List of Excipients in Branded Drug ERGOTAMINE TARTRATE, CAFFEINE

Generic Drugs Containing ERGOTAMINE TARTRATE, CAFFEINE

Company	Ingredient	NDC	Excipient
KMM Pharmaceuticals LLC	ergotamine tartrate, caffeine	52187-555	CELLULOSE, MICROCRYSTALLINE
KMM Pharmaceuticals LLC	ergotamine tartrate, caffeine	52187-555	CROSPOVIDONE
KMM Pharmaceuticals LLC	ergotamine tartrate, caffeine	52187-555	FD&C BLUE NO. 2--ALUMINUM LAKE

What are the Most Frequently-Used Excipients in ERGOTAMINE TARTRATE, CAFFEINE?

# Of NDCs	Excipient
1	CELLULOSE, MICROCRYSTALLINE
1	CROSPOVIDONE
1	FD&C BLUE NO. 2--ALUMINUM LAKE

Ergotamine Tartrate and Caffeine Excipient Strategy and Commercial Opportunities

Last updated: August 7, 2026

Ergotamine tartrate/caffeine is an old oral antimigraine combination with limited active-ingredient patent protection and a largely generic commercial profile. The main opportunities are reformulation, supply reliability, dose-form modernization, and regulatory positioning rather than composition-of-matter exclusivity. Excipient selection must address low-dose content uniformity, alkaloid stability, caffeine compatibility, dissolution, palatability, and control of ergot alkaloid exposure.

What is ergotamine tartrate and caffeine used for?

Ergotamine tartrate/caffeine is an antimigraine product combining an ergot alkaloid vasoconstrictor with caffeine. Historical oral products included:

Product type	Typical strength	Historical use
Tablet	Ergotamine tartrate 1 mg plus caffeine 100 mg	Acute migraine treatment
Rectal suppository	Ergotamine tartrate 2 mg plus caffeine 100 mg	Acute migraine treatment
Sublingual ergotamine	Ergotamine tartrate, product-specific strength	Acute migraine treatment

Cafergot was the best-known branded combination. The product was approved decades before modern pharmaceutical patent and exclusivity practices became standard. Its clinical role has declined because triptans, gepants, ditans, and injectable migraine therapies offer alternative safety and administration profiles.[1][2]

The commercial product opportunity is therefore concentrated in low-cost generic supply, niche dosage forms, and differentiated delivery systems.

What is the FDA regulatory status of ergotamine tartrate/caffeine?

The combination has an established U.S. regulatory history, but branded Cafergot is not a current growth product. Historical FDA labeling identified tablets containing 1 mg ergotamine tartrate and 100 mg caffeine, with suppositories containing 2 mg ergotamine tartrate and 100 mg caffeine.[1]

A modern applicant would need to determine whether the intended product can be submitted as:

1. An abbreviated new drug application, if a suitable reference product and dosage form remain available.
2. A 505(b)(2) application, if the product uses a changed formulation, delivery system, route, or dosage form.
3. A full new drug application, if the proposed product cannot rely adequately on an existing reference product.

The regulatory pathway depends heavily on the selected dosage form. A conventional tablet with the same active ingredients may have a different development path from a buccal film, orally disintegrating tablet, nasal product, or modified-release system.

FDA regulatory issues affecting formulation strategy

Key issues include:

• Demonstrating identity, strength, quality, purity, and stability of ergotamine tartrate.
• Controlling low-dose uniformity for ergotamine.
• Establishing dissolution and, where relevant, disintegration performance.
• Managing caffeine-related variability in exposure.
• Confirming bioequivalence against the applicable reference product.
• Controlling ergot alkaloid impurities and degradation products.
• Addressing strong contraindications and drug-interaction warnings in labeling.

Ergotamine is subject to clinically important interactions with potent CYP3A4 inhibitors and other vasoconstrictors. A reformulated product does not remove these safety obligations.[1][3]

What excipients are relevant to ergotamine tartrate/caffeine tablets?

