Allan D. Corpuz MD, FPCP !

Fellow, Section of Rheumatology UP-Philippine General Hospital

IV Methylprednisolone Therapy for Systemic Lupus Erythematosus

Pre-test

1. Methylprednisolone is a:!

a. mineralocorticoid b. glucocorticoid

!

2. It is used for the following diseases:!

a. post-traumatic osteoarthritis b. COPD exacerbations

c. SLE nephritis d. all of the above

e. none of the above

!

3. The effect of methylprednisolone on the immune system is to promote inflammation:!

a. true b. false

Pre-test

4. Pulse therapy is done to:!

a. decrease side effects and enhance therapeutic effects

b. enhance therapeutic effects despite enhanced side effects

!

5. The usual adult MPPT dose is:!

! ! ! a. 1 gm/day for 7 days b. 1gm/day for 3 days

c. 1 gm/day for 5 days d. any of the above

Methylprednisolone

• Mechanism of Action

• Indications

• Administration

• Adverse Effects

Mechanism of Action• Is a synthetic glucocorticoid

• Glucocorticoids

• steroid hormones, naturally occurring (i.e. cortisol) and synthetic drugs (prednisone, hydrocortisone, dexamethasone, methylprednisolone)

Mechanism of Action• Is a synthetic glucocorticoid

• Glucocorticoids

• steroid hormones, naturally occurring (i.e. cortisol) and synthetic drugs (prednisone, hydrocortisone, dexamethasone, methylprednisolone)

• functions to regulate BP and electrolyte balance and physiologic stress response

• effect on immune system: reduces inflammation and inhibits immune response

Genomic & Non-Genomic Effects

At any therapeutic

relevant dosage High doses/Pulse

Therapy -  Exhibit pharma effect via Classic

Genomic mechanisms -  At least 30mins before clinical

effect begins to show*

-  Early rapid non-genomic effect

and a delayed and more sustained

classic genomic effect (biphasic)** -  Non-genomic mechanisms rapid/

within minutes via (1) specific

receptor mediated activity or

(2)non-specific membrane-

associated physicochemical

activity***

Genomic/Non-genomic effects cannot be separated clinically!

*Barnes(PJ:(An-.inflammatory(ac-ons(of(glucocor-coids:(molecular(mechanisms,(Clin(Sci((Lond)(94:557–572,(1998.(

**Lipworth(BJ:(Therapeu-c(implica-ons(of(non.genomic(glucocor-.(coid(ac-vity,(Lancet'356:87–89,(2000.((***BuRgereit(F,(Wehling(M,(Burmester(GR:(A(new(hypothesis(of(modular(glucocor-coid(ac-ons:(steroid(treatment(of(rheuma-c(diseases(revisited,(Arthri,s'Rheum'41:761–767,(1998.((

(

Genomic Mechanisms

Transactivation Transrepression -  Responsible for side

effects of GC (DM,

Osteoporosis, Skin

atrophy, Growth

retardation and

Cushingoid appearance -  Anti-inflammatory effect

within a few days

- Responsible for anti-

inflammatory effects (within

a few hours)

SELECTIVE GC AGONISTS: MORE FAVORABLE BALANCE*

Genomic Mechanisms

Transactivation Transrepression -  Responsible for side

effects of GC (DM,

Osteoporosis, Skin

atrophy, Growth

retardation and

Cushingoid appearance -  Anti-inflammatory effect

within a few days

- Responsible for anti-

inflammatory effects (within

a few hours)

SELECTIVE GC AGONISTS: MORE FAVORABLE BALANCE*

Steroid Dosing (Prednisone Equivalent)

• Low dose: <7.5 mg

• Medium dose: 7.5-30mg/day

• High dose: >30 but <100 mg/day

• Very high: >100 mg/day

• Pulse therapy

Indications in

Rheumatologic Diseases

Acute exacerbations of rheumatic disorders: !

✴ Post-traumatic OA and synovitis

✴ Rheumatoid Arthritis ✴ Psoriatic arthritis ✴ Ankylosing spondylitis ✴ SLE ✴ Polymyositis ✴ Polyarteritis nodosa ✴ Acute rheumatic carditis

Acute exacerbations of rheumatic disorders: !

