7. Classes of Medications

Click on the + signs below to learn more about each medication or download the pdf to view the information in tables.

REGULATORY APPROVED MEDICATIONS

• Palovarotene

  TRADE 

  Sohonos™ in the United States, Canada and Australia 

  Sohonos Educational Program and must be completed by any healthcare professional who wants to prescribe Sohonos. 

  Educational materials can be found at is: SOH-US-000215-SOHONOS-Educational-Program-Materials-for-Prescribers-and-Pharmacists.pdf 

  CLASS 

  RAR-γ Agonist 

  PROPOSED MECHANISM OF ACTION AS IT RELATES TO FOP 

  Inhibits Ectopic Chondrogenesis 

  DOSING 

  For adults and pediatric patients 14 years and older:  5 mg daily. Stop daily dosing when flare-up dosing begins. Flare-up dosage for adults and pediatric patients 14 years and older is 20 mg daily for 4 weeks, followed by 10 mg daily for 8 weeks (for a total of 12 weeks of flare-up treatment), even if symptoms resolve earlier. Then return to daily dosing of 5 mg. 

  If, during the course of flare-up treatment, the patient experiences marked worsening of the original flare-up site or another flare-up at a new location, restart the 12-week flare-up dosing at 20 mg daily. 

  For flare-up symptoms that have not resolved at the end of the 12-week period, the 10 mg daily dosage may be extended in 4-week intervals and continued until the flare-up symptoms resolve 

  If new flare-up symptoms occur after the 5 mg daily dosing is resumed, flare-up dosing may be restarted. 

  For patients under 14 years of age (8-13 years for females and 10-13 years for males): Dosage is weight-based for both prophylactic and flare-up dosing. 

  See prescribing information at: 
  Microsoft Word - pi-mg-fda-comments-15aug2023-combined-rev 17Aug2023 (d2rkmuse97gwnh.cloudfront.net) 

  MAJOR SIDE-EFFECTS 

  FDA BLACK-BOX WARNING: TERATOGENICITY AND PREMATURE EPIPHYSEAL CLOSURE 

  Prescribing information can be found at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215559s000lbl.pdf

  The medication guide (for patients) can be found on the IpsenCares website (ipsencares.com): 
  https://d2rkmuse97gwnh.cloudfront.net/a88aa6d6-3ca0-4362-a711-d53c45ae33ff/1e0071ea-de05-46be-8b8d-90d92765c70f/1e0071ea-de05-46be-8b8d-90d92765c70f_source__v.pdf

  Premature Epiphyseal Closure: Premature epiphyseal closure occurred with SOHONOS. Assess baseline skeletal maturity before SOHONOS therapy and monitor linear growth in growing pediatric patients. 

  Growing pediatric patients are recommended to undergo baseline assessment of growth and skeletal maturity before starting treatment and continued clinical and radiographic monitoring every 6 to 12 months until patients reach skeletal maturity or final adult height. 

  Mucocutaneous Adverse Reactions: Dry skin, lip dry, pruritus, rash, alopecia, erythema, skin exfoliation, and dry eye occurred with SOHONOS. Prevent or treat with skin emollients, sunscreen, artificial tears. Dosage reduction may be required in some patients. 

  Metabolic Bone Disorders: Decreased vertebral bone mineral content and bone density may occur. Assess for vertebral fracture periodically using radiologic method. 

  Psychiatric Disorders: Depression, anxiety, mood alterations and suicidal thoughts and behaviors occurred with SOHONOS. Contact healthcare provider if new or worsening symptoms develop in patients treated with SOHONOS. 

  Night Blindness: May occur and make driving at night hazardous 

  Pregnancy: May cause fetal harm. 

CLASS I MEDICATIONS

• Prednisone (tablet form), Prednisolone (liquid form)

  TRADE 

  Deltasone 

  CLASS

  Corticosteroid

  PROPOSED MECHANISM OF ACTION AS IT RELATES TO FOP 

  Decreases lymphocyte and macrophage recruitment and tissue infiltration; potent anti-inflammatory drug: Decreases inflammation, swelling and edema especially when involving jaw, throat, and major joints.

  DOSING 

  2 mg/kg once daily in AM by oral administration (PO) x 4 days for acute flare-ups involving major joints (maximum of 100 mg/day). Flare-ups often result from over-use and soft tissue injuries. Prednisone 1-2 mgs/kg (per oral) once daily for 3-4 days to prevent flare-up after severe soft-tissue injury. May repeat for 4 days and then taper for as long as 2 weeks. 

