Understanding AIP | PANHEMATIN® (hemin for injection)

UNDERSTANDING ACUTE INTERMITTENT PORPHYRIA (AIP)

A Rare, Inherited Genetic Condition

AIP is caused by a partial deficiency of the enzyme porphobilinogen (PBG) deaminase,1 which can disrupt the body's normal heme production.2

What is AIP? Signs & Symptoms Diagnosis & Testing

What is AIP?

Porphyria, a group of rare disorders caused by abnormalities in the production of heme, a vital component of hemoglobin, results from a buildup of substances called porphyrins, which are normally involved in the heme production process.3

AIP, the most common of 4 hepatic porphyrias, affects the nervous system and often causes sudden, severe symptoms. If unrecognized and untreated, an AIP attack can progress, resulting in neurologic damage or death due to cardiac arrhythmia or paralysis.3

A portrayal of a woman holding her stomach
Patient portrayal.

What causes an acute AIP attack?

Exposure to one or more precipitating factors, such as endogenous steroid hormones or certain prescription drugs, may increase the body’s need for heme.3 The partial deficiency of Porphobilinogen (PBG) deaminase, the third enzyme in the multi-step heme biosynthetic pathway, can become rate-limiting in the production of heme.1 This can cause neurotoxic porphyrin precursors to accumulate as the body continues to signal for additional heme.2

AIP attacks disrupt the heme cycle

Follow the cycle below to understand where disruption occurs and how it drives the symptoms of AIP.

AIP Attack Cycle graphic

1

Precipitating factors, such as the use of certain prescription drugs, markedly increase demand for hepatic heme4

2

Decrease in the heme pool induces synthesis of ALA synthase to produce more heme4

ALA: δ-aminolevulinic acid

3

Partial deficiency of PBG deaminase, 3rd enzyme in the heme biosynthetic pathway, becomes rate-limiting3,4

PBG: porphobilinogen

4

A bottleneck forms, causing restriction of the 8-step heme biosynthetic pathway4

5

Neurotoxic porphyrin precursors, ALA and PBG, accumulate4

ALA: δ-aminolevulinic acid
PBG: porphobilinogen

6

The heme pool is depleted5

Internal or external precipitating factors can trigger attacks

The PBG deaminase enzyme deficiency in AIP predisposes patients to the effects of precipitating factors that can increase the demand for hepatic heme and lead to a chemical buildup that may cause symptoms to develop.3 Symptoms of an AIP attack can be general and nonspecific.3 However, symptoms can occur after certain triggering events,3 such as:

Luteal phase of a woman's menstrual cycle from changes in estrogen and progesterone levels, or as a result of hormone replacement therapy6,7

Cigarette smoking3

Use of certain prescription drugs that are metabolized by the heme-based cytochrome P450 (CYP) enzyme system3,8

Metabolic stress induced by exhaustion; acute viral or bacterial infection; surgery; or labor, delivery, or post-delivery periods3,6,9

Use of alcohol or illicit drugs such as amphetamines, cocaine, and derivatives9

Psychological stress3

Fasting or crash dieting, or a low-carbohydrate diet3,6

Dehydration2

Be aware of drugs to avoid

Many drugs that are commonly prescribed may increase the demand for hepatic heme and induce δ-aminolevulinic acid (ALA) synthase. These drugs may exacerbate attacks and should be avoided. These drugs may include3,7,10:

  • Some anti-infectives such as sulfonamides, erythromycin, and rifampin
  • Some sedatives such as barbiturates and some benzodiazepines
  • Some anti-epileptics such as phenytoin and carbamazepine

Medications and some weight-loss diets

Being mindful and paying attention to certain medicines, as well as lifestyle triggers, can help clinicians recognize possible AIP attacks in presenting patients. In 90 patients diagnosed with AIP in an observational study11:

37%

reported that medications triggered acute attacks

22%

reported that weight-loss diets triggered acute attacks

American Porphyria Foundation (APF) has developed a safe/unsafe drug database

Search the American Porphyria Foundation's safe/unsafe drug database for prescription and over-the-counter drugs that may trigger AIP attacks.

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Patient characteristics associated with AIP

Gender

  • AIP attacks are 4-5x more common in women than in men.9
  • In women, attacks occur during reproductive years, most commonly in their 30s and often during the luteal phase of the menstrual cycle.3,6

Family history and genetics

  • AIP is a genetic disease, so a parent and possibly siblings of the patient could have the enzyme deficiency.2
  • Because AIP is an autosomal dominant condition with low penetrance, 80% to 90% of individuals with the enzyme deficiency may never have symptomatic disease.6,9
A portrayal of a woman crossing her arms

Patient portrayal.

Gain insights into diverse and often non-specific symptoms associated with AIP

Learning to recognize characteristic patterns that might otherwise be overlooked can help with diagnostic challenges of AIP.

Patient Cases

Potential risks of untreated AIP attacks

Recurring and untreated attacks increase the risk of irreversible neuronal damage.3 Serious consequences of not treating an AIP attack may include3:

Peripheral neuropathy3

Paresis3

Respiratory and bulbar paralysis3

Chronic neuropathic pain3,12

Death from cardiac arrhythmia or paralysis during attack3

Signs & Symptoms

Recognizing signs of an attack are critical because symptoms of AIP often mimic those of other, more common diseases. This can make diagnosing AIP challenging.

