Orphacol
Cholic Acid for Inborn Errors of Bile Acid Synthesis
Quick Facts About Orphacol
Key Takeaways About Orphacol
- Orphan medicine for rare disease: Orphacol is designated as an orphan medicinal product by the EMA, treating extremely rare inborn errors of primary bile acid synthesis
- Lifelong treatment required: Treatment must not be stopped without medical supervision, as discontinuation can lead to permanent liver damage from toxic bile acid intermediate accumulation
- Weight-based dosing: The usual starting dose is 5 to 15 mg per kilogram of body weight per day, taken with meals and adjusted based on laboratory monitoring
- Safe in pregnancy with monitoring: It is very important to continue Orphacol during pregnancy; both mother and baby should be closely monitored by the treating physician
- Avoid phenobarbital: Orphacol must not be taken together with phenobarbital, and bile acid sequestrants should be taken at least 5 hours apart
What Is Orphacol and What Is It Used For?
Orphacol contains cholic acid, a primary bile acid normally produced in the liver. It is prescribed to treat inborn errors of primary bile acid synthesis – rare genetic disorders where the body lacks the enzymes needed to produce bile acids. Orphacol replaces the missing bile acids, preventing progressive liver damage and restoring fat-soluble vitamin absorption.
Bile acids are essential molecules synthesised in the liver from cholesterol. They play a critical role in digestion by emulsifying dietary fats and enabling the absorption of fat-soluble vitamins (A, D, E, and K) in the small intestine. Bile acids also regulate cholesterol homeostasis and maintain normal bile flow (choleresis) from the liver to the intestine. Under normal physiological conditions, the primary bile acids – cholic acid and chenodeoxycholic acid – are produced through a complex enzymatic pathway involving multiple steps in the hepatocyte.
In patients with inborn errors of primary bile acid synthesis, one or more of the enzymes in this pathway are deficient due to genetic mutations. This results in two harmful consequences: first, the body cannot produce sufficient quantities of normal bile acids, leading to impaired fat digestion and fat-soluble vitamin deficiency; second, the enzymatic block causes accumulation of atypical, toxic bile acid intermediates in the liver. These toxic intermediates are directly hepatotoxic and, over time, cause progressive cholestatic liver disease that can advance to cirrhosis, liver failure, and death if left untreated.
The specific enzyme deficiencies that Orphacol can treat include 3β-hydroxy-Δ5-C27-steroid oxidoreductase (3β-HSD) deficiency and Δ4-3-oxosteroid 5β-reductase (5β-reductase) deficiency. These are among the most commonly identified inborn errors of bile acid synthesis, although the conditions remain extremely rare, with an estimated combined prevalence of fewer than 1 in 50,000 to 100,000 live births worldwide. Other bile acid synthesis defects, such as cerebrotendinous xanthomatosis (CTX) caused by sterol 27-hydroxylase (CYP27A1) deficiency, may also benefit from cholic acid therapy, although treatment approaches may differ.
By providing exogenous cholic acid, Orphacol restores the negative feedback mechanism on bile acid synthesis. This suppresses the production of toxic intermediates through downregulation of the rate-limiting enzyme cholesterol 7α-hydroxylase (CYP7A1). Simultaneously, the administered cholic acid itself enters the enterohepatic circulation, promoting normal bile flow, improving fat and fat-soluble vitamin absorption, and halting the progression of liver damage. Clinical evidence has shown that early initiation of cholic acid therapy can normalise liver function tests, resolve jaundice, and prevent the need for liver transplantation in many patients.
Orphacol was approved by the European Medicines Agency (EMA) under “exceptional circumstances” because the disease it treats is so rare that it was not possible to conduct standard large-scale clinical trials. The EMA reviews new data on Orphacol annually. It is classified as an orphan medicinal product, a designation given to medicines that treat conditions affecting fewer than 5 in 10,000 people in the European Union.
What Should You Know Before Taking Orphacol?
Before starting Orphacol, your doctor will perform blood and urine tests to establish your baseline liver function and bile acid profile. You must not take Orphacol if you are allergic to cholic acid or if you are taking phenobarbital. Regular laboratory monitoring is required throughout treatment.
Because Orphacol is used to treat a serious, lifelong metabolic condition, careful medical evaluation is essential before starting therapy. Your doctor will take a detailed medical history, perform a physical examination, and order laboratory investigations including liver function tests (serum transaminases, bilirubin, gamma-glutamyl transferase), serum bile acid profiles, and urine bile acid analysis. These baseline values are critical for determining the appropriate starting dose and for monitoring your response to treatment over time.