  • Do not use after minor bumps or bruises. 

  • Do not use for flare-ups involving chest or back (see text). 

  • Use prednisone prophylactically as directed for dental or surgical procedures. 

  May also use longer treatment with taper for flare-ups in the submandibular region, especially those that affect breathing or swallowing. 

  Prednisone or prednisolone should be started within 24 hours of the onset of a flare-up for maximal effectiveness. 

  (Medication should be taken with food). 

  For patients with frequent flare-ups requiring prolonged steroid treatments, consider a bisphosphonate to prevent steroid-induced osteoporosis (see text). 

  FOR PATIENTS IN ENDEMIC REGIONS, ANTI- PARASITIC PRECAUTIONS MAY BE NEEDED 

  Alternatively, high dose intravenous corticosteroid (methylprednisolone or prednisolone sodium) therapy may be considered but must be performed during an inpatient hospitalization to monitor for potential side effects of hypertension. 

  The protocol for IV corticosteroid therapy is as follows: 

  7-15 mg/kg of methylprednisolone or 20-30 mg/kg of prednisolone sodium IV daily on three consecutive days. 

  Some prefer to administer it on alternate days as some patients tolerate it better. For example: 

  Day 1: 20-30 mg/kg of methylprednisolone IV 

  Day 2: No medication 

  Day 3: 20-30 mg/kg of methylprednisolone IV 

  Day 4: No medication 

  Day 5: 20-30 mg/kg of methylprednisolone IV 

  Total daily dose of methylprednisolone or prednisolone sodium should not exceed 1000 mg 

  MAJOR SIDE EFFECTS 

  • Acne 

  • Adrenal suppression

  • Avascular necrosis of hip

  • Cataracts

  • Chronic dependency

  • Cushing’s disease

  • Diabetes

  • Glaucoma

  • Growth retardation

  • Hypertension 

  • Immune suppression

  • Osteoporosis

  • Peptic ulcers

  • Skin bruising

  • Sleep & mood disturbance

  • Weight gain

• Ibuprofen

  TRADE

  Advil/Motrin

  CLASS

  Non-steroidal anti-inflammatory medication (non-specific COX-1 and COX-2 inhibitor)

  PROPOSED MECHANISM OF ACTION AS IT RELATES TO FOP

  Anti-inflammatory and anti-angiogenic; symptomatic relief during a flare-up; Potential use in prevention by inhibiting production of inflammatory prostaglandins

  DOSING

  Peds: 4–10 mg/kg PO every 6 hrs, as needed.

  Adult: 200–800 mg PO every 6 hrs, as needed.

  Medication must be taken with food.

  MAJOR SIDE EFFECTS

  • Gastrointestinal bleeding

  • Impaired renal function

• Indomethacin

  TRADE

  Indocin

  CLASS

  Non-steroidal anti- inflammatory medication (non-specific COX-1 and COX-2 inhibitor)

  PROPOSED MECHANISM OF ACTION AS IT RELATES TO FOP

  Anti-inflammatory and anti- angiogenic; symptomatic relief during a flare-up; Potential use in prevention by inhibiting production of inflammatory prostaglandins

  DOSING

  Peds: 2–4 mg/kg/day PO; or 150–200 mg/day (whichever is less); divided tid.

  Adult: 50 mg PO tid or Indocin – SR (sustained release) at a dose of 75 mg. PO bid.

  Medication must be taken with food.

  MAJOR SIDE EFFECTS

  • Gastrointestinal bleeding 

  • Impaired renal function

• Celecoxib

  TRADE

  Celebrex

  CLASS

  COX-2 inhibitor

  PROPOSED MECHANISM OF ACTION AS IT RELATES TO FOP

  Anti-inflammatory and anti-angiogenic; symptomatic relief during a flare-up; Potential use in prevention by inhibiting production of inflammatory prostaglandins

  DOSING

  Peds and Adults: 100–200 mg po bid for maintenance, at discretion of M.D.

  • For acute & chronic flare-ups, not to exceed maximum anti-angiogenic dose of 250 mgs/M2 PO bid or 6 mg/kg PO bid (whichever is lower; rounded-up or rounded-down to the closest multiple of 100 mg) and not to exceed a maximum total daily dose of 600 mgs. for more than 16 months.

  Medication should be taken with a fatty snack for maximum absorption.

