ISoP Training Course- Zagreb, 3-4 April 2014 Medical assessment of drug induced rhabdomyolysis and metabolic disorders

Marco Tuccori, ISoP EC member Unit of Adverse Drug Reacon Monitoring University Hospital of Pisa, Pisa, Italy

At the forefront of pharmacovigilance around the world 1 ISoP training course Zagreb 3-4 April 2014

Proacve Pharmacovigilance, Risk Management and Pharmacovigilance in the Era of Personalised Medicine

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At the forefront of pharmacovigilance around the world 2 Summary

• Metabolic adverse reactions • Muscular adverse reactions • Definitions and classifications • Signs and symptoms • Main (alternative) causes • Drugs most frequently involved • Biological plausibility • Drug-induced lipids metabolism alterations • Drug-induced glucose metabolism alterations

At the forefront of pharmacovigilance around the world 3 Metabolic Adverse Reacons

Metabolism is the set of life-sustain- ing chemical transformations within the cells of living organisms. These enzyme-catalyzed reactions allow organisms to grow and reproduce, maintain their structures, ? and respond to their environments. DRUGS

Lipids Myopathies

Carbohydrates

At the forefront of pharmacovigilance around the world 4 Muscular adverse events Definions and Classificaons

Term ACC/AHA/NHLBI NLA FDA Myopathy Any disease of the Symptoms of myalgia (muscle CK > 10 ULN muscle pain or soreness), weakness. Or cramps, plus CK > 10 ULN Myalgia Muscle aches or NA NA weakness without CK elevaon Myosiss Muscle symptoms with NA NA increased CK Rhabdomyolysis Muscle symptoms CK > 10.000 IU/L or CK > 10 ULN CK > 50 ULN, associated with marked plus elevaon in serum creane evidence of organ CK elevaons, pically > or medical intervenon with iv damage, such as renal 10 ULN hydraon compromise ACC/AHA/NHLBI: American College of cardiology/American Heart Associaon/Naonal Heart, Lung and Blood Instute; NLA: Naonal Lung Associaon; FDA: Food and Drug Administraon; NA: not available, ULN: upper limit of normal; CK: crean kinase

Joy TR, Hegele RA. Ann Intern Med 2009; 150:858-868 5 Muscular adverse events Mechanisms

Myocytes ++ Ca RYR SR ATP ++ Ca++ Ca++ Ca

Na+ Na+ Potassium ATP ATP Aldolase + + K K Phosphate ATP Depleon Myoglobin CK Myocytes LDH AST Proteolytic Cell breaks ++ Ca enzyme down activation KIDNEY IMPAIRMENTS

Keltz E et al., Musc Lig Ten J 2013;3:303-312 6 Rhabdomyolysis Signs and symptoms

Clinical presentation

Classic triad: muscle aches, weakness, tea coloured urine Other symptoms: muscular tenderness, swelling, cramps, stiffness Most common muscle groups involved: lower back, thighs and calves Physical examination: limb induration, skin changes due to ischemic damage (not always present) Definitive diagnosis: CK elevations and urine myoglobin

At the forefront of pharmacovigilance around the world 7 Creane kinase

Creatine kinase (CK), or creatine phosphokinase (CPK) catalyses the conversion of creatine and consumes ATP to create phospocreatine (PCr) and ADP. In tissues and cells that consume ATP rapidly, especially skeletal muscle, PCr serves as an energy reservoir for the rapid buffering and regeneration of ATP in situ. Thus, CK is much expressed in such tissues.

Serum CK is the most sensitive indicator of muscle damage. Serum CK begin to rise approximately 2-12 hours after the onset of muscle injury, peaks within 24-72 hours and declines gradually in 7-10 days.

At the forefront of pharmacovigilance around the world 8 Myoglobin

Myoglobin Plasma globulins

Muscle damage 0-0.003 mg/dL Blood Urine 100g of muscle 0.5-1.5 mg/dL tissue degraded

Elevated serum myoglobin and myoglobinuria are reliable indicators for rhabdomyolysis but present some limitations: 1) Serum myoglobin levels rise and drop much faster than CK levels (1-6 hours), thus have a low negative predictive value and may not be used as a ruling out test. 2) Myoglobinuria is not always visible or may resolved early (100 mg/dL to cause dark urine). 3) Urine dipstick test also react with the globin fargment of hemoglobin (non specific test)

