Normosang. Human hemin. Normosang Product Monograph 1 of 59

Transcription

1 Normosang Human hemin Normosang Product Monograph 1 of 59

2 ABBREVIATIONS AD ADP AIP ALA ALAD AR C (O) C (max) CAS COPRO CPO CYP EPNET FECH FRCBS Haem-S HCP HO INN MDS NaCl PBG PBGD PPOX PROTO PT PTT qs SD SnPP SmPC t 1/2 TT URO UROD UROS Autosomal dominant Delta-aminolaevulinate dehydratase deficiency porphyria Acute intermittent porphyria Delta-aminolaevulinic acid ALA dehydratase Autosomal recessive Maximum plasma concentration extrapolated to the origin Maximum plasma concentration Chemical Abstracts Service Coproporphyrin Coproporphyrinogen oxidase Cytochrome P450 European Porphyria Network Ferrochelatase Finnish Red Cross Blood Service Haem synthase Hereditary coproporphyria Haem oxygenase International non-proprietary name Myelodysplastic syndrome Sodium chloride Porphobilinogen Porphobilinogen deaminase Protoporphyrinogen oxidase Protoporphyrin Prothrombin time Partial thromboplastin time Quantum satis, quantum sufficit (as much as is needed) Standard deviation Tin protoporphyrin Summary of product characteristics Elimination half-life Thrombin time Uroporphyrin Uroporphyrinogen decarboxylase Uroporphyrinogen III synthase Normosang Product Monograph 2 of 59

3 V VP Volume of distribution Variegate porphyria Normosang Product Monograph 3 of 59

4 CONTENTS 1. EXECUTIVE SUMMARY 1.1 Acute Attacks of Hepatic Porphyria 1.2 Normosang 2. ACUTE PORPHYRIAS 2.1 Introduction Porphyria Definition and Classification Prevalence 2.2 Description of Acute Attacks Factors Precipitating Acute Attacks Pathophysiology Clinical Penetrance 2.3 Diagnosis Introduction Diagnosing an Acute Attack Identifying the Type of Acute Porphyria 2.4 Management Preventing Acute Attacks Treating Acute Attacks 3. CHEMISTRY AND PHARMACY 3.1 Physicochemical Properties of Human Hemin 3.2 Normosang Pharmaceutical Development Composition Presentation Stability and Storage Viral Safety Sterility 4. PHARMACOLOGY AND TOXICOLOGY 4.1 Introduction 4.2 Antiporphyrogenic Activity Animal Studies Postulated Mechanism of Action Antiporphyrogenic Activity in Clinical Studies 4.3 Effect on Erythropoiesis and Myocardial Cytochrome Function 4.4 Safety Pharmacology Effect on Cytochrome-Catalysed Metabolism Central Nervous System Effects Effect on Plasma Protein Binding Effects on Haemostasis Iron Overload 4.5 Toxicology Page Normosang Product Monograph 4 of 59

5 5. PHARMACOKINETICS AND PHARMACODYNAMICS 5.1 Plasma Protein Binding 5.2 Pharmacokinetic Parameters Pharmacokinetic Parameters Following a Single Dose Pharmacokinetic Parameters Following a 4-Day Treatment Course Pharmacokinetic Parameters Following Prolonged Treatment 5.3 Distribution, Metabolism and Excretion 5.4 Drug Drug Interactions 6. CLINICAL EFFICACY 6.1 Introduction 6.2 Acute Porphyric Attack Treatment Comparative Studies - Normosang vs Placebo - Normosang vs Haematin - Normosang vs Normosang Plus Tin Protoporphyria Open-Label Studies - Overview - Sardh et al (Eur J Intern Med 2009) - Hift and Meissner (Medicine [Baltimore] 2005) - Nordmann and Deybach (Ann Med Interne [Paris] 1993) - Mustajoki and Nordmann (Arch Intern Med 1993) - Kostrzewska (Mater Med Pol 1991) - Kordač et al (Ann Med 1989) - Herrick et al (Lancet 1987) - Mustajoki (Br Med J (Clin Res Ed) 1986) 7. CLINICAL SAFETY 7.1 Introduction 7.2 Clinical Trial Data Healthy Volunteer Studies Clinical Studies in Acute Intermittent Porphyria Studies in Indications Other than Acute Porphyria 7.3 Clinical Safety from Post-Marketing Experience 7.4 Use in Pregnancy and Lactation 8. DOSAGE AND ADMINISTRATION 8.1 Dosage 8.2 Preparation and Administration Preparation of the Solution Infusion Technique 9. SUMMARY OF PRODUCT CHARACTERISTICS Normosang Product Monograph 5 of 59

6 1. EXECUTIVE SUMMARY 1.1 Acute Attacks of Hepatic Porphyria Acute intermittent porphyria (AIP), variegate porphyria (VP), and hereditary coproporphyria (HCP) are a group of rare inherited disorders of haem biosynthesis in which accumulation of haem precursors is a consequence of deficiency of a haem biosynthesis enzyme. This accumulation predisposes patients to episodic, acute and potentially life-threatening attacks of predominantly neurologic and gastrointestinal symptoms, with or without cutaneous symptoms. The rate of haem synthesis is primarily controlled via delta-aminolaevulinic acid (ALA) synthase, the first enzyme in the haem synthesis pathway. Activity of this enzyme in the liver is regulated by the free intracellular haem pool through a negative feedback mechanism. Therapeutically increasing levels of haem suppresses ALA synthase activity, thereby reducing the levels of ALA, porphobilinogen (PBG) and other haem precursors. Normosang was developed to provide a standard haem preparation of controlled quality that is suitable for clinical use in terms of stability, efficacy and safety. 1.2 Normosang Normosang 25 mg/ml, concentrate for solution is indicated for the treatment of acute attacks of hepatic porphyria (AIP, VP and HCP). The active substance in Normosang is human hemin (haem chloride), which is isolated and extensively purified from human red blood cell concentrates. Results from clinical trials, and more than 22 years post-marketing experience in Europe, show that Normosang rapidly and substantially reduces the excretion of haem precursors. This is associated with improvement or resolution of acute porphyric symptoms in the majority of patients (>90%), particularly when treatment is started immediately or soon after the onset of the attack. Indeed, with prompt initiation of Normosang therapy, clinical improvement enables most patients to be discharged immediately or soon after the last infusion. The European Porphyria Network (EPNET) recommends Normosang as the specific treatment of choice for acute attacks of hepatic porphyria. Normosang Product Monograph 6 of 59