The most commercially practical platform is an immediate-release tablet. The excipient strategy should focus on manufacturability and uniformity rather than complex release control.

Recommended functional excipient categories

Formulation function	Candidate excipient classes	Strategic purpose
Dilution	Microcrystalline cellulose, lactose, mannitol, dibasic calcium phosphate	Provides tablet mass and improves content uniformity
Binding	Povidone, copovidone, pregelatinized starch, hydroxypropyl cellulose	Supports granule and tablet strength
Disintegration	Crospovidone, croscarmellose sodium, sodium starch glycolate	Promotes rapid tablet breakup
Lubrication	Magnesium stearate, sodium stearyl fumarate, stearic acid	Controls ejection and manufacturing friction
Glidancy	Colloidal silicon dioxide, talc	Improves powder flow
Taste masking	Film coating, polymeric coating, sweeteners, flavors	Reduces bitterness and improves patient acceptance
Moisture control	Protective film coating, low-moisture excipient system, desiccant packaging	Limits degradation and potency loss

The principal technical problem is the very low ergotamine dose relative to the total tablet weight. A direct-compression process can create segregation and content-uniformity risks unless particle size, density, geometric dilution, and blend time are tightly controlled.

Wet granulation may improve uniformity and flow, but water exposure must be evaluated against ergotamine stability. Dry granulation can reduce moisture exposure while improving flow and compressibility. Direct compression offers the lowest process complexity but places the greatest burden on powder engineering.

How should excipients address low-dose content uniformity?

Content uniformity is the central formulation issue for ergotamine tartrate/caffeine tablets.

A 1 mg ergotamine dose can represent less than 1% of the tablet mass. Small segregation effects can produce clinically meaningful potency variation. A robust development program should consider:

• Particle-size matching between ergotamine tartrate and the principal filler.
• Pre-dilution of ergotamine with a compatible filler.
• Controlled order of addition during blending.
• Low-shear blending sufficient to disperse the active without causing demixing.
• In-process blend sampling based on a validated sampling plan.
• Avoidance of excessive lubricant blending.
• Container-closure systems that prevent vibration-driven segregation.
• Finished-product testing for dosage-unit uniformity rather than reliance only on assay.

Mannitol and microcrystalline cellulose are attractive for immediate-release systems because they support flow, compactability, and rapid disintegration. Lactose can be commercially useful but requires compatibility and moisture assessment. Dibasic calcium phosphate may improve flow and robustness but can alter compaction and dissolution behavior.

What excipients can improve dissolution and onset?

The historical clinical positioning of ergotamine/caffeine depends on acute migraine use. A slow-dissolving tablet weakens the product’s value proposition.

Crospovidone, croscarmellose sodium, and sodium starch glycolate can support rapid disintegration. The selection should be based on:

• Dissolution across relevant pH conditions.
• Sensitivity to compression force.
• Compatibility with the active ingredients.
• Water uptake and tablet porosity.
• Stability under the proposed packaging conditions.

A highly soluble filler may accelerate wetting, while hydrophobic lubricants can slow dissolution when overused. Magnesium stearate concentration and blending time therefore require tight control.

Caffeine can influence wetting, crystallinity, and blend behavior. Its substantially higher dose may dominate the blend’s physical properties, creating a risk that the low-dose ergotamine fraction segregates during processing. Particle engineering or a separate ergotamine premix can mitigate this risk.

What formulation opportunities exist beyond conventional tablets?

Orally disintegrating tablets

An orally disintegrating tablet could improve use during migraine episodes, particularly for patients with nausea. Mannitol, crospovidone, low-substituted hydroxypropyl cellulose, and taste-masking polymers are common development tools.

The primary challenges are ergotamine bitterness, tablet friability, moisture sensitivity, and the need to prove that the altered dosage form does not create clinically relevant exposure differences.

Sublingual or buccal products

Sublingual or buccal delivery could create differentiation through faster disintegration and reduced dependence on gastrointestinal transit. These products may qualify for 505(b)(2) treatment if they materially change the delivery system.