✴ Post-traumatic OA and synovitis

✴ Rheumatoid Arthritis ✴ Psoriatic arthritis ✴ Ankylosing spondylitis ✴ SLE ✴ Polymyositis ✴ Polyarteritis nodosa ✴ Acute rheumatic carditis

Pulse GC

• first used in patients with SLE to treat DPGN

• Pulse-GC doses (0.5-1g of MP IV daily) also effective for pneumonitis, serositis, vasculitis and thrombocytopenia

• also for neuropsychiatric SLE*

Pulse GC• for very severe DPGN or RPGN:

• Pulse-GC doses work faster than oral high dose GC therapy

• probably permit use of both a moderate dose of GCs (0.5mkd) at therapy initiation and a faster tapering dose of GC

• synergistic with IV Cyclophosphamide

• Pulse GC: nongenomic effects that allow faster and more effective action than conventional high dose GCs

Pulse GC• RCT on RA: Pulse-GC cause no

bones loss compared to oral GC

• Lipodystrophy and diabetogenic effects of pulse GC may also be less severe

• Complications such as GC-induced osteonecrosis, major infections and mood disorders or psychosis may still occur

• Seizures, myalgia, arthralgias, dangerous cardiac arrhythmias secondary to potassium deficits and anaphylaxis: rare but reported

High vs Low dose Pulse GC• Badsha et al: 55 patients!

• 500mg MP IV x 3 days: fewer serious infections (7/26) but same therapeutic response

• Most infections were gram-negative bacteria and occurred within 1 month of administration

• Hypoalbuminemia was a risk factor

• Magbitang, et al.: 42 patients!

• MEX-SLEDAI: 14

• 83% had lupus nephritis

• Anemia, hypoalbuminemia and significant proteinuria

• 67%: 1gram/day x 3 days

• 64% In-hospital complication rate, 21% mortality rate

• High dose MPPT: high In-hospital complication rate, but no mortality

• Nephritis and low platelet counts at baseline associated with mortality

Methylprednisolone Na succinate Available preparations

• Pfizer (Zuellig)!

• Solu-Medrol!

• US FDA Pregnancy Category: C!

• Regulatory Classification: Rx!

• pH: 7-8 when reconstituted!

• Packaging:!

• Solu-Medrol powd for inj 1g/16mL (P5,030.97)

• Solu-Medrol powd for inj 125mg/2mL (Act-O-Vial) (P1212.04)

• Solu-Medrol powd for inj 40mg/mL (Act-O-Vial) (P644.55)

• Solu-Medrol powd for inj 500mg/8mL (P3467.74)

Dosing• Pulse therapy (“MPPT”):

• suprapharmacologic doses; intermittent manner to enhance the therapeutic effect and reduce the side effects

• arbitrarily defined as treatment with more than 250 mg prednisone or its equivalent per day, for one or more days1

• No guidel ines on the frequency or t iming of administration of the i.v. pulses; includes single boluses, daily boluses given for 3 days in a row, or on alternate days for up to 12 days1

1 Sinha A, Bagga A. Pulse Steroid Therapy. Indian J Pediatr 2008; 75 (10): 1057-1066

Administration• IM Injection: - Use solution as reconstituted1 and inject a maximum of 250 mg deep into a

large muscle (i.e.gluteal muscle)

• Rotate injection sites

• SUBCUT Injection: - Not recommended (no information).

• IV Injection: - Doses up to 250 mg should be given over a period of at least 5 minutes and doses greater than 250 mg should be given over at least 30 minutes.

• IV Infusion: - For intermittent infusion, dilute with a compatible fluid to a maximum concentration of 3 g/100 mL and infuse over at least 30 minutes. For patients at risk of cardiovascular adverse effects the infusion should be given over 2 to 3 hours.

• For continuous infusion, dilute to the desired volume with an appropriate infusion solution to a concentration of 1 mg/mL.

• For infants and children: Dilute dose to 125 mg/mL or weaker and give intravenously over at least 5 minutes. For doses of 2 mg/kg or more the dose should be diluted and infused over at least 30 minutes.

