PYRUKYND mitapivat 20 mg Tablet, Film Coated
🆔 Identity & classification
Where does this data come from?
🏷️ RxNorm drug class
This medicine belongs to the Pyruvate Kinase Activator class.
Where does this data come from?
🏭 Manufacturer & labeler
Where does this data come from?
🩺 Clinical
- That depends on which brand you've been prescribed. If you're taking Pyrukynd, it's treating the underlying cause of your anemia from PK deficiency — it boosts a faulty enzyme in y...
- What exactly is mitapivat supposed to do for me?
- It really depends on which product you're on. If you're taking Pyrukynd, you should never stop it abruptly — stopping suddenly can trigger a rapid and dangerous breakdown of your r...
- Can I just stop taking it if I feel fine or if a side effect bothers me?
Patient education
Supplement & herbal interactions
Some supplements/herbs that may interact with Mitapivat — tap one for details:
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Ask a licensed pharmacist directly — free, answered by our team.
💊 What it looks like
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🧪 Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
💡 Tap an ingredient (hover on desktop) to see what it is and why it’s used.
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UNII M28OL1HH48
Croscarmellose sodium is a plant-based substance derived from cellulose. It acts as a disintegrant, helping tablets and capsules break down quickly in the digestive system so the medicine can be absorbed.
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UNII L06K8R7DQK
A synthetic blue dye approved by the FDA for use in medications and foods. It serves as a colorant to make pills and liquids visually distinct and easier to identify.
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UNII 3NXW29V3WO
Hypromellose is a plant-based thickener made from cellulose. It's used in medicines as a binder to hold ingredients together, a coating for tablets, and a thickener for liquids.
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UNII EWQ57Q8I5X
Lactose monohydrate is a natural sugar derived from milk. It serves as a filler and binder in tablets and capsules, helping create the proper size, texture, and consistency of the medicine.
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UNII 3OWL53L36A
A natural sugar alcohol derived from seaweed or synthesized in the lab. It's used as a filler to add bulk, a sweetener in sugar-free formulas, and a disintegrant to help tablets break apart in the stomach.
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UNII OP1R32D61U
Microcrystalline cellulose is a purified form of cellulose, a natural fiber from plant sources. It acts as a binder and filler in tablets and capsules, helping hold ingredients together and give the medicine its shape and size.
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UNII 7CV7WJK4UI
Sodium stearyl fumarate is a synthetic compound made from stearyl alcohol and fumaric acid. It acts as a lubricant and glidant in tablets and capsules, helping ingredients flow smoothly during manufacturing and preventing sticking.
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UNII 15FIX9V2JP
Titanium dioxide is a bright white mineral powder commonly used as a colorant and opacifying agent. It makes pills and tablets white or lighter in color and helps make coatings non-transparent.
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UNII XHX3C3X673
Triacetin is a clear, oily liquid made from glycerin and acetic acid. It works as a plasticizer and solvent in medicines, helping soften coatings and improve how liquids mix together in formulations.
9 inactive ingredients listed in the exact product block matched to this NDC.
Where does this data come from?
ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.Inactive ingredient FAQ
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💲 Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per each | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | Not in the retail survey — common for institutional, discontinued, or low-volume packs. | |
| Medicaid paysCMS SDUD · 12 mo | No recent Medicaid claims on file for this NDC — rare and low-volume NDCs are suppressed in the public data. | |
| Medicare drug plans payPart D · Q2 2026 | $479.82 | $26,869.67 / 56 tablets |
Where does this data come from?
🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Pyrukynd 20 mgthis 71334-0210-20 | Agios | 14 tablets | — | — | FDA listed | — |
Where does this data come from?
⏳ Availability & generic status
We did not find an FDA-approved generic match for this exact strength, form and route. Patent/protection dates below may affect future generic timing.
Why the date isn’t exact: Generic timing can change because patents may be challenged, settled, licensed, added, removed, or worked around with a narrower label — and FDA approval does not always mean a pharmacy can get the generic today.
🛈 What do these terms mean?
- Patent
- Legal protection listed in the Orange Book that may delay generic approval or launch. Issued by the U.S. Patent & Trademark Office.
- Substance patent
- Covers the active drug molecule itself — the hardest to design around. A generic generally can’t launch until it expires.
- Formulation (product) patent
- Covers a specific formulation or dosage form. A generic can sometimes work around it with a different formulation.
- Method-of-use patent
- A patent covering one specific approved use of the drug — not necessarily the whole molecule. A generic can sometimes launch with a “skinny label” that carves out the protected use and keeps the others.
- Skinny label
- A generic label that omits a still-patented use when the FDA allows it — letting a generic reach the market for the unprotected uses.
- Exclusivity
- FDA-granted marketing protection, separate from patents — e.g. 5-yr new chemical entity, 7-yr orphan drug, or a +6-month pediatric extension.
- Paragraph IV
- A generic applicant’s formal challenge to a listed patent. It can potentially lead to earlier generic entry, but often involves litigation or a settlement.
- RLD / RS
- Reference Listed Drug — the brand product the FDA uses as the reference for generic applications. Reference Standard — the product the FDA expects generics to compare against in bioequivalence testing.