7 2. ACUTE PORPHYRIAS Overview The porphyrias are a group of rare inherited disorders of haem biosynthesis Acute porphyrias are characterised by episodic, acute and potentially life-threatening attacks of predominantly neurologic and gastrointestinal symptoms with or without cutaneous symptoms Rapid and accurate diagnosis of the acute porphyrias is essential, particularly because Normosang can effectively induce remission if given soon after the onset of the attack Screening of families to identify presymptomatic carriers is crucial to decreasing the risk of acute attacks by facilitating counselling about the avoidance of potential percipients 2.1 Introduction Porphyria Definition and Classification The porphyrias are a heterogeneous group of inherited metabolic disorders of haem biosynthesis. Haem synthesis takes place in the liver where it is used in the production of cytochrome P450 enzymes (CYPs) and other haemoprotein enzymes and in the erythroid bone marrow where it is used in the formation of haemoglobin. 1-3 There are seven main forms of porphyria, each of which is caused by a partial deficiency of one of the last seven enzymes in the haem biosynthetic pathway (Figure 2a). 1 The porphyrias have also been classified historically as either erythropoietic or hepatic in origin depending on the principal site where the enzyme defect is expressed. 3 Neurologic and/or cutaneous symptoms may manifest depending on which enzyme in the pathway is affected. 4 Clinically, these porphyrias can be divided into two groups (Table 2a): 5 - Acute porphyrias, which are characterised by episodic, acute and potentially lifethreatening attacks of predominantly neurovisceral symptoms, with or without cutaneous symptoms - Non-acute porphyrias, which present with cutaneous symptoms An eighth form of porphyria X-linked dominant porphyria has recently been described. 6 This is caused by deletions in an isoform of the 5-aminolaevulinate synthase gene (ALAS2), which encodes the initial rate-regulating enzyme in erythroid haem biosynthesis, and leads to a mismatch between protoporphyrinogen production and the haem requirements of differentiating erythrocytes. The condition, which manifests in photosensitivity and liver disease, is characterised biochemically by excess levels of zinc protoporphyrin in the red blood cells. Unusually for an X- linked disease, the severity of symptoms is not worse in males than in females. 6 A number of reviews in the scientific literature have provided overviews of the clinical manifestation of these conditions, the challenges faced in the management of the disease and its associated symptomology as well as the clinical outcomes. 1-3 In addition, one longitudinal study detailed the outcome of a multidisciplinary approach to treatment over a period of 15 years. 7 Normosang Product Monograph 7 of 59

8 2.1.2 Prevalence Porphyria is a rare and predominantly inherited condition that can occur in all races and both sexes. 2,3 Prevalence rates vary from extremely rare (ALA-D deficiency porphyria) to 0.5 per 100,000 persons, 3 but it has been suggested that approximately 90% mutant gene carriers experience no clinical symptoms in their lifetime. 8 The prevalence of clinical manifestation of the acute porphyrias (AIP, VP and HCP) in most European countries may be as high as one in 100, Although porphyrias are considered to be relatively rare, or orphan diseases, their incidence is higher in certain populations. 7 One particular example is Sweden, where the prevalence of AIP is relatively high (one per 1500 people in northern Sweden) due to a founder effect. VP is about half as prevalent as AIP in most European countries, but is especially common in South Africa, again because of a founder effect. 9 Aminolaevulinate dehydratase deficiency porphyria (ADP) is a very rare autosomal recessive acute porphyria and only seven patients have been reported since its description in Figure 2a The Haem Biosynthetic Pathway 1 Reprinted from The Lancet, 13, Puy H, Gouya L, Deybach J-C, Porphyrias, , Copyright (2010), with permission from Elsevier. A summary description of the features of the eight types of porphyria is provided in Table 2a and greater detail is provided in a recent review of the current status and future challenges faced when treating this condition. 3 Normosang Product Monograph 8 of 59