At the forefront of pharmacovigilance around the world 9 Rhabdomyolysis: main causes

1) Increased energy demand Es. Exercise (extreme), Heat stroke, Seizures 2) Decreased energy production Es. Metabolic enzymes deficit, mitochondrial dyfunctions, hypokalemia 3) Direct muscle injuries Es. Crush injury, compartment syndrome, electrical injury, 3°degree burns, temeprature extreme (hyper or hypothermia) 4) Decreased oxygen delivery ES. Arterial thrombus, surgery, prolonged immobilization, trauma, shock 5)Infections 6)Endocrine abnormalities Es. Diabetic keto-acidosis, Addison’s disease, hypo/hyperthyroidsm 7) Toxins (carbon mono-oxide, venoms of snake; spider; wasp) 8) Drugs Es. Substance abuse, barbiturates, benzodiazepins, anaesthetics, neuroleptics, anabolic/corticosteroids, statin/fibrates

At the forefront of pharmacovigilance around the world 10 Stans

USA TODAY.COM 08/08/2001 Statins: estimate incidence of fatal Updated 12:41 PM ET rhabdomyolysis per milion FDA statement on Baycol withdrawal prescriptions (FDA data) FDA today announced that Bayer Drug Incidence Pharmaceutical Division is voluntarily Cerivastatin 3.16 withdrawing Baycol (cerivastatin) from the Lovastatin 0.19 U.S. market because of reports of sometimes fatal rhabdomyolysis (52 Simvastatin 0.12 cases), a severe muscle adverse reaction Atorvastatin 0.04 from this cholesterol-lowering (lipid- Pravastatin 0.04 lowering) product. The FDA agrees with Fluvastatin 0.00 and supports this decision. Staffa JA et al. N Engl J Med 346, 539, 2002 Risk factors: gender (female), age, Thompson PD et al. JAMA 289, 1681, 2003 concomitant disease (renal and hepatic failure), interactions

At the forefront of pharmacovigilance around the world 11 Stans Mechanisms of myopathy (1) Cholesterol reduction in the sarcolemma

Statins Mechanic Stress Cholesterol is Cholesterol reduction Membrane weakening important for the in the sarcolemma and rupture maintenance of the integrity of cell Cholesterol membranes Phospholipids

Staffa JA et al. N Engl J Med 346, 539, 2002 Bhardwaj S et al., Clin Interven Aging 2013;8:47-59

At the forefront of pharmacovigilance around the world 12 Stans Mechanisms of myopathy (2)

Acetyl-CoA HMG-CoA Mevalonate Mevalonate-phyrophosphate

Statins HMG-CoA-reductase (-) Isopentenyl-phyrophosphate Lack of prenylation of RabGTPase is Geranyil-phyrophosphate associated with Reduced prenylation vacuolization of muscular of structural and fibers in rat models functional proteins Farnesyl-phyrophosphate (apoptosis) (Sakamoto, 2007) Inhibition of Coenzime Q10 Squalene Lack of ATP formation syntesis and impairment of (energy deficit) the mithocondrial (Marcoff, 2007) respiratory chain Cholesterol

Marcoff L et al. J Am Coll Cardiol 49, 2231, 2007 Sakamoto K et al. FASEB J, 21, 4087, 2007

At the forefront of pharmacovigilance around the world Stans Interacons

Drug Metabolism Drugs enhancing the risk of myopathy with statins Lovastatin CYP3A4 CYP3A4* inhibitors Simvastatin CYP3A4 CYP3A4* inhibitors Pravastatin Sulphatation -

Fluvastatin CYP2C9 (CYP2C8 e CYP3A4) CYP2C9° inhibitors Atorvastatin CYP3A4 CYP3A4* inhibitors Rosuvastatin Limited involvement (10%) of - CYP2C9 and CYP2C19 *Cyclosporin, gemfibrozil, fibrates, azole antimycotics, macrolides antibiotics, protease inhibitors (anti-HIV), grapefruit juice; °Azole antimycotics, protease inhibitors (ritonavir)

Armitage J. Lancet 370, 1781, 2007

At the forefront of pharmacovigilance around the world 14 Other drugs Proton Pump Inhibitors

Ann Pharmacotherapy 2006;40(2): 352-353 Acute severe myopathy following a single infusion of omeprazole. Tuccori M, Giovannoni S, Giustini SE, Blandizzi C, Del Tacca M.