Abdominal pain

The most common symptom is severe abdominal pain, which is neuropathic in origin.3 Nonspecific, severe abdominal pain presents in more than 85% of patients during AIP attacks. AIP should be suspected in any patient with symptoms that are prominent for AIP, particularly abdominal pain, when initial clinical evaluation does not support another cause.13

Hyponatremia

Another symptom that can increase suspicion of an AIP attack is hyponatremia.13
When blood sodium levels are abnormally low, electrolyte abnormalities can cause dysregulation in fluid balance, blood pressure, and nerve and muscle function.

Patient portrayal.

Systemic symptoms

Disruption to critical system processes, leading to a range of gastrointestinal, neurological, cardiovascular, and urinary symptoms—range from mild to life-threatening.3

Gastrointestinal3

  • Abdominal pain
  • Nausea/vomiting
  • Constipation

Neurological3

  • Pain in extremities, back, chest, neck, or head
  • Paresis, mainly affecting proximal muscles
  • Hyponatremia, leading to seizures13
  • Psychiatric symptoms such as agitation, confusion, hallucinations, or depression

Cardiovascular3

  • Tachycardia
  • Systemic arterial hypertension

Urinary3

  • Dark or reddish urine when exposed to light or air

Diagnosis & Testing

A delayed diagnosis of AIP is common because of variable non-specific symptoms. Employing differential diagnosis may help clinicians rule out several conditions that share similar symptoms, and acts as a starting point for further investigation into confirming AIP.

Diagnosis of AIP can take up to 10 years.11

Doctor and patient portrayal.

Avoiding misdiagnosis

For patients presenting with symptoms that are prominent for AIP, a high index of suspicion for AIP should be maintained, particularly when abdominal pain is reported, and when an initial clinical evaluation does not support another cause.3 Due to their non-specificity, the clinical features of AIP are not sufficient to confirm a diagnosis of AIP. Using differential diagnosis, common clinical conditions mimicked by an AIP attack include9:

  • Dysmetabolic/endocrine
  • Neuropsychiatric
  • Cardiovascular
  • Hematological
  • Gastroenterological

Diagnostic testing for AIP

AIP can be diagnosed by laboratory testing at or near the time of symptoms when large amounts of porphyrin precursors (i.e., porphobilinogen (PBG) and δ-aminolevulinic acid (ALA)) and porphyrins accumulate in the body.3,14,15

Initial Testing Second-Line Testing DNA Studies

Initial Testing

Once AIP is suspected in a symptomatic patient, the diagnosis should be confirmed immediately with a PBG urine test. Any significant delay in testing could delay appropriate treatment and result in serious consequences.3

A markedly increased urinary PBG level (20-200 mg/L) is characteristic of acute attacks of acute hepatic porphyrias, particularly AIP, and is not a feature of non-porphyric diseases. Thus, the test is highly sensitive and specific for acute porphyric attacks when performed at or near the time of symptoms.3,16

Second-Line Testing

If PBG levels are elevated, second-line testing should be done to determine the precise type of acute porphyria. The following combined laboratory findings indicate AIP3:

  • ALA levels: increased3
  • Urine porphyrin levels, mostly uroporphyrin: markedly increased3
  • Erythrocyte PBG deaminase levels: decreased by ≈50%3
  • Fecal porphyrin levels: normal or slightly increased3
  • Plasma porphyrin levels: normal or slightly increased3

Second-line tests should be interpreted carefully, as they may lack sensitivity and/or specificity.3

DNA Studies

Once biochemical studies have confirmed the diagnosis of AIP, genetic confirmation through DNA analysis can identify the disease-causing genetic mutation(s).3 DNA analysis is also important for identification of asymptomatic carrier family members who may be at risk for developing acute attacks in the future.3

Laboratory findings that differentiate AIP from other acute porphyrias

An Increase In3

  • Urine porphyrin levels (mostly uroporphyrin) markedly increased
  • Fecal porphyrin levels normal or slightly increased
  • Plasma porphyrin levels normal or slightly increased

A Decrease In3

  • Erythrocyte PBG deaminase levels decreased by ~50%

AIP Discussion Guide

Receiving a rare disease diagnosis can be stressful. Patients, as well as their families, will have many questions and concerns. Help them start a conversation and understand AIP in more detail by sharing this discussion guide.