9 Table 2a Different Types of Human Porphyria 5 Disorder Deficient enzyme Type a Neurovisceral symptoms Skin lesions Inheritance Acute porphyrias Acute intermittent porphyria PBGD Hepatic - AD Variegate porphyria PPOX Hepatic b,c AD Hereditary coproporphyria CPO Hepatic b,c AD ALA dehydratase-deficiency porphyria ALAD Hepatic - AR Non-acute porphyrias Porphyria cutanea tarda UROD Hepatic c AD Congenital erythropoietic porphyria UROS Erythropoietic c AR (Günther disease) Erythropoietic protoporphyria FECH Erythropoietic d AD X-linked dominant protoporphyria ALAS2 Erythropoietic d n/a a. Primary site of excess porphyrin or precursor production; b. Skin lesions and neurovisceral symptoms may occur alone or together; c. Fragile skin, blisters; d. Acute photosensitivity without fragile skin, blisters PBGD, porphobilinogen deaminase; AD, autosomal dominant; PPOX, protoporphyrinogen oxidase; CPO, coproporphyrinogen oxidase; ALA, delta-amino-laevulinic acid; ALAD, ALA dehydratase; AR, autosomal recessive; UROD, uroporphyrinogen decarboxylase; UROS, uroporphrinogen III synthase; FECH, ferrochelatase 2.2 Description of Acute Attacks Although all clinical features of an acute attack can be explained by lesions in the nervous system, a broad range of largely unspecified neurovisceral symptoms often accompany clinical presentation. These can include abdominal pain, nausea and vomiting, diarrhoea, tachycardia, hypertension, fever, muscle weakness and respiratory paralysis. Attacks may also be accompanied by a variety of neurological and psychiatric signs and symptoms. 1,3 When diagnosis is not timely or treatment is inadequate the consequences can be fatal, with mortality rates approaching 10% particularly in cases of respiratory paralysis. 1,3,10 Various case histories provided in the literature highlight the complex symptomatology of patients who experience porphyric attack(s), the difficulty in establishing a diagnosis, 14,15 and the varied approaches to treatment once a diagnosis has been established. 16, Factors Precipitating Acute Attacks In most cases, an acute attack is precipitated by some trigger event that acts as a porphyrinogenic challenge. Factors that can trigger acute attacks include hormone fluctuations associated with menstruation and pregnancy, a wide range of prescribed drugs (see Section 2.4.1), illicit drugs, endogenous steroid hormones, alcohol misuse, smoking, infection, dieting and starvation. 3,5 The triggering factors in acute porphyria operate via the induction of ALA synthase in haem biosynthesis pathway. PBG and ALA accumulate as a consequence of the enzyme deficiency. 1 Thus, the acute attack is invariably accompanied by excess formation and renal excretion of ALA and PBG. However, acute attacks can also be triggered by factors that increase haem degradation. 1 For example, starvation can directly induce ALAS1 or increase the demand for haem synthesis in the liver, subsequently reversing inhibition of ALAS1. Acute attacks can be prevented by maintaining a high carbohydrate intake (eg by administering parenteral glucose and/or adding starchy foods to the diet). 1 Normosang Product Monograph 9 of 59

10 2.2.2 Pathophysiology The pathogenesis of the clinical features is poorly understood but possible mechanisms include damage by free radicals, direct neurotoxicity by ALA, and haem deficiency in nervous tissue. 18 The leading theory proposed for the cause of porphyrias is that ALA or other metabolites that are over-produced by the liver become neurotoxic. 1,19,20 The hepatic origin of the neurotoxins associated with porphyrias is highlighted by the fate of otherwise healthy individuals who receive liver transplants from donors who have this genetic predisposition. 21 It is also highlighted by the substantial benefits seen following transplantation in patients with severe AIP. 22 The enzyme activity in each of the acute porphyrias is only partially deficient, and in normal circumstances the remaining activity (<50% in AIP, VP and HCP, and <5% in ADP) is usually sufficient to maintain normal haem homeostasis. 23 However, the enzyme deficiency predisposes patients to acute attacks in situations where there is an increased need for haem for the synthesis of CYPs and other hepatic haemoproteins. 23 The rate of haem synthesis is primarily controlled via ALA synthase, the first enzyme in the haem synthesis pathway. The activity of this enzyme in the liver is regulated by the free intracellular haem pool by a negative feedback mechanism (Figure 2a). 1 ALA synthase activity increases as the basal haem concentration declines, resulting in increased levels of ALA and, subsequently, increased levels of PBG and porphyrins. In patients with acute porphyria the conversion of ALA, PBG and porphyrins to haem is compromised by their enzyme deficiency. Depending on the enzyme affected, specific patterns of tissue accumulation and excretion of haem precursors develop (Table 2b), and these are associated with characteristic clinical features. 4 Increased hepatic ALA synthase activity during acute attacks has been demonstrated in patients with acute porphyrias. ALA synthase induction is a secondary phenomenon, resulting from the exposure to several factors (see Section 2.2.2). During ALA synthase induction and increased ALA production, PBG deaminase can become the rate limiting step. This accounts for the especially marked increases in ALA and PBG produced and excreted during acute attacks. 24 The characteristic pattern of tissue accumulation and excretion of haem precursors for the three main acute porphyrias (AIP, VP and HCP) is shown in Table 2b. 4 Table 2b Biochemical Features of the Main Acute Porphyrias 4 Urine Faeces ALA/PBG URO COPRO URO COPRO PROTO Acute intermittent porphyria A R ++ + Hereditary coproporphyria A R Variegate porphyria A R ALA, delta-amino-laevulinic acid; PBG, porphobilinogen; URO, uroporphyrin, COPRO, coproporphyrin, PROTO, protoporphyrin; A, during an attack; R, during remission Normosang Product Monograph 10 of 59

11 2.2.3 Clinical Penetrance AIP, VP and HCP all show low clinical penetrance. Without genetic tools, however, it is very difficult to evaluate the true disease burden within a given population. 24,25 Approximately 80% of patients who inherit these disorders remain asymptomatic throughout life but it is not easy to predict which individuals are likely to suffer an acute attack. 1,5 In some people the disease remains latent, even in the presence of precipitating factors. Many patients might experience only one attack in their whole lifetime. 1 Other people experience frequent and sometimes life-threatening attacks, even in the apparent absence of precipitating factors. 5 Acute attacks are rare before puberty and are most common in people in their 30s. 17 The majority (>80%) of acute attacks occur in females aged years. 26,27 This, together with the fact that relapses in women often occur premenstrually and in pregnancy, highlights the important role of hormones in the clinical expression of acute porphyrias Diagnosis Introduction Due to the rarity of porphyria, and because the symptoms are often variable, they can be easily misdiagnosed. Conditions also considered within the differential diagnosis can include appendicitis with peritonitis, nephrolithiasis, spinal cord compression, aortic dissection, an expanding aneurysm, neurologic or psychiatric disorders, and patients can be labelled as drug seekers due to frequent visits to the emergency department. 28 Prompt diagnosis followed by early intervention may induce remission and, hence, greatly improve prognosis by preventing the development of severe and chronic neuropathic symptoms (see Section 6). 29 Incorrect diagnosis often leads to inadequate and inappropriate treatments eg barbiturates, for symptoms of pain, inadequate patient management (eg exploratory abdominal surgery) which can aggravate the attack and possibly lead to more serious neurological complications. 23 It is important, therefore, that when a patient presents with a combination of severe abdominal pain, nausea/vomiting, cardiovascular abnormalities, and especially, neurological symptoms, porphyria should be suspected, particularly if there is a family history of the condition. Consequently, considerable attention has been given to how an attack can be correctly diagnosed. 1,2,16,23,30 van Tuyll van Serooskerken and colleagues have proposed a cascade of diagnostic procedures to aid a precise diagnosis of porphyria (see box). 30 Recommended diagnostic procedures 1. Take a thorough medical history, including a family history, putative occurrence of acute attacks, physical examination to detect primary or secondary skin lesions 2. Conduct biochemical analysis for porphyrins and porphyrin precursors in urine, faeces and serum 3. Request specialist enzyme activity analyses for exact diagnosis of type of porphyria 4. Request genetic analysis to identify specific mutations to confirm type of porphyria and/or indicate severity of condition Normosang Product Monograph 11 of 59