- TE / AB rating
- FDA therapeutic-equivalence rating. An AB rating generally means the FDA considers a generic therapeutically equivalent to — and substitutable for — the brand.
- LOE (loss of exclusivity)
- The latest patent or exclusivity currently listed — the loss-of-exclusivity / latest-listed-protection date shown on this page. Paragraph-IV challenges and settlements can move the real date earlier; FDA approval and a manufacturer’s decision to market can move it later.
Built from the FDA Orange Book. The bars above are scaled to each protection’s expiry; the red LOE marker is the last one to lapse.
| Patent | Type | Use code | Expires |
|---|---|---|---|
| US 11878049 ↗ | Method of use | U-4390 | Jul 31, 2041 |
| US 10632114 ↗ | Method of use | U-4391 | May 3, 2032 |
| US 9682080 ↗ | Method of use | U-4392 | May 3, 2032 |
| US 9193701 ↗ | Method of use | U-4393 | Oct 26, 2032 |
| US 11878049 ↗ | Method of use | U-3782 | Jul 31, 2041 |
| US 11878049 ↗ | Method of use | U-3782 | Jul 31, 2041 |
| US 11878049 ↗ | Method of use | U-3782 | Jul 31, 2041 |
| US 11793806 ↗ | Method of use | U-3320 | Apr 12, 2033 |
| US 11793806 ↗ | Method of use | U-3320 | Apr 12, 2033 |
| US 11793806 ↗ | Method of use | U-3320 | Apr 12, 2033 |
| US 9193701 ↗ | Method of use | U-3319 | Oct 26, 2032 |
| US 9193701 ↗ | Method of use | U-3319 | Oct 26, 2032 |
| US 9193701 ↗ | Method of use | U-3319 | Oct 26, 2032 |
| US 9682080 ↗ | Method of use | U-3319 | May 3, 2032 |
| US 9682080 ↗ | Method of use | U-3319 | May 3, 2032 |
| US 9682080 ↗ | Method of use | U-3319 | May 3, 2032 |
| US 9980961 ↗ | Method of use | U-3319 | May 3, 2032 |
| US 9980961 ↗ | Method of use | U-3319 | May 3, 2032 |
| US 9980961 ↗ | Method of use | U-3319 | May 3, 2032 |
| US 10632114 ↗ | Method of use | U-3320 | May 3, 2032 |
| US 10632114 ↗ | Method of use | U-3320 | May 3, 2032 |
| US 10632114 ↗ | Method of use | U-3320 | May 3, 2032 |
| US 11234976 ↗ | Method of use | U-3321 | Oct 11, 2038 |
| US 11234976 ↗ | Method of use | U-3321 | Oct 11, 2038 |
| US 11234976 ↗ | Method of use | U-3321 | Oct 11, 2038 |
| US RE49582 ↗ | Drug substance | — | Apr 11, 2035 |
| US RE49582 ↗ | Drug substance | — | Apr 11, 2035 |
| US RE49582 ↗ | Drug substance | — | Apr 11, 2035 |
| US RE49582 ↗ | Drug substance | — | Apr 11, 2035 |
| US 11254652 ↗ | Drug substance | — | Nov 21, 2038 |
| US 11254652 ↗ | Drug substance | — | Nov 21, 2038 |
| US 11254652 ↗ | Drug substance | — | Nov 21, 2038 |
| US 11254652 ↗ | Drug substance | — | Nov 21, 2038 |
| Code | What it grants | Expires |
|---|---|---|
| NCE | New Chemical Entity (5-year) | Feb 17, 2027 |
| ODE-392 | Orphan Drug Exclusivity (7-year) | Feb 17, 2029 |
| NCE | New Chemical Entity (5-year) | Feb 17, 2027 |
| ODE-392 | Orphan Drug Exclusivity (7-year) | Feb 17, 2029 |
| NCE | New Chemical Entity (5-year) | Feb 17, 2027 |
| ODE-392 | Orphan Drug Exclusivity (7-year) | Feb 17, 2029 |
| NCE | New Chemical Entity (5-year) | Feb 17, 2027 |
| NP | New Product | Dec 23, 2028 |
| ODE-522 | Orphan Drug Exclusivity (7-year) | Dec 23, 2032 |
Is there a generic version of PYRUKYND 20 MG TABLET?
The FDA approved a generic — why can’t I get it at my pharmacy yet?
Why do different websites show different generic release dates?
What does “FDA listed” mean?
What does a patent or protection date mean here?
What does “current Orange Book estimate” mean?
Can a generic come out before the last patent expires?
Can a generic come out after the listed dates?
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Where does this data come from?