Contraindications
You should not take Orphacol if any of the following apply to you:
- Allergy to cholic acid or any of the other ingredients in this medicine (listed in the contents section below), including lactose monohydrate, colloidal anhydrous silica, magnesium stearate, gelatin, titanium dioxide (E 171), or indigotine (E 132)
- Concurrent use of phenobarbital – phenobarbital, a medicine used to treat epilepsy, is strictly contraindicated with Orphacol because it interferes with the metabolism of cholic acid and can render the treatment ineffective
Never stop taking Orphacol without consulting your doctor. Abrupt discontinuation of cholic acid therapy can lead to rapid re-accumulation of toxic bile acid intermediates in the liver, resulting in progressive and potentially permanent liver damage. Even if you feel well, the underlying enzyme deficiency persists, and continuous treatment is required to prevent disease progression.
Warnings and Precautions
Talk to your doctor before taking Orphacol if you have any of the following conditions or circumstances:
- Liver problems beyond the bile acid synthesis defect – additional liver conditions may affect how your body handles cholic acid, potentially requiring dose adjustments
- Rapid growth periods (children and adolescents) – more frequent monitoring of laboratory tests is needed during periods of rapid growth, as the dose may need to be increased to match the growing body’s requirements
- Intercurrent illness – fever, infections, or other acute illnesses can temporarily affect liver function and may necessitate closer monitoring or temporary dose adjustments
- Lactose intolerance – Orphacol capsules contain lactose monohydrate; if you have a known intolerance to certain sugars, contact your doctor before taking this medicine
During treatment, your doctor will regularly perform blood and urine tests to monitor how your body is responding to Orphacol. These tests typically include liver function panels (serum transaminases, bilirubin, alkaline phosphatase, GGT), serum bile acid concentrations, and urinary bile acid metabolite profiles. The frequency of monitoring is usually more intensive during the initial phase of treatment and during dose adjustments, and may be reduced to every 3–6 months once a stable therapeutic response has been established.
Pregnancy and Breastfeeding
If you are planning to become pregnant, consult your doctor to discuss your treatment plan. If you suspect you may be pregnant, perform a pregnancy test immediately. It is very important to continue taking Orphacol during pregnancy, because stopping treatment could result in accumulation of toxic bile acid intermediates, which could harm both you and your unborn baby.
If you become pregnant while taking Orphacol, your doctor will carefully evaluate your treatment to determine the most appropriate dose. As a precautionary measure, both you and your unborn child will be monitored closely throughout the pregnancy. This monitoring typically includes more frequent liver function tests and ultrasound examinations to assess foetal development.
Orphacol can be used during breastfeeding. Cholic acid is a naturally occurring bile acid that is present in breast milk in small quantities. However, you should inform your doctor if you are breastfeeding or planning to breastfeed so that appropriate monitoring can be arranged for your infant.
Driving and Operating Machinery
Orphacol is not expected to have any effect on your ability to drive or use machines. Cholic acid is a naturally occurring substance in the body, and at therapeutic doses used for replacement therapy, it does not affect the central nervous system or impair cognitive function, reaction times, or motor coordination.
How Does Orphacol Interact with Other Drugs?
Orphacol has clinically significant interactions with phenobarbital (contraindicated), bile acid sequestrants, aluminium-containing antacids, ciclosporin, and ursodeoxycholic acid. Always tell your doctor about all medications you are taking, including over-the-counter products and supplements.
Drug interactions with Orphacol primarily involve substances that either bind to bile acids in the gastrointestinal tract (reducing absorption) or affect bile acid metabolism. Because Orphacol is a replacement therapy for a critical metabolic function, even moderate reductions in its bioavailability can have clinically significant consequences. The following table summarises the most important known interactions.