Download Guide

References: 1. Whatley SD, Badminton MN. Acute Intermittent Porphyria. 2005 Sep 27 [Updated 2013 Feb 7]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. 2. Gonzalez-Arriaza HL, Bostwick JM. Acute porphyrias: A case report and review. Am J Psych. 2003;160(3);450-458. 3. Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med. 2005;142:439-450. 4. Balwani M, Wang B, Anderson KE, et al. Acute hepatic porphyrias: Recommendations for evaluation and long-term management. Hepatology. 2017;66(4):1314-1322. doi:10.1002/hep.29313 5. Khanderia U, Bhattacharya A. Acute intermittent porphyria: pathophysiology and treatment. Pharmacotherapy. 1984;4(3):144-150. doi:10.1002/j.1875-9114.1984.tb03340. 6. Besur S, Hou W, Schmeltzer P, Bonkovsky HL. Clinically important features of porphyrin and heme metabolism and the porphyrias. Metabolites. 2014; 4:977‍-10‍06. 7. Crimlisk HL. The little imitator—porphyria: A neuropsychiatric disorder. J Neurol Neurosurg Psychiatry. 1997;62:319-328. 8. Thunell S, Pomp E, Brun A. Guide to drug porphyrogenicity prediction and drug prescription in the acute porphyrias. Br J Clin Pharmacol. 2007;64(5):668-679. doi:10.1111/j.0306-5251.2007.02955. 9. Ventura P, Cappellini MD, Rocchi E. The acute porphyrias: A diagnostic and therapeutic challenge in internal and emergency medicine. Intern Emerg Med. 2009;4:297-308. 10. Stein P, Badminton M, Barth J, Rees D, Stewart MF. Best practices guidelines on clinical management of acute attacks of porphyria and their complications. Ann Clin Biochem. 2013;50:217-223. 11. Bonkovsky HL, Maddukuri MD, Yazici C, et al. Acute porphyrias in the USA: Features of 108 subjects from Porphyrias Consortium. Am J Med. 2014;127:1233-1241. 12. Simon A, Pompilus F, Querbes W, et al. Patient Perspective on Acute Intermittent Porphyria with Frequent Attacks: A Disease with Intermittent and Chronic Manifestations. Patient. 2018;11(5):527-537. doi:10.1007/s40271-018-0319-3 13. Wang B, Rudnick S, Cengia B, Bonkovsky HL. Acute hepatic porphyrias: Review and recent progress. Hepatol Commun. 2019;3(2):193-206. 14. American Porphyria Foundation. Porphyrins and porphyria diagnosis. http://porphyriafoundation.com. Published 2010-2017. Accessed September 20, 2018. 15. American Porphyria Foundation. Testing for porphyria. http://porphyriafoundation.com. Published 2010-2017. Accessed September 20, 2018. 16. American Porphyria Foundation. First-line tests. http://porphyriafoundation.com. Published 2010-2017. Accessed September 20, 2018.

INDICATION AND USAGE

PANHEMATIN is a hemin for injection indicated for the amelioration of recurrent attacks of acute intermittent porphyria temporally related to the menstrual cycle in susceptible women, after initial carbohydrate therapy is known or suspected to be inadequate.

Limitations of Use

  • Before administering PANHEMATIN, consider an appropriate period of carbohydrate loading (i.e., 400 g glucose/day for 1 to 2 days).
  • Attacks of porphyria may progress to a point where irreversible neuronal damage has occurred. PANHEMATIN therapy is intended to prevent an attack from reaching the critical stage of neuronal degeneration. PANHEMATIN is not effective in repairing neuronal damage.

IMPORTANT SAFETY INFORMATION

PANHEMATIN is contraindicated in patients with known hypersensitivity to this drug.

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INDICATION AND IMPORTANT SAFETY INFORMATION

INDICATION AND USAGE

PANHEMATIN is a hemin for injection indicated for the amelioration of recurrent attacks of acute intermittent porphyria temporally related to the menstrual cycle in susceptible women, after initial carbohydrate therapy is known or suspected to be inadequate.

Limitations of Use

  • Before administering PANHEMATIN, consider an appropriate period of carbohydrate loading (i.e., 400 g glucose/day for 1 to 2 days).
  • Attacks of porphyria may progress to a point where irreversible neuronal damage has occurred. PANHEMATIN therapy is intended to prevent an attack from reaching the critical stage of neuronal degeneration. PANHEMATIN is not effective in repairing neuronal damage.

IMPORTANT SAFETY INFORMATION

PANHEMATIN is contraindicated in patients with known hypersensitivity to this drug.

Risk of Phlebitis: Phlebitis is possible. Utilize a large arm vein or a central venous catheter for administration to minimize the risk of phlebitis.

Iron and Serum Ferritin: Elevated iron and serum ferritin may occur. Monitor iron and serum ferritin in patients receiving multiple administrations of PANHEMATIN.

Anticoagulant Effects: PANHEMATIN has transient and mild anticoagulant effect. Avoid concurrent anticoagulant therapy.

Renal Effects: Reversible renal shutdown has been observed with an excessive hematin dose (12.2 mg/kg in a single infusion). Strictly follow recommended dosage guidelines.

Transmissible Infectious Agents: PANHEMATIN may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. There is also the possibility that unknown infectious agents may be present in the product.

The most common adverse reactions (>1% of patients) are headache, pyrexia, infusion site reactions, and phlebitis.

To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions: Avoid CYP inducing drugs such as estrogens, barbituric acid derivatives and steroid metabolites which induce δ-aminolevulinic acid synthetase 1 (ALAS1) through a feedback mechanism.

PANHEMATIN® (hemin for injection), for intravenous infusion only, is available as powder for reconstitution in 350 mg vials.

Please see full Prescribing Information.