12 Diagnosing an Acute Attack Diagnosis of an acute attack of porphyria requires laboratory confirmation as many of the associated symptoms are also shared by other diseases and disorders. Analysis of urine and stools for excess PBG remains the essential first-line diagnostic test for porphyria and may also accurately predict the exact type of porphyria. 31,32 There are overlaps in the biochemical profiles of different types of porphyria; newer diagnostic techniques involving direct DNA analysis offer previously unconsidered insights into the underlying cause of an attack. 31 Knowledge of the exact type of porphyria can help patients to avoid specific triggers of acute attacks. 18,32 The availability of DNA testing also facilitates genetic testing and counselling for affected families. Signs and symptoms The clinical features of an acute attack vary greatly. The most frequently expressed symptom is severe abdominal pain, which may be accompanied by neurological and psychiatric symptoms (Figure 2b). 1,3,18 The neurological aetiology of the pain means that while it is severe, the lack of associated inflammation means that the abdomen is not necessarily tender and there are no peritoneal signs, fever or leukocytosis. 28 Muscular weakness, particularly a proximal myopathy affecting the arms, is common. However, muscular weakness can progress to tetraparesis, respiratory paralysis and arrest resembling Guillain-Barré syndrome. In the majority of cases mild sensory changes accompany predominantly motor neuropathy often in a bathing trunk distribution. 1,18 Marked constipation, nausea, vomiting, postural hypotension and hypertension are other common features. Hyponatraemia occurs as a result of dehydration, neurotoxicity, or occasionally inappropriate antidiuretic hormone secretion. 18,28 Figure 2b Frequency of Signs and Symptoms in Acute Porphyria 18 Reproduced from Diagnosis and management of porphyria, Thadani H, Deacon A, Peters T, 320, , copyright 2000 with permission from BMJ Publishing Group Ltd. Normosang Product Monograph 12 of 59

13 Laboratory Findings Acute attacks in patients with AIP, VP and HCP are associated with increased urinary excretion of PBG and to a lesser extent by ALA. Examination of urine for excess PBG is, therefore, the essential investigation when working up a patient presenting with a suspected attack of acute porphyria. 1,5 A fresh, random urine sample (10 20 ml) collected without any preservative but protected from light should be immediately sent to a specialist laboratory for analysis of PBG and ALA. PBG is stable in urine in the dark at 4 o C for up to 48 hours and for at least 1 month at -20 o C. 5 Urine darkens on standing owing to polymerisation of PBG to porphyrins and other pigments. 18 This darkening of a urine sample on standing is a strong indicator of porphyria (Figure 2c). 3,18 However, discolouration of urine can occur in other situations and the absence of red urine does not exclude the diagnosis of porphyria. Figure 2c Discolouration of Urine in Acute Porphyria Discolouration occurs within about 30 minutes Identifying the Type of Acute Porphyria Once the diagnosis of an acute porphyria attack has been established, further investigation is required to identify the type of acute porphyria; however, this should not be a reason to delay treatment. 23 Even when the patient comes from a family known to have a particular type of porphyria, the type of porphyria should be confirmed. Examples of two inherited porphyrias in the same family have been reported. 5 Identifying the specific acute porphyria is important in order to provide appropriate information, such as factors that may increase the risk of an acute attack, to patients and their families. 5 The differential diagnosis of acute porphyria is based on clinical symptoms (Table 2a and Figure 2b) and biochemical analyses (Table 2b). Plasma porphyrin fluorescence emission spectroscopy is also useful as a front-line test in all acute porphyrias because a peak at nm establishes the diagnosis of VP. 5,16 It does not distinguish AIP from HCP as an emission peak at 620 nm may be present in both conditions. The absence of a peak at nm excludes VP. Enzyme measurements are not essential and may be misleading due to overlap between normal and disease ranges. 5 Demonstration of a disease-specific mutation in the appropriate gene identifies porphyria but, by itself, gives no indication of disease activity. 5,16 Where available, molecular diagnosis to identify the causative mutation in symptomatic patients provides final confirmation of the type of porphyria. AIP is associated with mutations on chromosome 11q24 in the HMBS gene; VP with mutations on chromosome 3q19 of PPOX, and HCP with mutations on 1q22 23 of CPOX. 16 Normosang Product Monograph 13 of 59