📊 Medicare Part D spend CMS · PART D · 2026 (Q1)
🔬 Reported adverse events (FAERS)
Top reported reactions
Age at onset
Reporter sex
Serious outcomes
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📦 Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Status |
|---|---|---|---|
| 71334-0210-20 You're viewing this | 4 BLISTER PACK in 1 CARTON (71334-210-20) / 14 TABLET, FILM COATED in 1 BLISTER PACK (71334-210-14) | 2022-02-18 | Active |
🧭 About this NDC listing & data coverage
What data is (and isn’t) available for this NDC — tap to expand
| NDC identity (package / product / labeler codes) | ✓ Available |
| Labeler | ✓ Available |
| Product & package description | ✓ Available |
| Marketing category & status | ✓ Available |
| Active ingredient / dosage form / route | ✓ Available |
| FDA label (SPL via DailyMed) | ✓ Available |
| Package photos | ✓ Available |
| Inactive ingredients (structured) | ✓ Available |
| NADAC pharmacy acquisition price (CMS) | — Not published for this NDC CMS publishes NADAC only for NDCs reported in its retail-pharmacy survey. |
| Orange Book / therapeutic-equivalence data | ✓ Available |
| HCPCS J-code billing crosswalk | — Not published for this NDC Most self-administered / retail products have no J-code — that is normal. |
| Medicaid utilization (CMS SDUD) | — Not published for this NDC CMS reports utilization only for NDCs with Medicaid claims above its privacy threshold. |
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📄 Full prescribing information FDA SPL
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE PYRUKYND is indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency. PYRUKYND is a pyruvate kinase activator indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency. ( 1 )
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION Starting dosage: 5 mg orally twice daily with or without food. ( 2.1 ) See Full Prescribing Information for dose titration and taper schedule. ( 2.1 , 2.3 ) The tablet should be swallowed whole. ( 2.1 )
2.1Recommended Dose PYRUKYND is taken with or without food and swallowed whole. Do not split, crush, chew, or dissolve the tablets. The starting dosage for PYRUKYND is 5 mg orally twice daily.
To gradually increase hemoglobin (Hb), titrate PYRUKYND from 5 mg twice daily to 20 mg twice daily, and then to the maximum recommended dose of 50 mg twice daily, with these dose increases occurring every 4 weeks (see Table 1). Assess Hb and transfusion requirement before increasing to the next dose level, as some patients may reach and maintain normal Hb at 5 mg twice daily or 20 mg twice daily. Discontinue PYRUKYND if no benefit has been observed by 24 weeks, based on the hemoglobin and hemolysis laboratory results and transfusion requirements.
Table 1: Dose Titration Schedule Duration Dosage Week 1 through Week 4 5 mg twice daily Week 5 through Week 8 If Hb is below normal range or patient has required a transfusion within the last 8 weeks: Increase to 20 mg twice daily and maintain for 4 weeks. If Hb is within normal range and patient has not required a transfusion within the last 8 weeks: Maintain 5 mg twice daily. Week 9 through Week 12 If Hb is below normal range or patient has required a transfusion within the last 8 weeks: Increase to 50 mg twice daily and maintain thereafter.
If Hb is within normal range and patient has not required a transfusion within the last 8 weeks: Maintain current dose (5 mg twice daily or 20 mg twice daily). Maintenance If Hb decreases, consider up-titration to the maximum of 50 mg twice daily as per the above schedule.
2.2Missed Dose If a dose of PYRUKYND is missed by 4 hours or less, administer the dose as soon as possible. If a dose of PYRUKYND is missed by more than 4 hours, do not administer a replacement dose, and wait until the next scheduled dose. Subsequently, return to the normal dosing schedule.
2.3Interruption or Discontinuation To reduce the risk of acute hemolysis, avoid abrupt interruption or abrupt discontinuation of PYRUKYND when possible [see Warnings and Precautions (5.1) ] . Taper the dose to gradually discontinue the medication (see Table 2). Monitor patients for signs of acute hemolysis and worsening of anemia.
Table 2 Dose Taper Schedule Current Dose Dose Taper Schedule Day 1-7 Day 8-14 Day 15 5 mg twice daily 5 mg once daily Discontinue N/A 20 mg twice daily 20 mg once daily 5 mg once daily Discontinue 50 mg twice daily 50 mg once daily 20 mg once daily Discontinue Abbreviations: N/A = not applicable.
2.4Recommended Dosage for Drug Interactions Strong CYP3A Inhibitors Avoid co-administration of strong CYP3A inhibitors with PYRUKYND [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . Moderate CYP3A Inhibitors Monitor Hb and for increased risks of adverse reactions from PYRUKYND. When used with a moderate CYP3A inhibitor, do not titrate PYRUKYND beyond 20 mg twice daily [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] .
Strong CYP3A Inducers Avoid co-administration of strong CYP3A inducers with PYRUKYND [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . Moderate CYP3A Inducers Consider alternative therapies that are not moderate CYP3A inducers during treatment with PYRUKYND. If there are no alternative therapies, monitor Hb and titrate beyond the 50 mg twice daily dose, if necessary, but do not exceed a maximum recommended dose of 100 mg twice daily [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] .