Stability

• Reconstituted Solution: - Store at room temperature and use within 24 hours of reconstitution.

• Diluted Solution: - Stable up to concentration of 3 g/100 mL for 24 hours at room temperature

Compatibility• Compatible Fluids: - Glucose 5%, sodium chloride 0.9%,

glucose 5% in sodium chloride 0.9%

• Compatible Drugs: - Chloramphenicol, clindamycin, dopamine, granisetron, heparin, noradrenaline, ranitidine, verapamil

• Compatible via Y-Site: - Aciclovir, amifostine, amiodarone, aztreonam,, bivalirudin, cefepime, ceftazidime, dexmedetomidine, dopamine, granisetron, linezolid, metronidazole, midazolam,, morphine sulfate, pethidine, piperacillin-tazobactam, remifentanil, tacrolimus,

• Compatible in Syringe: - Metoclopramide

Incompatibilty

• Incompatible Fluids: - No information.

• Incompatible Drugs: - Aminophylline, benzylpenicillin, calcium gluconate, ciprofloxacin, cisatracurium, dolasetron, filgrastim, glycopyrrolate, insulin soluble, metaraminol, ondansetron, pantoprazole, potassium chloride, propofol, rocuronium, tigecycline

Special Considerations• Each gram of methylprednisolone sodium

succinate contains 2 mmol of sodium.

• Solutions with a slight haze should be discarded.

• There are reports of cardiac arrhythmias and/or circulatory collapse and/or cardiac arrest following rapid administration of large IV doses (over less than 10 minutes).

Dosing• Pulse therapy (“MPPT”):

• Adults, usually 1-2 g of methylprednisolone

• Initially the duration of infusion was based on a study in normal adults, and was 10 to 20 minutes.1

• Rapid infusions associated with higher risk of hemodynamic abnormalities, and hence administration over 1-3 hours is preferred. 2

• Dexamethasone may also be used

1 Novak E, Stubbs SS, Seekman CC, Hearron MS. Effects of a single large intravenous dose of methylprednisolone sodium succinate. Clin Pharmacol Ther 1970; 11 : 711-717.!!

2 Miura M, Ohki H, Yoshiba S, Ueda H, Sugaya A, Satoh M et al. Adverse effects of methylprednisolone pulse therapy in refractory Kawasaki disease. Arch Dis Child 2005; 90 : 1096–1097.

Administration: Methylprednisolone sodium succinate (Solu Medrol)

• SOLU-MEDROL should not be diluted or mixed with other solutions

• Use only the accompanying diluent or Bacteriostatic Water For Injection with Benzyl Alcohol when reconstituting SOLU-MEDROL. Use within 24-48 hours after mixing.

• to avoid compatibility and stability problems, whenever possible, it is recommended that SOLU MEDROL be administered separate from other drugs and as either IV medication chamber, or as an IV "piggy-back" solution

• Cardiac arrhythmias and/or cardiac arrest have been reported after rapid administration (greater than 0.5 gram administered over a period of less than 10 minutes).

• Bradycardia has been reported, may be unrelated to the speed or duration of infusion.

• When high dose therapy is desired, the recommended dose of SOLU-MEDROL Sterile Powder is 30 mg/kg administered intravenously over at least 30 minutes. This dose may be repeated every 4 to 6 hours for 48 hours.

Administration: Methylprednisolone sodium succinate (Solu Medrol)

Suggested dosing: Solu Medrol

Rheumatic disorders 1 g/day for one, two, three or four days IV or 1 g/month for six months IV

!Systemic lupus erythematosus

1 g/day for three days IV

!Multiple sclerosis

1 g/day for three days IV or 1 g/day for five days IV

!Edematous states e.g. glomerulonephritis, lupus nephritis

30 mg/kg every other day for four days IV or 1 g/day for three, five or seven days IV

Pharmacology• Pharmacodynamics

• has a greater anti-inflammatory potency than prednisolone and even less tendency than prednisolone to induce sodium and water retention

• Pharmacokinetics

• Absorption

• 30 mg/kg over a 20 minute period or 1 g over 30 to 60 minutes, peak methyl-prednisolone plasma concentrations of approximately 20 mcg/mL were achieved