Major Interactions
| Drug | Category | Effect | Recommendation |
|---|---|---|---|
| Phenobarbital | Antiepileptic | Interferes with cholic acid metabolism, rendering Orphacol treatment ineffective | Contraindicated – must not be used together |
| Cholestyramine | Bile acid sequestrant | Binds to cholic acid in the gut, preventing absorption and reducing therapeutic effect | Take Orphacol at least 5 hours before or after cholestyramine |
| Colestipol | Bile acid sequestrant | Binds to cholic acid in the gut, preventing absorption and reducing therapeutic effect | Take Orphacol at least 5 hours before or after colestipol |
| Colesevelam | Bile acid sequestrant | Binds to cholic acid in the gut, preventing absorption and reducing therapeutic effect | Take Orphacol at least 5 hours before or after colesevelam |
Other Interactions
| Drug | Category | Effect | Recommendation |
|---|---|---|---|
| Aluminium-containing antacids | Antacid / heartburn relief | Can bind to cholic acid and reduce its absorption from the gastrointestinal tract | Take Orphacol at least 5 hours before or after aluminium-containing antacids |
| Ciclosporin | Immunosuppressant | May affect the efficacy of Orphacol through altered bile acid metabolism | Inform your doctor; monitoring of both drug levels may be required |
| Ursodeoxycholic acid | Bile acid (secondary) | Can reduce the efficacy of Orphacol when taken simultaneously by competing for the same transport and feedback mechanisms | If both prescribed: take one in the morning and the other in the evening; for multiple daily doses, space several hours apart |
It is essential to tell your doctor or pharmacist about all medicines you are taking, have recently taken, or might take in the future. This includes prescription medications, over-the-counter drugs, vitamins, mineral supplements, and herbal remedies. Some interactions may not be fully characterised due to the rarity of the condition treated by Orphacol and the limited number of patients studied.
What Is the Correct Dosage of Orphacol?
The usual starting dose of Orphacol is 5 to 15 mg per kilogram of body weight per day, taken orally with a meal. Your doctor will determine the exact dose based on your laboratory results and adjust it over time based on your response to treatment.
Orphacol dosing is individualised and weight-based. Before starting treatment, your doctor will evaluate your baseline laboratory tests – including liver function panels, serum bile acid profiles, and urinary bile acid metabolites – to determine the most appropriate starting dose. The dose will then be adjusted during follow-up visits based on your clinical response and laboratory monitoring results.
Adults
Adult Dosage
The usual starting dose for adults is 5 to 15 mg per kilogram of body weight per day. For example, a 70 kg adult would typically start with a daily dose of 350 mg to 1,050 mg of cholic acid. The capsules should be taken with a meal (morning and/or evening), swallowed whole with water, and taken at approximately the same time each day to maintain consistent blood levels.
If the prescribed dose requires more than one capsule per day, the dose may be split between morning and evening meals. For instance, one capsule in the morning with breakfast and one capsule in the evening with dinner. However, if you are also taking ursodeoxycholic acid, these two medicines must be taken several hours apart (see Drug Interactions section above).
Children and Infants
Paediatric Dosage (1 month to 17 years)
The dosing principle is the same as for adults: 5 to 15 mg per kilogram of body weight per day. The dose is calculated based on the child’s current weight and may need to be increased as the child grows. More frequent laboratory monitoring is recommended during periods of rapid growth to ensure the dose remains adequate.
For infants and young children who cannot swallow capsules, the capsules may be opened and the contents mixed with infant formula or with apple/orange juice or apple/apricot juice designed for infants. The mixture should be consumed immediately after preparation. This method ensures that the full dose is administered even when the child cannot take intact capsules.
Elderly Patients
Elderly Dosage
No specific dose adjustment is generally required for elderly patients. The same weight-based dosing principle of 5 to 15 mg/kg/day applies. However, as with all patients, the dose should be individualised based on laboratory monitoring results. Elderly patients may have age-related changes in liver and kidney function that could influence bile acid metabolism, so closer monitoring may be warranted during dose adjustments.
Missed Dose
If you forget to take a dose of Orphacol, take your next dose at the normal scheduled time. Do not take a double dose to make up for a missed dose. Consistency is important for maintaining stable bile acid levels, but a single missed dose is unlikely to cause immediate harm. However, if you frequently forget doses, speak with your doctor about strategies to improve adherence, as regular dosing is essential for preventing disease progression.
Overdose
If you take more Orphacol than prescribed, contact your doctor as soon as possible. Your doctor will evaluate your liver function through laboratory tests and advise you when it is safe to resume your normal dosing regimen. There is limited clinical experience with cholic acid overdose due to the rarity of the condition, but excessively high bile acid levels could potentially cause gastrointestinal symptoms such as diarrhoea or abdominal discomfort, and in severe cases might affect liver function.
What Are the Side Effects of Orphacol?