2.5Dose Modifications for Adverse Reactions and Hemoglobin Levels Above Normal If a dose reduction is required because of an adverse reaction or tolerability, or for Hb above normal, the dose may be reduced to the next lower dose level, 20 mg twice daily or 5 mg twice daily. If a patient needs to…
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS 5 mg tablets: round, blue, film-coated tablets with "M5" printed on one side. 20 mg tablets: round, blue, film-coated tablets with "M20" printed on one side. 50 mg tablets: oblong, blue, film-coated tablets with "M50" printed on one side. Tablets: 5 mg, 20 mg, and 50 mg. ( 3 )
⛔ Contraindications ▾
4 CONTRAINDICATIONS None None ( 4 )
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS Acute Hemolysis: Avoid abrupt interruption or abrupt discontinuation of PYRUKYND to minimize the risk of acute hemolysis. A gradual reduction in dosing rather than abrupt cessation is recommended when possible. ( 5.1 ) Hepatocellular Injury in Another Condition: Obtain liver tests prior to the initiation of PYRUKYND and monthly thereafter for the first 6 months and as clinically indicated.
Interrupt PYRUKYND if clinically significant increases in liver tests are observed or alanine aminotransferase is >5 times the upper limit of normal (ULN). Discontinue PYRUKYND if hepatic injury due to PYRUKYND is suspected. ( 5.2 )
5.1Acute Hemolysis with Abrupt Treatment Interruption Acute hemolysis with subsequent anemia has been observed following abrupt interruption or discontinuation of PYRUKYND in a dose-ranging study. Avoid abruptly discontinuing PYRUKYND. Gradually taper the dose of PYRUKYND to discontinue treatment if possible [see Dosage and Administration ( 2.3 , 2.6 )] .
When discontinuing treatment, monitor patients for signs of acute hemolysis and anemia including jaundice, scleral icterus, dark urine, dizziness, confusion, fatigue, or shortness of breath .
5.2Hepatocellular Injury in Another Condition In patients with another condition treated with mitapivat at a higher dose than that recommended for patients with PK deficiency, liver injury has been observed. These events were characterized by a time to onset within the first 6 months of treatment with peak elevations of alanine aminotransferase of >5×ULN with or without jaundice. All patients discontinued treatment with PYRUKYND, and these events improved upon treatment discontinuation.
Obtain liver tests prior to the initiation of PYRUKYND and monthly thereafter for the first 6 months and as clinically indicated. Interrupt PYRUKYND if clinically significant increases in liver tests are observed or alanine aminotransferase is >5 times the upper limit of normal (ULN). Discontinue PYRUKYND if hepatic injury due to PYRUKYND is suspected.
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS The following clinically significant adverse reaction is described elsewhere in labeling: Acute Hemolysis with Abrupt Treatment Discontinuation [see Warn ings and Preca utions (5.1) ]. Hepatocellular Injury in Another Condition [see Warnings and Precautions (5.2) ] . The most common adverse reactions including laboratory abnormalities (≥ 10%) in patients with PK deficiency were estrone decreased (males), increased urate, back pain, estradiol decreased (males), and arthralgia.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Agios Pharmaceuticals at 1-833-228-8474 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 155 patients received PYRUKYND, 79% of whom were exposed for longer than 24 weeks. PYRUKYND was administered up to 50 mg orally twice daily in 67 patients with PK deficiency in the ACTIVATE trial (N=40) and the ACTIVATE-T trial (N=27) [see Clinical Studies (14) ] .
ACTIVATE Trial In the ACTIVATE trial patients with PK deficiency who were not regularly transfused received PYRUKYND in incremental doses up to 50 mg twice daily (N=40) or placebo (N=39). Serious adverse reactions occurred in 10% of patients receiving PYRUKYND in the ACTIVATE Trial, including atrial fibrillation, gastroenteritis, rib fracture, and musculoskeletal pain, which each occurred in 1 patient. In the ACTIVATE trial, the most common adverse reactions including laboratory abnormalities (≥10%) in patients with PK deficiency were estrone decreased (males), increased urate, back pain, estradiol decreased (males), and arthralgia.
Table 3 summarizes the adverse reactions in the ACTIVATE trial. Table 3: Adverse Reactions (≥ 5%) in Patients Receiving PYRUKYND in ACTIVATE PYRUKYND (N=40) Placebo (N=39) Adverse Reaction All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%) Back pain a 15% 0 8% 0 Arthralgia b 10% 0 5% 0 Hypertriglyceridemia c 8% 5% 3% 0 Gastroenteritis 8% 3% 0 0 Hot flush d 8% 0 0 0 Oropharyngeal pain 8% 0 5% 0 Hypertension 5% 5% 0 0 Arrhythmia e 5% 0 0 0 Breast discomfort 5% 0 0 0 Constipation 5% 0 0 0 Dry mouth f 5% 0 0 0 Paresthesia 5% 0 0 0 Grades: Per the CTCAE definition.
Grouped Term Definitions a Includes back pain, sciatica, and flank pain. b Includes arthralgia and joint swelling. c Includes hypertriglyceridemia and blood triglycerides increased. d Includes hot flush and flushing. e Includes arrhythmia, tachycardia, heart rate increased and atrial fibrillation. f Includes dry mouth and dry lip. Laboratory abnormalities of PYRUKYND included increased urate (15%). Variations in Reproductive Hormones In ACTIVATE, increases in serum testosterone and decreases in serum estrone and estradiol were observed in men receiving PYRUKYND (Table 4).