14 2.4 Management The information in this section is based on the recommendations of the European Porphyria Network (EPNET). 5 The EPNET mission is to improve the lives of porphyria patients by improving the diagnosis and treatment of these rare conditions. EPNET consists of 33 European specialist centres from 21 countries that work together to develop an up-to-date consensus based approach to the management of patients and families with porphyria, ensuring treatment conforms to uniform standards. There are associate members from Australia, Brazil, New Zealand, South Africa and the USA Preventing Acute Attacks Family screening to identify individuals with latent (presymptomatic) porphyria is essential for the management of autosomal dominant porphyrias (AIP, VP and HCP). Individuals with symptomatic, clinically overt, and presymptomatic porphyria should be advised to: Avoid factors that may increase the risk of an acute attack (see Section 2.2.3) 18 Wear a wrist bracelet or neck pendant indicating that they suffer from porphyria to help avoid the administration of unsafe drugs (see box) in the event of an accident 18 Inform any doctor, surgeon or dentist of their condition before any treatment that might precipitate an attack commences 33 The EPNET website ( Comprehensive lists of drugs that are considered safe and unsafe for use in the acute porphyrias are available the EPNET website ( The EPNET information is based on the Napos Drug Database for Acute Porphyrias ( a drug database that was originally built to aid healthcare professionals and patients in the Nordic countries. This resource classifies drugs into five categories with regard to their potential ability to precipitate acute attacks, ie according to their porphyrinogenicity. In addition, since porphyrin gene carriers vary in their susceptibility to drug-induced acute attacks, the Napos website enables clinicians to estimate the likelihood of an attack according to a patient s age, gender, and previous and current disease activity. The information provided to treating physicians is also categorised by country and in the national language to facilitate information exchange and choice of treatment options available nationally Treating Acute Attacks Acute attacks of porphyria generally require urgent treatment and hospitalisation. 2,23 If carefully managed an acute attack should not last longer than 1 2 weeks. However, an attack should not be considered lightly even if the presenting symptoms are mild, as the consequences may become life-threatening should severe neurological complications (eg motor paralysis) develop, and recovery may be protracted if adequate treatment is not provided. Any involvement of the nervous system requires immediate admission to a hospital intensive care unit due to the possible development of respiratory paralysis. 1,3 Normosang Product Monograph 14 of 59

15 Symptomatic Treatment As soon as an acute attack of porphyria is suspected, any drugs or other provoking agents should be withdrawn and appropriate supportive treatments started using drugs that are safe in acute porphyria (Table 2c). 5,31 A urine specimen should be collected for PBG analysis as soon as possible to confirm the nature of the attack. 2,30 During this initial period, the patient will often be placed in an intensive care unit for close observation while the diagnosis is being confirmed. 30 This initial response should also include treatments to address any underlying infections and glucose infusions to reverse hypoglycaemia. 15,34 The list of drugs provided by the EPNET website (see box) details drugs that should not be used to treat the patient. Analgesia: Opiates are the most effective analgesics for use in an acute attack. Patients can often need treatment with high doses of opiates to manage their pain, however, since acute attacks are usually short-lived and infrequent, opiates may be used in high doses without fear of addiction. They often need to be combined with an antiemetic and a phenothiazine, such as promazine or chlorpromazine, to abate restlessness and anxiety the latter may help to decrease the requirement for analgesics. 1 In some patients, residual neuropathic pain continues once the acute attack has settled. It is important to recognise that this pain differs from that of the acute attack itself; wherever possible try to avoid using addictive analgesics for longer-term management 5 Fluid balance: Care must be taken in managing fluid balance, especially when giving dextrose infusions for treating hypoglycaemia. Large volumes of hypotonic dextrose can lead to hyponatraemia, which in turn may precipitate convulsions. 16 Hyponatraemia should be corrected slowly as patients with acute attacks are particularly prone to cerebral oedema and osmotic demyelination. Restriction of water intake to around 500 ml per day may be sufficient, but if symptoms necessitate saline infusion, the rate of correction should not exceed 8 mmol/l in any 24-hour period 5 Carbohydrate support: Impaired nutrition may aggravate acute porphyria (see Section 2.2.1), so it is important to ensure that adequate calories are provided. They are preferably given as carbohydrate-rich food supplements orally or, if necessary, via a nasogastric tube. These patients often experience severe vomiting, requiring carbohydrates to be given by infusion of normal saline with 5% dextrose. 16 Just 2 L of this solution provides 100 g of glucose per day, although see warning about hyponatraemia above. As soon as patients are able to take food orally, they should be transferred to a diet in which carbohydrate provides 55 60% of the energy needed to maintain their normal weight 5 In addition to these neurovisceral treatments, it may be necessary to address additional presenting symptoms that could result in significant morbidity and mortality, such as cardiovascular or neurological symptoms. Cardiovascular symptoms: Cardiovascular complications, such as hypertension and tachycardia, are rarely severe enough to require therapy in their own right, but should be addressed with beta blockers should this occur. Very occasionally, the acute attack is accompanied by a severe adrenergic crisis with dangerous hypertension, encephalopathy, seizures and ischaemic changes on CT scan of the brain. In these cases, intravenous infusion of magnesium sulphate may be effective in controlling the adrenergic symptoms and Normosang should be administered to alleviate the attack 1,3,16 Neurological symptoms: The onset of a motor neuropathy is often marked by severe pain and stiffness in the thighs and back followed by loss of tendon reflexes and motor paralysis. When vital capacity becomes severely reduced by paralysis of the intercostal muscles, artificial ventilation is necessary and may have to be continued for several months until recovery occurs 5 Normosang Product Monograph 15 of 59