Commercial barriers include:

• Taste and mucosal irritation.
• Dose loading constraints.
• Uniformity of a low-dose alkaloid.
• Adhesion and residence time.
• Demonstration of comparable or clinically appropriate exposure.
• Greater manufacturing complexity than tablets.

Oral films

A fast-dissolving film could target patients who cannot swallow tablets during a migraine. The active dose is technically feasible, but film uniformity becomes a major issue. Ergotamine may require a separate premix or controlled-solids dispersion to prevent localized potency variation.

Film products also require careful control of residual solvents, moisture, folding endurance, tensile strength, and packaging.

Suppositories

The historical suppository form remains a niche opportunity where oral administration is difficult. A fatty or polyethylene glycol base can be selected according to melting behavior, drug release, and storage stability.

The principal barriers are patient acceptance, manufacturing complexity, supply-chain requirements, and a smaller market than oral products. A suppository may be commercially defensible only where it offers a clear administration advantage.

Nasal delivery

Nasal ergotamine/caffeine could provide rapid administration, but it would be a higher-risk development program. The product would require assessment of nasal tolerability, dose deposition, device performance, absorption variability, and local vasoconstrictive effects. The combination of an old active ingredient and a new route would likely require substantial clinical and regulatory work.

What patents protect ergotamine tartrate and caffeine products?

The active ingredients are old and are not protected by meaningful modern composition-of-matter patents. Historical Cafergot patents and product rights have expired. The commercial patent estate is therefore likely to depend on later-developed claims covering:

• Specific oral films.
• Sublingual or buccal delivery systems.
• Novel particle-size distributions.
• Stabilized ergotamine compositions.
• Taste-masked formulations.
• Fixed-dose combinations with additional migraine agents.
• Device-enabled nasal or transmucosal delivery.
• Manufacturing processes that produce defined impurity profiles.

Patent value would depend on claim scope and enforceability. A narrow excipient claim covering a routine filler, lubricant, or disintegrant would generally be weak. Stronger protection would require a demonstrated technical effect tied to a defined composition or process, such as improved ergotamine stability, superior dose uniformity, faster dissolution, or reduced degradation.

How many patents cover the current product?

The practical answer is that no meaningful unexpired composition-of-matter estate is expected to protect the historical ergotamine tartrate/caffeine tablet. Product-specific patent exposure should be confirmed against the applicable FDA Orange Book, international registers, and current patent databases before launch planning.

Historical patent expiration does not eliminate freedom-to-operate risk. A new applicant can still encounter formulation, device, manufacturing, or use patents filed by later developers.

What is the Orange Book status of ergotamine tartrate/caffeine?

The Orange Book status depends on the specific reference-listed product and dosage form. Historical Cafergot approvals may appear as discontinued products or legacy approval records rather than as an actively marketed branded product with current commercial exclusivity.

For a generic applicant, the key questions are:

• Whether an active reference-listed product exists.
• Whether the proposed strength and dosage form match the reference.
• Whether any listed patents remain active.
• Whether an ANDA can be filed against the relevant reference.
• Whether a 505(b)(2) pathway is required because the reference is discontinued or the formulation differs materially.

A Paragraph IV strategy would have limited value if no unexpired Orange Book patents are listed. The principal regulatory risk may instead be reference-product availability and the ability to establish bioequivalence.

When does ergotamine tartrate/caffeine lose exclusivity?

Historical exclusivity and patent protection have already expired for the conventional ergotamine/caffeine combination. No biosimilar exclusivity framework applies because this is a small-molecule drug, not a biologic.

The relevant launch barriers are now:

1. Regulatory approval.
2. Reference-product and bioequivalence strategy.
3. API sourcing.
4. Ergot alkaloid impurity control.
5. Manufacturing economics.
6. Market access and pharmacy substitution.
7. Supply continuity.