These changes in hormones persisted throughout the study period. In patients who discontinued PYRUKYND and had follow-up hormone measurements, the hormone changes returned close to the baseline levels 28 days after discontinuing PYRUKYND. In female patients, sex hormone analysis was limited due to physiologic variations in hormones during the menstrual cycle and the use of hormonal contraceptives.
Table 4: Laboratory Abnormalities in Reproductive Hormones in Men Receiving PYRUKYND ACTIVATE Parameter PYRUKYND (16 males) n (%) Placebo (15 males)n (%) Reproductive hormone analyses a Estrone decreased (males) Estradiol decreased (males) Blood testosterone increased (males) 9 (56.3) 2 (12.5) 1 (6.3) 0 1 (6.7) 1 (6.7) a Decreases in estrone and estradiol to below the lower limit of the reference range and increases in testosterone to above the upper limit of the reference range where baseline was within normal limits.
ACTIVATE-T Trial The adverse reactions reported in the population…
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS Strong CYP3A Inhibitors and Inducers: Avoid concomitant use. ( 7.1 ) Moderate CYP3A Inhibitors: Do not titrate PYRUKYND beyond 20 mg twice daily. ( 7.1 ) Moderate CYP3A Inducers: Consider alternatives that are not moderate inducers.
If there are no alternatives, adjust PYRUKYND dosage. ( 7.1 ) Sensitive CYP3A, CYP2B6, CYP2C substrates including hormonal contraceptives: Avoid concomitant use with substrates that have narrow therapeutic index. ( 7.2 ) UGT1A1 Substrates: Avoid concomitant use with substrates that have narrow therapeutic index.
( 7.2 ) P-gp Substrates: Avoid concomitant use with substrates that have narrow therapeutic index. ( 7.2 )
7.1Effect of Other Drugs on PYRUKYND Strong CYP3A Inhibitors Clinical Impact Co-administration of PYRUKYND with strong CYP3A inhibitors increased mitapivat plasma concentrations [see Clinical Pharmacology (12.3) ] . Increased mitapivat plasma concentrations may increase the risks of adverse reactions of PYRUKYND. Prevention or Management Avoid co-administration of strong CYP3A inhibitors with PYRUKYND [see Dosage and Administration (2.5) ] .
Moderate CYP3A Inhibitors Clinical Impact Co-administration of PYRUKYND with moderate CYP3A inhibitors will increase mitapivat plasma concentrations [see Clinical Pharmacology (12.3) ] . Prevention or Management Monitor Hb and for increased risks of adverse reactions with PYRUKYND. Do not titrate PYRUKYND beyond 20 mg twice daily [see Dosage and Administration (2.5) ] .
Strong CYP3A Inducers Clinical Impact Co-administration of PYRUKYND with strong CYP3A inducers decreased mitapivat plasma concentrations [see Clinical Pharmacology (12.3) ] . Decreased mitapivat plasma concentrations will reduce the efficacy of PYRUKYND. Prevention or Management Avoid co-administration of strong CYP3A inducers with PYRUKYND [see Dosage and Administration (2.5) ] .
Moderate CYP3A Inducers Clinical Impact Co-administration of PYRUKYND with moderate CYP3A inducers will decrease mitapivat plasma concentrations [see Clinical Pharmacology (12.3) ] . Prevention or Management Consider alternative therapies that are not moderate CYP3A inducers during treatment with PYRUKYND. If there are no alternative therapies, monitor Hb and titrate beyond 50 mg twice daily, if necessary, but do not exceed a maximum recommended dose of 100 mg twice daily [see Dosage and Administration (2.5) ] .
7.2Effect of PYRUKYND on Other Drugs CYP3A Substrates Clinical Impact PYRUKYND induces CYP3A. Co-administration of PYRUKYND will decrease systemic concentrations of drugs that are sensitive CYP3A substrates, including hormonal contraceptives (e.g., ethinyl estradiol) [see Clinical Pharmacology (12.3) ] . Prevention or Management Monitor patients for loss of therapeutic effect of sensitive CYP3A substrates with narrow therapeutic index when co- administered with PYRUKYND.
Advise patients using hormonal contraceptives to use an alternative non-hormonal contraceptive method or add a barrier method of contraception during treatment with PYRUKYND. CYP2B6 and CYP2C Substrates Clinical Impact PYRUKYND induces CYP2B6, CYP2C8, CYP2C9, and CYP2C19 enzymes in vitro , and may decrease systemic concentrations of drugs that are sensitive substrates of these enzymes [see Clinical Pharmacology (12.3) ] . Prevention or Management Monitor patients for loss of therapeutic effect of sensitive substrates of these enzymes with narrow therapeutic index when co-administered with PYRUKYND.