16 Table 2c Recommended Symptomatic Treatment 5 Indication Pain Vomiting Sedation, decrease analgesic requirement Convulsions Hypertension/tachycardia Muscle weakness/paralysis Constipation Drugs or procedures Morphine (oral, sublingual, intravenous or subcutaneous) Pethidine Diamorphine Prochlorperazine Promazine Chlorpromazine Promazine Correct any hyponatraemia a Intravenous diazepam Clonazepam Magnesium sulphate Propranolol b Atenolol Monitor progress Early physiotherapy Bulk forming laxative Neostigmine bromide a. Hyponatraemia, which is common during acute attacks, should be controlled since severe cases may provoke convulsions; b. Even low doses may provoke severe hypotension and bradycardia Targeted Treatment In addition to symptomatic treatment, specific treatment to repress hepatic ALA and PBG should be started immediately. In some reports patients receive glucose then, if he or she does not respond within 2 days, intravenous hemin may be added. The efficacy of glucose and haem compounds have never been compared in controlled studies but information about their respective clinical efficacy can be gleaned from several series; these show that hemin is clinically more effective than glucose. 32,35 37 Specific Treatment with Normosang Normosang, where available, is the treatment of choice for an acute attack of porphyria. Normosang should be started as soon as the diagnosis is established unless the attack is mild and clearly resolving. 5 For patients who have previously had an unequivocally diagnosed attack of acute porphyria, it may be necessary to initiate Normosang treatment before the results of laboratory investigations are available. 3 See Section 3 for more information on Normosang. References 1. Puy H, Gouya L, Deybach JC (2010) Porphyrias. Lancet 375: Ventura P, Cappellini MD, Rocchi E (2009) The acute porphyrias: a diagnostic and therapeutic challenge in internal and emergency medicine. Intern Emerg Med 4: Siegesmund M, van Tuyll van Serooskerken AM, Poblete-Gutiérrez P, Frank J (2010) The acute hepatic porphyrias: Current status and future challenges. Best Pract Res Clin Gastroenterol 24: Nordmann Y, Puy H, Deybach JC (1999) The porphyrias. J Hepatol 30: The European Porphyria Network website. accessed 2 Aug Normosang Product Monograph 16 of 59

17 6. Whatley SD, Ducamp S, Gouya L, Grandchamp B, Beaumont C, Badminton MN et al (2008) C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload. Am J Hum Genet 83: Schneider-Yin X, Harms J, Minder EI (2009) Porphyria in Switzerland, 15 years experience. Swiss Med Wkly 139: Kappas A, Sassa S, Galbraith R, Nordmann Y 1995, "The Porphyrias," in The metabolic basis of inherited disease, 7 edn, C. Schriver et al., eds., McGraw-Hill, New York, pp Meissner PN, Dailey TA, Hift RJ, Ziman M, Corrigall AV, Roberts AG et al (1996) A R59W mutation in human protoporphyrinogen oxidase results in decreased enzyme activity and is prevalent in South Africans with variegate porphyria. Nat Genet 13: Lip GY, McColl KE, Moore MR (1993) The acute porphyrias. Br J Clin Pract 47: Menegueti MG, Gil Cezar AT, Casarini KA, Muniz Cordeiro KS, Basile-Filho A, Martins-Filho OA et al (2011) Acute intermittent porphyria associated with respiratory failure: a multidisciplinary approach. Crit Care Res Pract: Lee KG, Hyun JJ, Seo YS, Keum B, Yim HJ, Jeen YT et al (2010) Liver cirrhosis induced by porphyria cutanea tarda: a case report and review. Gut Liver 4: Santos ABO, Gozzani JL, Groke DF (2010) Neuropathic pain in a patient with porphyria. Case report. Rev Bras Anestesiol 60: Michaels BD, Del Rosso JQ, Mobini N, Michaels JR (2010) Erythropoietic protoporphyria: a case report and literature review. J Clin Aesthet Dermatol 3: Mehta M, Rath GP, Padhy UP, Marda M, Mahajan C, Dash HH (2010) Intensive care management of patients with acute intermittent porphyria: Clinical report of four cases and review of literature. Indian J Crit Care Med 14: Cappellini MD, Brancaleoni V, Graziadei G, Tavazzi D, Di Pierro E (2010) Porphyrias at a glance: diagnosis and treatment. Intern Emerg Med 5(Suppl 1):S Luder AS, Mamet R, Farbstein I, Schoenfeld N (2009) Awareness is the name of the game: clinical and biochemical evaluation of a case of a girl diagnosed with acute intermittent porphyria associated with autism. Cell Mol Biol 55: Thadani H, Deacon A, Peters T (2000) Diagnosis and management of porphyria. BMJ 320: Meyer UA, Schuurmans MM, Lindberg RL (1998) Acute porphyrias: pathogenesis of neurological manifestations. Semin Liver Dis 18: Sima AA, Kennedy JC, Blakeslee D, Robertson DM (1981) Experimental porphyric neuropathy: a preliminary report. Can J Neurol Sci 8: Dowman JK, Gunson BK, Bramhall S, Newsome PN, Badminton MN (2011) Liver transplantation from donors with acute intermittent porphyria. Ann Intern Med 154: Soonawalla ZF, Orug T, Badminton MN, Elder GH, Rhodes JM, Bramhall SR et al (2004) Liver transplantation as a cure for acute intermittent porphyria. Lancet 363: Anderson KE, Bloomer JR, Bonkovsky HL, Kushner JP, Pierach CA, Pimstone NR et al (2005) Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med 142: Floderus Y, Sardh E, Möller C, Andersson C, Rejkjaer L, Andersson DEH et al (2006) Variations in porphobilinogen and 5-aminolevulinic acid concentrations in plasma and urine from asymptomatic carriers of the acute intermittent porphyria gene with increased porphyrin precursor excretion. Clin Chem 52: Kauppinen R (2004) Molecular diagnostics of acute intermittent porphyria. Expert Rev Mol Diagn 4: Bylesjö I, Wikberg A, Andersson C (2009) Clinical aspects of acute intermittent porphyria in northern Sweden: a population-based study. Scand J Clin Lab Invest 69: Normosang Product Monograph 17 of 59