A reformulated product could obtain new regulatory exclusivity or patent protection only if it meets the statutory requirements for the applicable pathway. A simple excipient substitution generally would not create substantial commercial exclusivity.

Which companies are challenging ergotamine tartrate/caffeine?

The market is primarily generic and fragmented. Competition is more likely to arise from generic manufacturers, contract manufacturers, specialty pharmacies, and alternative migraine products than from branded patent challengers.

The strongest competitive threats come from:

• Triptans, including sumatriptan and rizatriptan.
• Gepants, including ubrogepant, rimegepant, and zavegepant.
• Ditan therapy, including lasmiditan.
• Nonprescription analgesic combinations.
• Injectable and nasal migraine products.
• Compounded or specialty-dispensed ergotamine products where legally available.

These alternatives reduce the commercial attractiveness of a conventional ergotamine/caffeine tablet unless the product has a cost, availability, or administration advantage.

What generic entry risks exist for ergotamine tartrate/caffeine?

Generic entry risk is high for conventional tablets because the active ingredients are old and formulation complexity is manageable. The most important risks for a new entrant are operational rather than patent-based.

Manufacturing and IP barriers

Potential barriers include:

• Limited suppliers capable of producing qualified ergotamine tartrate.
• Agricultural or fermentation-related variability in ergot alkaloid starting materials.
• Tight impurity specifications.
• Low-dose content-uniformity failures.
• Batch rejection from dissolution or stability deviations.
• Limited commercial scale.
• Packaging requirements for moisture and light protection.
• Difficulty supporting a discontinued or poorly documented reference product.

A company that develops a reliable, validated low-dose blending process may have a stronger competitive position than a company relying on broad formulation patents.

How strong is the patent estate for ergotamine tartrate/caffeine?

The patent estate for the historical product is weak. The active ingredients are long established, and the core tablet concept is conventional. A new entrant would face limited legacy patent risk but also limited ability to obtain broad blocking claims.

Asset category	Expected protection strength
Ergotamine tartrate composition	Very weak or expired
Caffeine composition	Very weak or expired
Conventional fixed-dose tablet	Weak
Standard excipient substitution	Weak
Defined rapid-disintegration platform	Moderate if supported by data
Buccal, sublingual, or nasal delivery	Moderate to strong if claims are technically specific
Novel stabilization or impurity-control process	Moderate
Device-integrated administration system	Potentially strong
Method-of-use claims for migraine	Generally limited by prior art and existing treatment knowledge

Method-of-use patents may be possible for a new patient population, dosing regimen, or combination, but broad acute-migraine use claims would face substantial prior-art challenges.

What licensing deals could support commercialization?

Licensing opportunities are more likely to involve technology and supply than historical brand rights. Relevant transaction targets include:

• Rights to an approved reference product or legacy NDA.
• A qualified ergotamine tartrate API source.
• A transmucosal or oral-film platform.
• A taste-masking technology.
• A validated low-dose blending process.
• A specialty-pharmacy distribution network.
• A regional marketing authorization.

A license is most commercially useful when it reduces regulatory uncertainty or secures API continuity. Licensing an expired brand name alone would have limited strategic value unless the brand retains substantial prescriber recognition in a specific market.

What commercial opportunities exist for excipient suppliers?

Excipient companies can participate through differentiated functionality rather than commodity supply.

The strongest opportunities are:

1. Low-moisture direct-compression systems for ergotamine-containing tablets.
2. Co-processed excipients that improve low-dose uniformity.
3. Rapid-disintegration platforms for orally disintegrating tablets.
4. Taste-masking systems for buccal, sublingual, or oral-film products.
5. Protective film coatings and high-barrier packaging combinations.
6. Excipient systems compatible with dry granulation.
7. Analytical and formulation services for ergot alkaloid impurity control.

A co-processed excipient with demonstrated improvement in content uniformity and dissolution could support a formulation patent or trade-secret manufacturing advantage. The commercial case is stronger when the excipient platform can be reused across other low-dose, high-potency products.