• Distribution

• widely distributed throughout the body ; readily crosses the blood-brain barrier; crosses the placental barrier

Pharmacology• Pharmacokinetics

• Metabolism

• metabolised in the liver to inactive metabolites

• Excretion

• mean elimination half-life ranges for total methylprednisolone is in the range of 1.8 to 5.2 hours

• 75% in urine, 9% in feces, rest in bile

• N o d o s e a d j u s t m e n t n e c e s s a r y f o r re n a l f a i l u re ; methylprednisolone is dialyzable

ContraindicationsMethylprednisolone sodium succinate is contraindicated:

• in patients who have systemic fungal infections

• in patients with known hypersensitivity to methylprednisolone or any component of the formulation

• for use by intrathecal, epidural, local injection or any other unspecified route of administration

!Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids

Drug interactionsDrugs that inhibit CYP3A4 activity generally decrease hepatic clearance, resulting in increased plasma concentration of methylprednisolone:

!• Antifungals such as ketoconazole and itraconazole

• Antiemetics such as aprepitant and fosaprepitant

• Immunosuppressants such as ciclosporin

• Macrolide antibacterials such as clarithromycin, erythromycin and troleanomycin

• HIV-Protease inhibitors such as indinavir and ritonavir

• Calcium channel blockers such as diltiazem.

• Isoniazid

• Oral contraceptives such as ethinylestradiol and norethisterone

• Grapefruit juice

Drug interactions

Drugs that induce CYP3A4 activity generally decrease hepatic clearance, resulting in decreased plasma concentration of methylprednisolone:

!•Anticonvulsants such as phenobarbita l , phenytoin,

carbamazepine and primidone

•Bactericidal antibiotics such as rifampicin and rifabutin

Adverse Effects: What to watch out for…

Most symptoms were transient in duration, mild in severity, and required no medical treatment1.!!42 possible complications occurring within two weeks of HIVMP therapy. !!In 18 instances medical intervention was required for problems that included hypertension, seizures,  gastric erosions,  sepsis, and other  infections. It is impossible to attribute all of the complications to HIVMP alone because of underlying disease, use of other medications at the time of therapy, or both.

1 Baethge BA, Lidsky MD, Goldberg JW A study of adverse effects of high-dose intravenous (pulse) methylprednisolone therapy in patients with rheumatic disease. The Annals of Pharmacotherapy [1992, 26(3):316-320]!

Adverse Effects Pertains to its physiologic effects as a glucocorticoid - recall:

HYPERTENSION!

ARRHYTHMIAS!

HYPERGLYCAEMIA!

SEIZURES!

GASTRIC EROSIONS/ULCERS!

S E P S I S a n d O T H E R INFECTIONS!

Adverse Effects: What to watch out for…refer the following immediately

HYPERTENSION!

ARRHYTHMIAS!

HYPERGLYCEMIA!

SEIZURES!

GASTRIC EROSIONS/ULCERS!

SEPSIS and OTHER INFECTIONS!

1 Baethge BA, Lidsky MD, Goldberg JW A study of adverse effects of high-dose intravenous (pulse) methylprednisolone therapy in patients with rheumatic disease. The Annals of Pharmacotherapy [1992, 26(3):316-320]!

Questions ?

Post-test1. Methylprednisolone is a:!

a. mineralocorticoid b. glucocorticoid

!

2. It is used for the following diseases:!

a. post-traumatic osteoarthritis b. COPD exacerbations

c. SLE nephritis d. all of the above

e. none of the above

!

3. The effect of methylprednisolone on the immune system is to promote inflammation:!

a. true b. false

Post-test

4. Pulse therapy is done to:!

a. decrease side effects and enhance therapeutic effects

b. enhance therapeutic effects despite enhanced side effects

!

5. The usual adult MPPT dose is:!

! ! ! a. 1 gm/day for 7 days b. 1gm/day for 3 days

c. 1 gm/day for 5 days d. any of the above

THANK YOU FOR YOUR KIND ATTENTION!

More patient information on Rheumatologic Diseases: www.allancorpuzmd.com