18 27. Andersson C, Innala E, Bäckström T (2003) Acute intermittent porphyria in women: clinical expression, use and experience of exogenous sex hormones. A population-based study in northern Sweden. J Intern Med 254: Thompson WD (2011) Case report: acute intermittent porphyria in a 21-year-old active duty male. J Spec Oper Med 2: Frank J, Poblete-Gutiérrez P (2011) Delayed diagnosis and diminished quality of life in erythropoietic protoporphyria: results of a cross-sectional study in Sweden. J Intern Med 269: van Tuyll van Serooskerken AM, Poblete-Gutiérrez P, Frank J (2010) The porphyrias: clinic, diagnostics, novel investigative tools and evolving molecular therapeutic strategies. Skin Pharmacol Physiol 23: Harper P, Wahlin S (2007) Treatment options in acute porphyria, porphyria cutanea tarda and erythropoietic protoporphyria. Curr Treat Options Gastroenterol 10: Elder GH, Hift RJ (2001) Treatment of acute porphyria. Hosp Med 62: Jose J, Saravu K, Shastry BA, Jimmy B (2008) Drug use in porphyria: a therapeutic dilemma. Singapore Med J 49:e Liu G, Li X, Hu Y-L, Anderson G, Qian J, Nie G (2011) Identification of two novel PBGD mutations in acute intermittent porphyria patients accompanying anemia in mainland China. Blood Cell Mol Dis 47: Tenhunen R, Mustajoki P (1998) Acute porphyria: treatment with heme. Semin Liver Dis 18: Watson CJ, Pierach CA, Bossenmaier I, Cardinal R (1978) Use of hematin in the acute attack of the inducible hepatic porphyrias. Adv Intern Med 23: Fuchs T, Ippen H (1987) Treatment of acute intermittent porphyria with a new protein-bound lyophilized hematin. Dtsch Med Wochenschr 112: Normosang Product Monograph 18 of 59

19 3. CHEMISTRY AND PHARMACY Overview Human hemin is the active substance in Normosang 25 mg/ml concentrate for solution Normosang contains 250 mg hemin per ampoule, which is solubilised and stabilised as a complex with arginine suspended in a mixture of ethanol, propylene glycol, and water Unopened Normosang ampoules have a shelf-life of 2 years when stored between 2 8 C and protected from light. Prepared solutions should be used within 1 hour of dilution 3.1 Physicochemical Properties of Human Hemin The active ingredient of Normosang is human hemin. Although hemin (haem chloride) is not described in any pharmacopoeia, its physicochemical properties are well established as it is purified from human red blood cells without chemical modification of the molecule (Table 3a). Table 3a Physicochemical Properties of Human Hemin International nonproprietary name (INN): Chemical name There is no INN for hemin Chloro [7, 12-diethenyl-3, 8, 13, 17-tetramethyl-21H, 23H-porphine-2, 18-dipropanoato (4-)-N 21, N 22, N 23, N 24 ] ferrate (2-) dihydrogen Empirical formula C 34 H 32 Cl Fe N 4 O 4 CAS number Structural formula Relative molecular mass Appearance Dark powder (may have a violet shade in reflected light and a brown shade in transmitted light) Solubility Freely soluble in diluted ammonium hydroxide and sodium hydroxide solutions (as haematin) Soluble in strong organic bases (eg dimethylaniline, p-toluidine and trimethylamine), and concentrated sulphuric acid (with loss of iron) Sparingly soluble in 70 80% alcohol Practically insoluble in carbonate solutions and diluted acid solutions Practically insoluble (but stable) in water Normosang Product Monograph 19 of 59

20 3.2 Normosang Pharmaceutical Development From the early 1970s, acute attacks of hepatic porphyria were treated with haematin (haem hydroxide) solutions prepared in hospital pharmacies. These preparations had poor stability, which meant that they could not be subjected to the quality control analyses normally performed on drug preparations before clinical use. 1 Haematin infusions in patients with porphyria were associated with mild to severe phlebitis in about 38% cases 2 and a high risk of coagulation disturbances 3,4 side effects possibly caused by degradation products of haematin. 5 Decomposition of the drug may have also been responsible for its limited efficacy in some clinical situations. 6 A lyophilised (freeze-dried) haematin preparation commercially available in the USA represented an advance in formulation standard, but prepared solutions have also been shown to be highly unstable. 5 Normosang was developed in order to provide a standard haem preparation of controlled quality suitable for clinical use in terms of stability, efficacy and safety. Following evaluation of several solvent systems, a formulation containing arginine (to solubilise hemin), and the cosolvents ethanol and propylene glycol (primarily to act as stabilisers), was developed. 6 This formulation was shown to be more stable than haematin solutions made in the laboratory or prepared by dissolving commercial lyophilised haematin Composition The quantitative composition and properties of Normosang 25 mg/ml concentrate for solution for infusion is shown in Table 3b. Normosang is diluted in 0.9% saline before administration (see Section 8). After dilution of one 10 ml ampoule in 100 ml of 0.9% NaCl solution, the diluted solution contains 2273 µg/ml of human hemin. 7 Table 3b Quantitative composition of Normosang per ampoule 7 Active substance Human hemin 250 mg Excipients L-arginine 267 mg Ethanol 96% (v/v) 1000 mg Propylene glycol 4000 mg Water for injection (qs) 10 ml Appearance Dark coloured solution Ph About Presentation Normosang 25 mg/ml concentrate for solution for infusion is supplied in cartons containing four 10 ml glass ampoules, with tracking labels. As hemin is extracted from human red blood cell concentrates, it is strongly recommended that every time Normosang is administered to a patient, the name and batch number of the product are recorded on the tracking label in order to maintain a link between the patient and the batch of the product. 7 Normosang Product Monograph 20 of 59