Trazodone Omeprazole Ramipril HCZ Aspirin

At the forefront of pharmacovigilance around the world 15 Other drugs Proton Pump Inhibitors

Eur J Clin Pharmacol. 2006 Jun;62(6):473-9. Myopathy including polymyositis: a likely class adverse effect of proton pump inhibitors? Clark DW1, Strandell J. 292 reports of various myopathies with PPIs (868 cases of 'myalgia‘ were excluded) Positive dechallenge: 69 patients Positive rechallenge: 5 patients (1 case of a cross reaction with 3 different PPIs) 33% of reports a PPI was the only administered drug Myositis or polymiositis: 27 patients Rhabdomyolisis: 35 patients (9 positive dechallenge) Time to onset of rhabdomyolisis (n = 17): within 1 week (n = 9); 2-12 weeks (n = 3) Cross-sectional slice of human skeletal muscle showing acute muscle fiber In 12 cases of rhabdomyolisis, a statin was taken necrosis (hematoxylin and eosin stain; concomitantly × 400 original magnification).

At the forefront of pharmacovigilance around the world 16 Rhabdomyolysis Syndromes

Malignant hyperthermia

Ryanodine Receptor ALOTANE Exon 44 Massive (anesthetic gases) Gene RyR1 intracellular ++ Rhabdomyolysis Mutation Mutation Ca Ala2350Thr Arg2355Trp HALOPERIDOL release Mutation (Neuroleptic drugs) Gly2355Ala

Neuroleptic malignant syndrome

At the forefront of pharmacovigilance around the world 17 Other drugs Gabapenn

Ann Pharmacotherapy 2007;41(7):1301-5. Gabapentin-induced severe myopathy Tuccori M, Lombardo G, Lapi F, Vannacci A, Blandizzi C, Del Tacca M.

At the forefront of pharmacovigilance around the world 18 Iatrogenic Cushing Syndrome Chorcosteroids

Cushing syndrome (corticosteroids users): TEST • Low ACTH level • Low cortisol level • No response to a cosyntropin stimulation test • Higher than normal fasting glucose • Low blood potassium level • Low bone density, as measured by dual x-ray absorptiometry (DEXA) • High cholesterol, particularly high triglycerides and low high-density lipoprotein (HDL)

Aninflammatory effect Gluconeogenesis Corsole Protein mobilizaon Protein mobilizaon

At the forefront of pharmacovigilance around the world 19 Lipodystrophy Anretrovirals

Reverse transcriptase inhibitors Protease inhibitors (Zidovudine, didanosine, (saquinavir, ritonavir, Lamivudine, Abacavir, Tenofovir, indinavir, nelfinavir..) Efavirenz, Nevirapine, Stavudine…)

At the forefront of pharmacovigilance around the world 20 Lipodystrophy Anretrovirals

Proposed definition of human immunodeficiency virus lipodystrophy

Carr A. AIDS 2003;17 Suppl 1:s141-8 21 Drug-induced hyperglycaemia

• 5% of all diabetes are drug-induced (triggering diabetes in patients at risk) • Early symptoms: polyuria, polydipsia, asthenia, weight loss • No ketonuria, no signs of autoimmunity (antibodies anti-insuline, ...) • Ruling out alternative causes: pre-existing diabetes (33% of new cases are undisclosed); checking for positive dechallenge Main drugs associated with hyperglycaemic effects (screening in paents with risk factors before starng the treatment) Drug Class Drugs Anhypertensive Thyazidic diurecs An-asthma Beta-2-agonists Anretrovirals Protease inhibitors Immunosuppressants Cyclosporin, tacrolimus Hormons Corcosteroids, ACTH, estrogens, thyroid hormones Anpsychocs Olanzapine, clozapine

At the forefront of pharmacovigilance around the world 22 Drug-induced hypoglycaemia Andiabec drugs

• “Traditional” insulines are associated with the higher risk (frequence of hypoglicaemia are reduced by 30% with fast or intermediate acting insulines) • No cases or very low frequence of hypoglicaemic events with metformin, glytazones, acarbose, GLP1 analogues, DDP4 inhibitors • Higher risk with glinides and sulphanilureas (1-3 cases for 100 patient years) • Early symotoms: tremor, sweating, general malaise • Late symptoms: neuroglycopenia (cephalea, confusion, syncope, coma) • Diagnosis: plausible temporal relationship

At the forefront of pharmacovigilance around the world 23