  MAJOR SIDE EFFECTS

  • Gastrointestinal bleeding

  •  Impaired renal function

  •  Concern of cardiovascular and cerebrovascular risks

  • NOT TO BE TAKEN BY PATIENTS WITH KNOWNALLERGIESTO SULFONAMIDES OR BY PATIENTS WITH ASPIRIN-SENSITIVE ASTHMA

CLASS II MEDICATIONS

• Montelukast

  TRADE

  Singulair

  CLASS

  Leukotriene receptor antagonist

  PROPOSED MECHANISM OF ACTION AS IT RELATES TO FOP

  Blocks inflammatory mediators; complementary action to cyclo-oxygenase inhibitors.

  DOSING

  Peds:
  2-5 yo: 4 mg PO at bedtime
  6-14 yo: 5 mg PO at bedtime

  Adults: 10mg PO at bedtime

  MAJOR SIDE EFFECTS

  • Generally well-tolerated. Rarely: angioedema, headache, flu-like syndrome, fatigue, abdominal pain; possible association with behavior/mood changes, suicidal thinking and behavior, and suicide. Patients should be monitored for changes in behavior and mood.

• Cromolyn

  TRADE

  Gastrocrom

  CLASS

  Mast cell stabilizer

  PROPOSED MECHANISM OF ACTION AS IT RELATES TO FOP

  Reduces mast cell degranulation, but poorly absorbed from GI tract. May be more effective if used chronically

  DOSING

  Peds:
  0-2 yo: 20 mg/kg/d PO div qid
  2-12 yo: 100 mg PO qid

  Adults: 200 mg PO qid

  MAJOR SIDE EFFECTS

  • Generally, extremely well-tolerated. Rarely: throat Irritation, dry throat, cough, bitter taste.

• Pamidronate

  TRADE

  Aredia

  CLASS

  Aminobis-phosphonate

  PROPOSED MECHANISM OF ACTION AS IT RELATES TO FOP

  Anti-angiogenic; possibly anti-inflammatory; potential inhibition of early angiogenic fibroproliferative lesion; well-established effects on decreasing bone remodeling in normotopic skeleton and in protecting normotopic skeleton from profound osteopenic effects of chronic intermittent high dose glucocorticoids.

  DOSING

  Peds (2-3 yo): 0.75 mg/kg/day by slow IV infusion for three days;

  For children older than 3 yo and for adolescents and adults: 1.0 mg/kg/day for three days.

  Medication should be infused slowly each day over 4–5 hours.

  Note: On the first day of the first cycle of treatment, the patient must receive half the dose. In case of fever, give standard acetaminophen treatment.

  The 3-day cycle of treatment should be repeated no more than 4 times annually. For dilution instructions, see text.

  Patients should have the following blood tests checked prior to pamidronate treatment: serum calcium, phosphate albumin, alkaline phosphatase, 25-hydroxyvitamin D, BUN, creatinine, CBC.

  All patients should receive adequate supplemental dietary calcium and vitamin D daily during and indefinitely following pamidronate treatment.

  MAJOR SIDE EFFECTS

  Generally well-tolerated. Contraindicated in renal dysfunction.

  • An acute phase reaction characterized by fever, malaise, and myalgia occurs commonly during IV infusion of pamidronate and may persist for 18-24 hours. Pre-treatment with acetaminophen may lessen symptoms.

  • In case of fever or other symptoms of acute phase reaction, give standard acetaminophen treatment.

  • Pamidronate should not be used in patients who are hypocalcemic as tetany may result, and subsequent management of hypocalcemia can be very difficult in patients with FOP.

  Daily oral calcium and vitamin D supplementation should be provided to all patients who receive pamidronate (not just on days of infusion, but daily on a continual basis for at least two weeks). Frequent high-dose use of aminobisphosphonates in children can lead to osteopetrosis and possibly low energy femoral fractures.

  See also cautions in text for osteonecrosis of jaw.

• Zoledronate

  TRADE

  Zometa

  CLASS

  Aminobis-phosphonate

  PROPOSED MECHANISM OF ACTION AS IT RELATES TO FOP

  Anti-angiogenic; possibly anti-inflammatory; potential inhibition of early angiogenic fibroproliferative lesion; well-established effects on decreasing bone remodeling in normotopic skeleton and in protecting normotopic skeleton from profound osteopenic effects of chronic intermittent high dose glucocorticoids.

  DOSING

  All patients should receive adequate supplemental dietary calcium and vitamin D daily during and indefinitely following zoledronate treatment.

  Children and Adolescents: safety and efficacy not established.

  Adults: 5 mg IV over at least 15 minutes.