21 3.2.4 Stability and Storage Unopened ampoules should be kept in the outer carton to protect them from light and stored in a refrigerator at 2 8ºC. When stored under these conditions, Normosang has a shelf-life of 2 years. 7 Prepared solutions should be used within 1 hour of dilution. 7 Details of infusion preparation are given in Section Viral Safety The hemin present in Normosang is purified from human red blood cell concentrates. When medicinal products are prepared from human blood or plasma, the risk for transmission of infective agents (in particular viruses and prion proteins) cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens. 7 The manufacturing process for Normosang ameliorates this risk by: Selection of blood donations: Red blood cells used in the manufacture of Normosang are supplied by the Finnish Red Cross Blood Service (FRCBS) and the Sanquin Blood Supply Foundation (Sanquin) in The Netherlands. 8 The FRCBS and Sanquin apply stringent measures in the selection of donors and the screening of individual donations for specific markers of infections. Specific criteria are used to exclude donors and these comply with national and international requirements and recommendations; tests for viral markers are conducted using validated screening methods Manufacturing steps for the inactivation/removal of viruses: The extraction of hemin from red blood cells and its subsequent purification includes effective steps for the inactivation/removal of viruses. These steps have been shown to be effective against enveloped viruses (eg human immunodeficiency virus [HIV], hepatitis B and C viruses [HBV/HCV]), non-enveloped viruses (eg porcine parvovirus) Sterility Normosang is produced according to validated aseptic manufacturing processes that comply with the requirements for Good Manufacturing Practices for Medicinal Products. The bulk Normosang solution is manufactured in a clean room Grade B environment. This solution is then sterilised by filtration and filled into ampoules in a clean room Grade A environment (under laminar flow conditions). 8 References 1. Tokola O, Tenhunen R, Volin L, Mustajoki P (1986) Pharmacokinetics of intravenously administered haem arginate. Br J Clin Pharmacol 22: McColl KE, Moore MR, Thompson GG, Goldberg A (1981) Treatment with haematin in acute hepatic porphyria. Q J Med 198: Morris DL, Dudley MD, Pearson RD (1981) Coagulopathy associated with hematin treatment for acute intermittent porphyria. Ann Intern Med 95: Glueck R, Green D, Cohen I, Ts ao C (1983) Hematin: unique effects on hemostasis. Blood 61: Simionatto CS, Cabal R, Jones RL, Galbraith RA (1988) Thrombophlebitis and disturbed hemostasis following administration of intravenous hematin in normal volunteers. Am J Med 85: Normosang Product Monograph 21 of 59

22 6. Tenhunen R, Tokola O, Lindén IB (1987) Haem arginate: a new stable haem compound. J Pharm Pharmacol 39: Normosang summary of Product Characteristics (2012) Available at arch, accessed Nov Data on File, Orphan Europe, Immeuble Le Guillaumet, Paris La Défense Normosang Product Monograph 22 of 59

23 4. PHARMACOLOGY AND TOXICOLOGY Overview Normosang (2 5 mg/kg) shows marked antiporphyrogenic activity for: Correcting the haem deficit and restoring CYP-related metabolism, during both acute attacks and remission periods Reducing elevated levels of ALA, PBG and other potentially harmful haem precursors Normosang (3 mg/kg) has a favourable pharmacological safety profile, with: No clinically significant effects on haemostasis A wide therapeutic margin of safety in terms of impairment of oxidative metabolism of exogenous substances, drug drug interactions mediated via plasma protein binding, central nervous system and cardiovascular effects Animal toxicology studies have revealed no effects that would prevent the administration of Normosang to humans 4.1 Introduction Normosang is indicated for the treatment of acute attacks of hepatic porphyria (AIP, VP and HCP). 1 Porphyrias are characterised biochemically by decreased formation of haem due to defective activity of enzymes involved in haem biosynthesis. This leads to increased ALA synthase activity, and thereby, increased accumulation and excretion of ALA, PBG and porphyrins, as well as a relative deficiency in CYPs (see Section 2). 4.2 Antiporphyrogenic Activity Animal Studies The antiporphyrogenic efficacy of Normosang was mainly assessed in model studies in rats, in which porphyria was induced using 2-allyl-2-isopropylacetamide, 2,3 which causes a major increase in the activity of ALA synthase, increased excretion of porphyrin precursors, appearance of abnormal hepatic green pigment and a decrease in concentration and activity of CYPs. Overall these studies showed that Normosang (1 10 mg/kg) dose-dependently: 2,3 Corrects the haem deficiency Significantly inhibits the induction of hepatic ALA synthase (at a dose of 10 mg/kg) Restores the activity of HO (at a dose of <5 mg/kg; increased HO activity was only seen after higher doses of Normosang ) Reduces the urinary excretion of PBG and ALA (at doses of 1mg/kg and 2.5 mg/kg, respectively) The antiporphyrogenic effects seen with Normosang were comparable with those for freshly prepared haematin and were more potent than those for lyophilised haematin used at equivalent doses. 2,3 A study among iron-loaded rats showed that apart from HO, UROD and Haem-S, Normosang (12 mg/kg) had no effect on other enzymes involved in haem synthesis or degradation. 4 Normosang Product Monograph 23 of 59

24 4.2.2 Postulated Mechanism of Action The mechanisms of action leading to the antiporphyrogenic effects of Normosang seen in animal studies are related to: An easy dissociation of haem from haem arginate The formation of haem-haemopexin complexes (haemopexin preferentially binds free haem molecules for transport to the liver 5 ) that are able to bind to specific receptors on the plasma membrane of hepatocytes An expansion of the haem pool with induction of HO activity (Figure 4a) 2 Induced HO activity, together with the incorporation of haem into haemoproteins (eg CYPs), would prevent the potential toxic effects due to accumulation of free haem (ie membrane lipid peroxidation and formation of hydroxyl radicals); 6 that have sometimes been observed with haematin therapies. 7 Indeed, patients treated with hemin experience rapid improvements in liver biochemical markers. 8 This suggests that hemin therapy enhances hepatic function, probably by reconstituting hepatic cytochromes and other hepatic haemoproteins. 8 Figure 4a Postulated mechanism of action of Normosang 2 Normosang (Haem arginate) rapid dissociation in blood Arginate Haem Haemopexin Haem-haemopexin complex Hepatic haem pool Haem-haemopexin complex binds to hepatocytes Haem oxygenase Risk of haem toxicity Haem ALA incorporated in S CYPs ALA PBG Improvement/ resolution of clinical symptoms CYPs, cytochrome P450 enzymes; ALA, delta-aminolaevulinic acid; PBG, porphobilinogen Normosang Product Monograph 24 of 59