Like all medicines, Orphacol can cause side effects, although not everybody experiences them. The most commonly reported side effects include itching (pruritus) and diarrhoea, though exact frequencies cannot be determined from available data. Elevated liver enzymes and gallstones have also been reported with long-term use.
Because Orphacol treats an extremely rare condition and was approved under exceptional circumstances, the side effect profile is based on limited patient data from clinical studies and post-marketing surveillance. The frequency categories below are based on the available evidence, but many side effects are listed as “frequency not known” because the exact incidence cannot be reliably calculated from the small number of patients studied.
It is important to distinguish between side effects of the medicine itself and symptoms of the underlying bile acid synthesis defect. Your doctor will use regular laboratory monitoring to differentiate between the two and to adjust your treatment accordingly.
Frequency Not Known
Cannot be estimated from available data
- Pruritus (itching) – contact your doctor if itching persists for more than three days
- Diarrhoea – contact your doctor if diarrhoea persists for more than three days
- Elevated liver enzymes (serum transaminases) – detected through routine blood tests; your doctor will determine appropriate action
Long-Term Effects
Reported with prolonged use
- Gallstones (cholelithiasis) – may develop with long-term cholic acid therapy; your doctor may perform periodic imaging to monitor for this
The limited side effect profile of Orphacol reflects the fact that cholic acid is a naturally occurring substance in the human body. At therapeutic replacement doses, the body handles exogenous cholic acid through the same enterohepatic circulation pathway that processes endogenously produced bile acids. Nevertheless, individual variation in response is possible, and any unusual or persistent symptoms should be reported to your healthcare provider.
It is important to report suspected side effects after a medicine has been authorised. This allows ongoing monitoring of the medicine’s benefit-risk balance. Healthcare professionals and patients are encouraged to report suspected adverse reactions to their national pharmacovigilance authority (e.g., the EMA in Europe, the FDA in the United States, or the MHRA in the United Kingdom).
How Should You Store Orphacol?
Store Orphacol at or below 25°C (77°F). Keep the capsules in their original blister packaging and store them out of the sight and reach of children. Do not use after the expiry date printed on the packaging.
Proper storage is essential to ensure that Orphacol retains its full therapeutic potency throughout its shelf life. The following storage guidelines should be observed:
- Temperature: Store at no more than 25°C (77°F). Do not freeze. Avoid exposing the capsules to excessive heat or direct sunlight, as this may degrade the active ingredient.
- Packaging: Keep the capsules in their original blister packaging until ready to use. The blister provides a moisture barrier that helps maintain the stability of the capsule contents.
- Child safety: Keep this medicine out of the sight and reach of children. The capsules may look similar to sweets and could be accidentally ingested by a young child.
- Expiry date: Do not use Orphacol after the expiry date stated on the carton and blister pack. The expiry date refers to the last day of that month.
- Disposal: Do not throw away medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. These measures help protect the environment.
What Does Orphacol Contain?
The active ingredient in Orphacol is cholic acid (50 mg or 250 mg per capsule). The capsules also contain lactose monohydrate and other standard pharmaceutical excipients.
Each Orphacol capsule contains the following ingredients:
Active Ingredient
- Orphacol 50 mg: Each hard capsule contains 50 mg of cholic acid
- Orphacol 250 mg: Each hard capsule contains 250 mg of cholic acid
Other Ingredients (Excipients)
Capsule contents: Lactose monohydrate, colloidal anhydrous silica, magnesium stearate
Capsule shell (50 mg): Gelatin, titanium dioxide (E 171), indigotine (E 132) – resulting in a blue and white capsule
Capsule shell (250 mg): Gelatin, titanium dioxide (E 171), indigotine (E 132), yellow iron oxide (E 172) – resulting in a green and white capsule
Orphacol capsules contain lactose monohydrate as an excipient. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. The amount of lactose in each capsule is small, but it may be relevant for patients with severe lactose intolerance or galactosaemia.
Appearance and Pack Sizes
Orphacol capsules are oblong, hard capsules. The 50 mg capsules are blue and white, while the 250 mg capsules are green and white. They are packaged in blisters containing 10 capsules each. Available pack sizes are 30, 60, and 120 capsules. Not all pack sizes may be marketed in all countries.