  Dose adjustments for renal and hepatic impairments, hematologic toxicity and non-hematologic toxicities.

  MAJOR SIDE EFFECTS

  • Pre-treatment with acetaminophen may lessen symptoms. In case of fever or other symptoms of acute phase reaction, give standard acetaminophen treatment.

  • Zoledronate should not be used in patients who are hypocalcemic as tetany may result, and subsequent management in patients with FOP can be difficult.

  • Daily oral calcium and vitamin D supplementation should be provided to all patients who receive zoledronate (not just on days of infusion, but daily on a continual basis for at least two weeks).

  • Frequent high-dose use of aminobisphosphonates in children can lead to osteopetrosis and possibly low-energy femoral fractures.

  See also cautions in text for osteonecrosis of jaw.

  • No randomized placebo-controlled trials have been conducted to date to demonstrate efficacy; one case series suggests there may be benefits for decreasing intensity of flares, but data are anecdotal.

• Imatinib

  TRADE

  Gleevec

  CLASS

  Selective Tyrosine Kinase inhibitor

  PROPOSED MECHANISM OF ACTION AS IT RELATES TO FOP

  Off-target effects of blocking c-Kit, HIF-1α, PDGFRα, and multiple MAP kinases (Kaplan et al., 2018; Kaplan et al., 2021)

  DOSING

  Imatinib should always be prescribed under the guidance of an adult or pediatric oncologist or rheumatologist

  MAJOR SIDE EFFECTS

  Most Common Side-effects

  Bone marrow suppression: May cause bone marrow suppression (anemia, neutropenia, and thrombocytopenia), usually occurring within the first several months of treatment. Median duration of neutropenia is 2 to 3 weeks; median duration of thrombocytopenia is 2 to 4 weeks. Monitor blood counts weekly for the first month, biweekly for the second month, and as clinically necessary thereafter.

  Fluid retention/edema: Imatinib is commonly associated with fluid retention, weight gain, and edema (risk increases with higher doses and age >65 years)

  GI toxicity: Imatinib is associated with a moderate emetic potential; antiemetics may be recommended to prevent nausea and vomiting. May cause GI irritation; take with food and water to minimize irritation.

  Hepatotoxicity: Hepatotoxicity may occur; Monitor liver function (transaminases, bilirubin, and alkaline phosphatase) prior to initiation and monthly, or as needed thereafter.

  Nephrotoxicity: Imatinib is associated with a decline in renal function; may be associated with duration of therapy.

• Tofacitinib

  TRADE

  Xeljanz

  CLASS

  Janus kinase inhibitor

  PROPOSED MECHANISM OF ACTION AS IT RELATES TO FOP

  Janus kinase inhibitor, representing a new class of disease-modifying antirheumatic drugs (DMARDs), with anti-inflammatory properties and FDA approved for juvenile idiopathic arthritis as well as other rheumatologic conditions and ulcerative colitis.

  In an FOP case series by Nikishina, et al., 2023, levels of IL-1RA decreased in 4/5 individuals (80%) and increased in 1/5 (20%), suggesting that at least part of the mechanism of action in FOP is related to suppression of inflammatory cytokines.

  DOSING

  5mg twice daily (oral dosing) was found to be beneficial in an FOP case series by Nikishina, et al.., Pediatric Rheumatology 21:1-9, 2023. https://doi.org/10.1186/s12969-023-00856-1.

  Also available as an extended release formulation (XR) at 11 mg once daily and higher induction doses of 10 mg twice daily or 22 mg once daily (XR) for 8 weeks. An oral solution is also available at 1mg/ml.

  MAJOR SIDE EFFECTS

  FDA BLACK BOX WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE), and THROMBOSIS

  • Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported.

  • In patients 50 years of age and older with at least one cardiovascular risk factor, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed.

  • Malignancies, including lymphomas and solid cancers, were observed in clinical studies

  • Thrombosis, including pulmonary embolism (PE), deep venous thrombosis (DVT), and arterial thrombosis, have occurred in treated patients, and some resulted in death.

  • Reactions such as angioedema and urticaria that may reflect drug hypersensitivity have been observed.

  • Laboratory abnormalities have been observed including lymphopenia, neutropenia, anemia, liver enzyme elevations.

  • Use of live vaccinations should be avoided. Avoid with pre-existing gastrointestinal narrowing.

  • There is very limited information on use in pregnancy, lactation, and limited information about use in adults with FOP

  Prior to starting, evaluate for high risk infections, including TB screening.

  Caution with use in diabetes and hepatic impairment, as well as with concomitant use of NSAIDS.

