injection. As noted, the product contains less than 1 mmol (23 mg) of sodium per mL, making it essentially sodium-free.
Packaging
Givlaari is supplied in Type I glass vials, each containing 1 mL of solution for injection. The vials are sealed with a chlorobutyl rubber stopper and an aluminum flip-off cap. Each carton contains one single-use vial. Materials needed for administration that are not included in the package (such as sterile syringes, transfer needles, and injection needles) must be obtained separately by the healthcare provider.
Givlaari is developed and manufactured by Alnylam Pharmaceuticals, with the European marketing authorization held by Alnylam Netherlands B.V. Alnylam is a pioneer in RNAi therapeutics, having developed multiple approved medications using this innovative technology platform.
Frequently Asked Questions About Givlaari
Acute hepatic porphyria (AHP) is a family of rare genetic metabolic disorders caused by inherited enzyme deficiencies in the heme biosynthesis pathway in the liver. The most common subtype is acute intermittent porphyria (AIP), followed by variegate porphyria (VP) and hereditary coproporphyria (HCP). These defects lead to accumulation of the neurotoxic intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG), which cause severe attacks of abdominal pain, nausea, vomiting, tachycardia, hypertension, muscle weakness, seizures, and psychiatric symptoms. AHP affects approximately 1 in 100,000 people worldwide and is more common in women of reproductive age. Attacks can be triggered by hormonal changes, fasting, certain medications, alcohol, stress, and infections. Many patients also experience chronic symptoms between attacks.
In the pivotal ENVISION clinical trial, Givlaari reduced the annualized rate of porphyria attacks (requiring hospitalization, urgent healthcare visits, or intravenous hemin) by 74% compared to placebo. The median annualized attack rate was 1.0 in the Givlaari group versus 6.5 in the placebo group. Additionally, 50% of Givlaari-treated patients were attack-free during the 6-month treatment period, compared with 16.3% of placebo-treated patients. Givlaari also significantly reduced levels of ALA and PBG (the neurotoxic intermediates causing attacks), reduced hemin usage, and improved daily worst pain scores. Long-term extension data support sustained efficacy over 24 months and beyond.
Givlaari can cause elevations in liver transaminases (ALT and AST), which are enzymes that serve as markers of liver cell injury. In clinical trials, ALT elevations greater than 3 times the upper limit of normal occurred in approximately 15% of Givlaari-treated patients, primarily between 3 and 5 months after starting treatment. While most elevations were reversible with dose interruption or discontinuation, the potential for liver injury necessitates regular monitoring. Your doctor will check your liver enzymes before starting treatment and at regular intervals thereafter. If significant elevations are detected, treatment may be temporarily interrupted, permanently discontinued, or restarted at a lower dose, depending on the severity and your overall clinical picture.
Givlaari can affect the metabolism of many commonly used medications because it reduces the activity of several CYP450 liver enzymes (including CYP1A2, CYP2D6, CYP2C19, CYP3A4, and CYP2E1). This means some medications may have increased blood levels and prolonged effects when taken with Givlaari. Your doctor will review all your current medications and may need to adjust doses, switch to alternative drugs, or implement closer monitoring. It is essential that you tell your doctor about ALL medications, supplements, and over-the-counter products you are taking. Never stop or change your medications without consulting your doctor first.
Givlaari begins to reduce ALA and PBG levels relatively quickly after the first injection. In clinical studies, significant reductions in urinary ALA and PBG were observed within the first month of treatment. However, the full clinical benefit in terms of reduced attack frequency may take several months to become apparent, as the monthly dosing schedule allows for progressive and sustained ALAS1 mRNA silencing in the liver. Most patients in the ENVISION trial showed a meaningful reduction in attack frequency within the first 3 months. Your doctor will monitor your response to treatment through clinical assessments and laboratory tests, including measurement of urinary ALA and PBG levels.
While Givlaari significantly reduces the frequency of porphyria attacks, breakthrough attacks can still occur, particularly in the early months of treatment before the full therapeutic effect is established. If you experience symptoms of an acute attack (severe abdominal pain, nausea, vomiting, rapid heartbeat, muscle weakness, or neurological symptoms), contact your healthcare provider immediately. Acute attacks may still require treatment with intravenous hemin, pain management, and supportive care, even while you are on Givlaari. Your doctor will manage the acute episode according to standard protocols and will assess whether any adjustment to your Givlaari therapy is needed.
References
- European Medicines Agency (EMA). Givlaari (givosiran) – Summary of Product Characteristics. Last updated 2025. Available at: ema.europa.eu/en/medicines/human/EPAR/givlaari
- U.S. Food and Drug Administration (FDA). Givlaari (givosiran) – Prescribing Information. Last updated 2024. Available at: accessdata.fda.gov
- Balwani M, Sardh E, Ventura P, et al. Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria (ENVISION). N Engl J Med. 2020;382(24):2289-2301. doi:10.1056/NEJMoa1913147
- Sardh E, Harper P, Balwani M, et al. Phase 1 Trial of an RNA Interference Therapy for Acute Intermittent Porphyria. N Engl J Med. 2019;380(6):549-558. doi:10.1056/NEJMoa1807838
- Ventura P, Bonkovsky HL, Gouya L, et al. Efficacy and safety of givosiran for acute hepatic porphyria: 24-month interim analysis of the randomized phase 3 ENVISION study. Liver Int. 2022;42(1):161-172. doi:10.1111/liv.15090
- Pischik E, Kauppinen R. An update of clinical management of acute intermittent porphyria. Appl Clin Genet. 2015;8:201-214. doi:10.2147/TACG.S48605
- Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med. 2017;377(9):862-872. doi:10.1056/NEJMra1608634
- European Porphyria Network (EPNET). Guidelines for the Management of Acute Porphyria. Updated 2024. Available at: porphyria.eu
- World Health Organization (WHO). Model List of Essential Medicines. 23rd List, 2023. Available at: who.int
- Alnylam Pharmaceuticals. Givlaari (givosiran) – Full Prescribing Information and Patient Information. 2024.
Medical Editorial Team
Medical Content
Written by iMedic Medical Editorial Team – specialists in hepatology and clinical pharmacology with expertise in rare metabolic diseases and RNA therapeutics.
Medical Review
Reviewed by iMedic Medical Review Board – independent panel of board-certified physicians following EMA, FDA, and EPNET guidelines.
Evidence Standard
Evidence Level 1A – based on systematic reviews, meta-analyses, and randomized controlled trials (ENVISION phase III trial).
Editorial Policy
No commercial funding. Independent medical content following GRADE evidence framework. No pharmaceutical company sponsorship.
Published: November 1, 2025 | Last reviewed: February 1, 2026 | Next review: August 2026