UGT1A1 Substrates Clinical Impact PYRUKYND induces UGT1A1 in vitro and may decrease systemic concentrations of drugs that are UGT1A1 substrates [see Clinical Pharmacology (12.3) ] . Prevention or Management Monitor patients for loss of therapeutic effect of UGT1A1 substrates with narrow therapeutic index when co-administered with PYRUKYND. P-gp Substrates Clinical Impact PYRUKYND inhibits the P-gp transporter in vitro and may increase systemic concentrations of drugs that are P-gp substrates [see Clinical Pharmacolo…
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS Hepatic Impairment: Avoid use of PYRUKYND in patients with moderate or severe hepatic impairment. ( 8.6 )
8.1Pregnancy Risk Summary Available data from clinical trials of PYRUKYND are insufficient to evaluate for a drug- associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, mitapivat orally administered twice daily to pregnant rats and rabbits during organogenesis was not teratogenic at doses up to 13 and 3 times the maximum recommended human dose (MRHD) of 50 mg twice daily, respectively. Mitapivat administered orally to pregnant rats twice daily during organogenesis through lactation did not result in adverse developmental effects at doses up to 13 times the MRHD ( see Data ).
The estimated background risk of major birth defects for the indicated population is unknown. Estimated frequencies for other important background risks in the population are as follows: miscarriage 18%, growth retardation 24%, preterm birth 56%. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal Risk Untreated PK deficiency in pregnant women may precipitate acute hemolysis, pre-term labor, miscarriage and severe anemia requiring frequent transfusion. Additionally, preeclampsia and severe hypertension have been reported.
Data Animal Data In an embryo-fetal development study in rats, mitapivat was administered at doses of 5, 10, 25, and 100 mg/kg twice daily by oral gavage during the period of organogenesis (gestation days 6 to 17). There was a statistically significant 14% decrease in maternal net body weight gain at the high dose with associated decrease in food consumption. Enlarged or fused placenta and/or a distended amniotic sac, an increase in post-implantation loss (early and late resorptions), a decrease in the mean number of viable fetuses, lower mean fetal weights, and external, visceral, and skeletal malformations were observed at the high dose (100 mg/kg twice daily, 63 times the MRHD, based on area under the plasma drug concentration-time curve [AUC]).
No maternal or embryo-fetal toxicity was observed up to 25 mg/kg twice daily (13 times the MRHD, based on AUC). In an embryo-fetal development study in rabbits, mitapivat was administered at doses of 12.5, 30, and 62.5 mg/kg twice daily by oral gavage during the period of organogenesis (gestation days 7 to 20). Lower fetal weight was observed at 62.5 mg/kg twice daily (3 times MRHD, based on AUC) and correlated with reduced maternal body weight gain.
No effects on fetal morphology were observed. In a pre- and post-natal development study in rats, mitapivat was administered at doses of 5, 10, 25, and 100 mg/kg twice daily by oral gavage during the period of organogenesis and continuing to weaning (gestation day 7 to lactation day 20). Dystocia was observed at ≥25 mg/kg twice daily (≥13x MRHD, based on AUC).
At 100 mg/kg twice daily (63x MRHD, based on AUC) decreased maternal body weight gain, prolonged parturition, and dystocia occurred and resulted in maternal mortality, complete litter loss, decreased pup viability and decreased pup body weight. No adverse effects on pup growth and development, and reproductive performance were observed up to 50 mg/kg (13 times the MRHD, based on AUC).
8.2Lactation Risk Summary There are no data on the presence of PYRUKYND or its metabolites in human or animal milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PYRUKYND and any potential adverse effects on the breastfed child from PYRUKYND or from the underlying maternal condition.
8.4 Pediatric U…
🤰 Pregnancy ▾
8.1Pregnancy Risk Summary Available data from clinical trials of PYRUKYND are insufficient to evaluate for a drug- associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, mitapivat orally administered twice daily to pregnant rats and rabbits during organogenesis was not teratogenic at doses up to 13 and 3 times the maximum recommended human dose (MRHD) of 50 mg twice daily, respectively. Mitapivat administered orally to pregnant rats twice daily during organogenesis through lactation did not result in adverse developmental effects at doses up to 13 times the MRHD ( see Data ).
The estimated background risk of major birth defects for the indicated population is unknown. Estimated frequencies for other important background risks in the population are as follows: miscarriage 18%, growth retardation 24%, preterm birth 56%. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal Risk Untreated PK deficiency in pregnant women may precipitate acute hemolysis, pre-term labor, miscarriage and severe anemia requiring frequent transfusion. Additionally, preeclampsia and severe hypertension have been reported.
Data Animal Data In an embryo-fetal development study in rats, mitapivat was administered at doses of 5, 10, 25, and 100 mg/kg twice daily by oral gavage during the period of organogenesis (gestation days 6 to 17). There was a statistically significant 14% decrease in maternal net body weight gain at the high dose with associated decrease in food consumption. Enlarged or fused placenta and/or a distended amniotic sac, an increase in post-implantation loss (early and late resorptions), a decrease in the mean number of viable fetuses, lower mean fetal weights, and external, visceral, and skeletal malformations were observed at the high dose (100 mg/kg twice daily, 63 times the MRHD, based on area under the plasma drug concentration-time curve [AUC]).