• Canakinumab

  TRADE

  Ilaris

  CLASS

  IL-1β inhibitor

  PROPOSED MECHANISM OF ACTION AS IT RELATES TO FOP

  Antibody that blocks the IL-1β pro-inflammatory cytokine. This is FDA approved in children >=4 years of age for treatment of CAPS, Muckel-Well’s syndrome, and FCAS. In an FOP uncontrolled case series of 4 patients by Haviv, et al., 2024, flare activity was reduced by 61–89%.

  DOSING

  Follow FMF dosing regimen. At <40 kg weight, start at 2 mg/kg every 4 weeks. Can increase to 4 mg/kg. For > 40 kg, start at 150 mg every 4 weeks. Maximum dose 300 mg sq every 4 weeks (maximum dose used for FMF)

  MAJOR SIDE EFFECTS

  Increased risk of serious infection.

  Prior to starting, evaluate for high risk infections, including TB screening.

  Live vaccines are contraindicated.

  There is no information about use in pregnancy or lactation and limited information about use in adults with FOP.

CLASS III MEDICATIONS

• ACVR1/ALK2 Signal Transduction Inhibitor (STI)

  TRADE

  Saracatinib (Astra Zeneca; STOPFOP Investigators)

  CLASS

  Signal Transduction Inhibitor

  PROPOSED MECHANISM OF ACTION AS IT RELATES TO FOP

  Blocks ACVR1/ALK2 signal transduction

  DOSING

  Not applicable at present time; Ongoing Phase II clinical trial

  MAJOR SIDE EFFECTS

  See:
  www.clinicaltrials.gov

  www.ifopa.org/ongoing_clinical_trials_in_fop

• ACVR1/ALK2 Signal Transduction Inhibitor (STI)

  TRADE

  IPN60130 (Ipsen) – FALKON trial

  CLASS

  Signal Transduction Inhibitor

  PROPOSED MECHANISM OF ACTION AS IT RELATES TO FOP

  Blocks ACVR1/ALK2 signal transduction

  DOSING

  Not applicable at present time; Ongoing Phase II clinical trial

  MAJOR SIDE EFFECTS

  See:
  www.clinicaltrials.gov

  www.ifopa.org/ongoing_clinical_trials_in_fop

• ACVR1/ALK2 Signal Transduction Inhibitor (STI)

  TRADE

  INCB000928 (Incyte) – PROGRESS trial

  CLASS

  Signal Transduction Inhibitor

  PROPOSED MECHANISM OF ACTION AS IT RELATES TO FOP

  Blocks ACVR1/ALK2 signal transduction

  DOSING

  Not applicable at present time; Ongoing Phase II clinical trial

  MAJOR SIDE EFFECTS

  See:
  www.clinicaltrials.gov

  www.ifopa.org/ongoing_clinical_trials_in_fop

• mTOR Inhibitors

  TRADE

  Rapamycin (Kyoto University)

  CLASS

  mTOR Inhibitor

  PROPOSED MECHANISM OF ACTION AS IT RELATES TO FOP

  Inhibits ACVR1/ALK2 signal transduction

  DOSING

  Not applicable at present time; Ongoing Phase II clinical trial

  MAJOR SIDE EFFECTS

  Not yet determined

• Monoclonal Antibody Against Activin A

  TRADE

  Garetosmab (Regeneron)

  CLASS

  Activin A Antibody

  PROPOSED MECHANISM OF ACTION AS IT RELATES TO FOP

  Blocks Activin A signaling through mutant ACVR1/ALK2

  DOSING

  Not applicable at Present time; Ongoing Phase III clinical trial

  MAJOR SIDE EFFECTS

  See:
  www.clinicaltrials.gov

  www.ifopa.org/ongoing_clinical_trials_in_fop

• Monoclonal Antibody Against MMP-9

  TRADE

  Andecaliximab (āshibio)

  CLASS

  MMP-9 Antibody

  PROPOSED MECHANISM OF ACTION AS IT RELATES TO FOP

  Reduces Activin-A release from macrophages and matrix stores; likely multimodal actions on all HO factors

  DOSING

  Not applicable at Present time; Phase II/III clinical trial

  MAJOR SIDE EFFECTS

  See: Sandborn WJ, et al. Aliment Pharmacol Ther. 2016; 44(2): 157-69; Gossage DL, et al. Clin Ther. 2018; 40(1): 156-65; Sanbor WJ, et al. J Crohn’s Colitis. 2018; 12(9): 1021-9