Frequently Asked Questions About Orphacol
Orphacol contains cholic acid, a primary bile acid that the liver normally produces. It is prescribed for patients who have inborn errors of primary bile acid synthesis – rare genetic conditions where the body cannot manufacture bile acids due to enzyme deficiencies. These conditions can affect infants from 1 month of age through to adults. Without treatment, the lack of bile acids leads to poor fat and vitamin absorption, while toxic bile acid intermediates accumulate and progressively damage the liver. Orphacol replaces the missing bile acids, restoring normal bile flow, improving nutrient absorption, and preventing liver damage.
Orphacol capsules should be swallowed whole with water, taken with a meal at approximately the same time each day (morning and/or evening). Taking the capsules with food helps improve absorption. For infants and young children who cannot swallow capsules, the capsules can be opened and the contents mixed with infant formula or apple/orange juice designed for infants. The usual dose is 5 to 15 mg per kilogram of body weight per day, but your doctor will determine the exact dose based on your individual laboratory results.
Stopping Orphacol without medical supervision can lead to permanent liver damage. The underlying bile acid synthesis defect is a lifelong genetic condition – the enzyme deficiency does not resolve over time. Without continuous replacement therapy, toxic bile acid intermediates rapidly re-accumulate in the liver, causing progressive cholestatic liver disease. This can lead to jaundice, liver fibrosis, cirrhosis, and ultimately liver failure. You should never stop taking Orphacol unless specifically instructed to do so by your doctor.
Yes, and in fact it is very important to continue taking Orphacol during pregnancy. Stopping treatment could lead to accumulation of toxic bile acid intermediates that could harm both the mother and the developing baby. If you become pregnant while taking Orphacol, your doctor will evaluate the most appropriate dose and closely monitor both you and your baby throughout the pregnancy. This monitoring may include more frequent liver function tests and foetal ultrasound examinations. Orphacol can also be used during breastfeeding, although you should inform your doctor.
Yes, Orphacol is designated as an orphan medicinal product by the European Medicines Agency (EMA). This special designation is given to medicines that treat rare diseases affecting fewer than 5 in 10,000 people in the European Union. Orphacol was also approved under “exceptional circumstances” because the extreme rarity of inborn bile acid synthesis defects made it impossible to gather complete clinical data through standard large-scale clinical trials. The EMA reviews any new information about Orphacol annually and updates the product information accordingly.
The most commonly reported side effects of Orphacol include itching (pruritus) and diarrhoea, although the exact frequency cannot be calculated from the available data because the condition is so rare. Elevated liver enzymes (serum transaminases) have also been detected through routine monitoring blood tests. With long-term use, gallstones (cholelithiasis) have been reported. If you experience persistent itching or diarrhoea lasting more than three days, you should contact your doctor. Regular laboratory monitoring will help your doctor detect any changes in liver function early.
References
- European Medicines Agency (EMA). Orphacol – Summary of Product Characteristics. Last updated 2024. Available at: www.ema.europa.eu/en/medicines/human/EPAR/orphacol
- Heubi JE, Setchell KDR, Bove KE. Inborn errors of bile acid metabolism. Seminars in Liver Disease. 2007;27(3):282–294. doi:10.1055/s-2007-985073
- Setchell KDR, Heubi JE. Defects in bile acid biosynthesis – diagnosis and treatment. Journal of Pediatric Gastroenterology and Nutrition. 2006;43(Suppl 1):S17–S22. doi:10.1097/01.mpg.0000226386.79483.7b
- European Association for the Study of the Liver (EASL). Clinical Practice Guidelines: Management of cholestatic liver diseases. Journal of Hepatology. 2009;51(2):237–267. doi:10.1016/j.jhep.2009.04.009
- Gonzales E, Gerhardt MF, Fabre M, et al. Oral cholic acid for hereditary defects of primary bile acid synthesis: a safe and effective long-term therapy. Gastroenterology. 2009;137(4):1310–1320.e3. doi:10.1053/j.gastro.2009.07.043
- Clayton PT. Disorders of bile acid synthesis. Journal of Inherited Metabolic Disease. 2011;34(3):593–604. doi:10.1007/s10545-010-9259-3
- World Health Organization (WHO). Model List of Essential Medicines. 23rd list, 2023. Available at: www.who.int
- Bove KE, Heubi JE, Balistreri WF, Setchell KDR. Bile acid synthetic defects and liver disease: a comprehensive review. Pediatric and Developmental Pathology. 2004;7(4):315–334. doi:10.1007/s10024-002-0242-8
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