No maternal or embryo-fetal toxicity was observed up to 25 mg/kg twice daily (13 times the MRHD, based on AUC). In an embryo-fetal development study in rabbits, mitapivat was administered at doses of 12.5, 30, and 62.5 mg/kg twice daily by oral gavage during the period of organogenesis (gestation days 7 to 20). Lower fetal weight was observed at 62.5 mg/kg twice daily (3 times MRHD, based on AUC) and correlated with reduced maternal body weight gain.
No effects on fetal morphology were observed. In a pre- and post-natal development study in rats, mitapivat was administered at doses of 5, 10, 25, and 100 mg/kg twice daily by oral gavage during the period of organogenesis and continuing to weaning (gestation day 7 to lactation day 20). Dystocia was observed at ≥25 mg/kg twice daily (≥13x MRHD, based on AUC).
At 100 mg/kg twice daily (63x MRHD, based on AUC) decreased maternal body weight gain, prolonged parturition, and dystocia occurred and resulted in maternal mortality, complete litter loss, decreased pup viability and decreased pup body weight. No adverse effects on pup growth and development, and reproductive performance were observed up to 50 mg/kg (13 times the MRHD, based on AUC).
🧒 Pediatric Use ▾
8.4Pediatric Use Safety and effectiveness in pediatric patients have not been established.
🧓 Geriatric Use ▾
8.5Geriatric Use Clinical studies of PYRUKYND did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action Mitapivat is a pyruvate kinase activator that acts by allosterically binding to the pyruvate kinase tetramer and increasing pyruvate kinase (PK) activity. The red blood cell (RBC) form of pyruvate kinase (PK-R) is mutated in PK deficiency, which leads to reduced adenosine triphosphate (ATP), shortened RBC lifespan, and chronic hemolysis.
12.2Pharmacodynamics Mitapivat decreases 2,3 diphosphoglycerate (2,3-DPG) and increases ATP in healthy volunteers. Cardiac Electrophysiology At a dose 6 times the maximum recommended dose, mitapivat did not prolong the QT interval to any clinically relevant extent.
12.3Pharmacokinetics Mitapivat exposure increased in an approximately dose proportional manner over the clinically relevant dose range of 5 mg to 50 mg twice daily. The population pharmacokinetic model simulated Cmax, Ctrough, AUC0-12 and accumulation ratio of mitapivat at recommended dosages are listed in the table below. Table 5: Steady State Mitapivat Exposure at Recommended Dosages a Mitapivat Dosage C max (ng/mL) C trough (ng/mL) AUC 0-12 (ng*h/mL) Accumulation Ratio 5 mg twice daily 101.2 (17%) 10.1 (74%) 450.4 (28%) 1.2 20 mg twice daily 389.9 (18%) 32.3 (77%) 1623.8 (28%) 1.1 50 mg twice daily 935.2 (18%) 62.1 (80%) 3591.4 (28%) 1.0 a Pharmacokinetic parameters are presented as geometric mean (CV%).
The simulations were performed until 100 days after first dose. The interval of the last 12 hours was selected for steady state PK parameters calculation. Residual error was not included during simulation.
Absorption Median t max values at steady state were 0.5 to 1.0 hour post-dose across the dose range of 5 mg to 50 mg twice daily. The absolute bioavailability after a single dose was approximately 73%. Effect of Food Following administration of a single dose of PYRUKYND in healthy subjects, a high-fat meal (approximately 900 to 1,000 total calories, with 500 to 600 calories from fat, 250 calories from carbohydrate, and 150 calories from protein) did not change the exposure (AUC inf ) of mitapivat, but reduced the rate of mitapivat absorption, with a 42% reduction in C max and a delay in t max of 2.3 hours when compared to dosing under fasted conditions.
Distribution Mitapivat is highly protein bound (97.7%) in plasma with low RBC distribution (RBC-to-plasma ratio of 0.37). The mean volume of distribution at steady state (Vss) was
42.5L. Elimination The mean effective half-life (t1/2) of mitapivat ranged from 3 to 5 hours following multiple dose administrations of 5 mg twice daily to 20 mg twice daily in patients with PK deficiency. Population pharmacokinetics derived median CL/F at steady state was 11.5, 12.7, and
14.4L/h for the 5 mg twice daily, 20 mg twice daily, and 50 mg twice daily regimens, respectively. Metabolism In vitro studies showed that mitapivat is primarily metabolized by CYP3A4. Following a single oral dose of 120 mg of radiolabeled mitapivat to healthy subjects, unchanged mitapivat was the major circulating component.
Excretion After a single oral administration of radiolabeled mitapivat to healthy subjects, the total recovery of administered radioactive dose was 89.2%, with 49.6% in the urine (2.6% unchanged) and 39.6% in the feces (<1% unchanged). Specific Populations No clinically meaningful effects on the pharmacokinetics of mitapivat were observed based on age, sex, race, or body weight. Pediatric Population The pharmacokinetics of mitapivat in children and adolescents (˂18 years old) have not been studied.