How does ergotamine/caffeine compare with newer migraine drugs?

Factor	Ergotamine/caffeine	Triptans	Gepants	Ditan
Active-ingredient age	Very old	Established	Newer	Newer
Patent exposure	Low	Mixed	Higher	Higher
Generic competition	High or potential	High for older agents	Limited in many markets	Limited
Oral formulation complexity	Low to moderate	Low to moderate	Low to moderate	Low to moderate
Vasoconstrictive concern	Significant	Significant for class	Lower relative concern	Different safety profile
Differentiation opportunity	Delivery and supply	Cost and formulation	Access and convenience	Access and tolerability
Likely commercial margin	Low	Low to moderate	Higher where exclusivity remains	Higher where exclusivity remains

Ergotamine/caffeine is unlikely to compete on innovation. It can compete on price, availability, and dosage-form convenience in selected markets.

Key Takeaways

• Ergotamine tartrate/caffeine is an old small-molecule combination with expired core patent protection.
• Conventional tablet commercialization is primarily a regulatory, manufacturing, and supply-chain exercise.
• Low-dose ergotamine content uniformity is the central formulation risk.
• Microcrystalline cellulose, mannitol, crospovidone, croscarmellose sodium, povidone, and protective film coatings are logical development tools, subject to compatibility and performance testing.
• Orally disintegrating, buccal, sublingual, oral-film, and suppository products offer greater differentiation than standard tablets.
• New patent value would need to come from delivery technology, stabilization, impurity control, or a defined manufacturing process.
• Biosimilar risk is irrelevant because the product is a small molecule.
• Generic entry risk is high for conventional products, while API qualification and quality control may limit the number of reliable suppliers.
• The best commercial opportunity for excipient suppliers is a reusable low-dose formulation platform with demonstrated uniformity, dissolution, and stability benefits.

Frequently Asked Questions

Is ergotamine tartrate/caffeine still commercially viable?

It can be viable as a low-cost generic or niche dosage-form product, but expected margins are lower than for newer migraine therapies. Commercial success depends on reliable API supply and a clear administration advantage.

Which excipient is best for ergotamine tartrate tablets?

No single excipient is universally best. Microcrystalline cellulose or mannitol can support direct compression, while crospovidone or croscarmellose sodium can improve disintegration. The final choice must be based on uniformity, dissolution, stability, and manufacturability data.

Can ergotamine tartrate/caffeine receive new formulation patents?

Yes, but protection would need to cover a genuinely differentiated formulation, delivery system, stabilization approach, or manufacturing process. Routine substitution of common tablet excipients is unlikely to support strong claims.

Is a 505(b)(2) application suitable for a new ergotamine delivery system?

It may be suitable when the proposed product changes the route, dosage form, delivery mechanism, or formulation and can rely partly on prior findings for an approved product. The feasibility depends on the reference product and the clinical data required.

Are ergotamine/caffeine products exposed to biosimilar competition?

No. Ergotamine tartrate and caffeine are chemically synthesized or processed small-molecule active ingredients. Competitive pressure comes from generic drugs and newer migraine therapies, not biosimilars.

References

1. U.S. Food and Drug Administration. (n.d.). Cafergot prescribing information: Ergotamine tartrate and caffeine tablets and suppositories. FDA archival labeling.

2. U.S. Food and Drug Administration. (n.d.). Orange Book: Approved drug products with therapeutic equivalence evaluations. https://www.accessdata.fda.gov/scripts/cder/ob/

3. U.S. National Library of Medicine. (n.d.). Ergotamine and caffeine drug labeling. DailyMed. https://dailymed.nlm.nih.gov/

4. United States Pharmacopeia. (2024). USP-NF: Ergotamine tartrate and caffeine monographs. U.S. Pharmacopeial Convention.

5. International Council for Harmonisation. (2003). Q8(R2): Pharmaceutical development. ICH.

6. International Council for Harmonisation. (2009). Q10: Pharmaceutical quality system. ICH.