Hepatic Impairment Mitapivat undergoes extensive hepatic metabolism. The pharmacokinetics of mitapivat were studied in adult subjects with moderate hepatic impairment (Child-Pugh Class B). After a single oral administration of 50 mg mitapivat, subjects with moderate hepatic impairment demonstrated 36% greater exposure (AUC ∞ ) to mitapivat, compared to subjects with normal hepatic function.
Geometric mean C max values were similar between the groups…
🧬 Mechanism of Action ▾
12.1Mechanism of Action Mitapivat is a pyruvate kinase activator that acts by allosterically binding to the pyruvate kinase tetramer and increasing pyruvate kinase (PK) activity. The red blood cell (RBC) form of pyruvate kinase (PK-R) is mutated in PK deficiency, which leads to reduced adenosine triphosphate (ATP), shortened RBC lifespan, and chronic hemolysis.
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied PYRUKYND 28-Day Packs Tablet Strength Description Imprint NDC 5 mg Round, blue, film-coated tablets "M5" printed on one side 71334-205-05 20 mg Round, blue, film-coated tablets "M20" printed on one side 71334-210-20 50 mg Oblong, blue, film-coated tablets "M50" printed on one side 71334-215-50 PYRUKYND Taper Packs Tablet strength(s) Blister Wallet Configuration Tablet Description Imprint NDC 5 mg 5 mg blister wallet containing 7 tablets round, blue, film-coated tablets "M5" printed on one side 71334-220-11 20 mg and 5 mg 20 mg blister wallet containing 7 tablets 5 mg blister wallet containing 7 tablets round, blue, film-coated tablets round, blue, film-coated tablets "M20" printed on one side "M5" printed on one side 71334-225-12 50 mg and 20 mg 50 mg blister wallet containing 7 tablets 20 mg blister wallet containing 7 tablets oblong, blue, film- coated tablets round, blue, film-coated tablets "M50" printed on one side "M20" printed on one side 71334-230-13 Storage Store at 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature] .
Store the blister wallets in the original carton until use.
📋 Description ▾
11 DESCRIPTION The active ingredient of PYRUKYND is mitapivat, a pyruvate kinase activator, present as mitapivat sulfate. The chemical name of mitapivat sulfate is 8-quinolinesulfonamide, N-[4-[[4- (cyclopropylmethyl)-1-piperazinyl]carbonyl]phenyl]-, sulfate, hydrate (2:1:3). The chemical structure of mitapivat sulfate is: The molecular formula is (C 24 H 26 N 4 SO 3 ) 2 • H 2 SO 4 • 3H 2 O, and the molecular weight is 1053.23 for mitapivat sulfate.
Mitapivat sulfate is a white to off-white solid and is slightly soluble in water. PYRUKYND is available as 5 mg, 20 mg, and 50 mg tablets for oral administration. Each tablet contains 5 mg, 20 mg, or 50 mg mitapivat free base, provided as 5.85 mg, 23.4 mg, or 58.5 mg, respectively, of the sulfate hydrate salt, and the following inactive ingredients: croscarmellose sodium, mannitol, microcrystalline cellulose, and sodium stearyl fumarate.
The tablet film coating contains the inactive ingredients FD&C Blue No. 2, hypromellose, lactose monohydrate, titanium dioxide, and triacetin. The tablets are imprinted with black ink containing the inactive ingredients ammonium hydroxide, ferrosoferric oxide, isopropyl alcohol, n-butyl alcohol, propylene glycol, and shellac glaze. chemical structure
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Acute Hemolysis with Abrupt Treatment Interruption Inform patients of the risk of developing acute hemolysis and subsequent anemia following abrupt interruption or discontinuation of PYRUKYND. Inform patients to follow their healthcare provider’s instructions for discontinuing PYRUKYND.
Upon discontinuing PYRUKYND, tell patients to immediately report any symptoms suggestive of acute hemolysis including jaundice, scleral icterus, dark urine, dizziness, confusion, fatigue, or shortness of breath to their healthcare provider for further evaluation [see Warnings and Precautions (5.1) ] . Hepatocellular Injury in Another Condition Inform patients of the risk of hepatocellular injury observed in patients with another condition during the first 6 months of treatment with mitapivat at a higher dose than that recommended for patients with PK deficiency.
Tell patients to immediately report any symptoms suggestive of liver injury including jaundice, dark urine, right upper quadrant pain, nausea, vomiting, or loss of appetite to their healthcare provider for further evaluation [see Warnings and Precautions (5.2) ] . Drug Interactions Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications, vitamins, and herbal products [see Drug Interactions (7) ]. Dosing and Storage Instructions Instruct patients to swallow the tablets whole with or without food and not to split, crush, chew, or dissolve the tablets.
Advise patients if a dose of PYRUKYND is missed by 4 hours or less, to take the scheduled dose as soon as possible. If a dose of PYRUKYND is missed by more than 4 hours, advise the patient to not take a replacement dose and wait until the next scheduled dose. PYRUKYND ® is a registered trademark of Agios Pharmaceuticals, Inc. © 2022 Agios Pharmaceuticals, Inc.
Manufactured for and Distributed by: Agios Pharmaceuticals, Inc. Cambridge, MA 02139 AG-PI-004