Mast Cell Activation Syndrome: A Practical Escalation Protocol | ESSI

Mast Cell Activation Syndrome: A Practical Escalation Protocol

Understanding the Stepwise Pharmacologic Approach to MCAS

By Andrea Vidali, MD — Reproductive Endocrinologist & Immunologist

IMPORTANT MEDICAL DISCLAIMER: This article is provided for educational and informational purposes only. It does not constitute medical advice, diagnosis, or treatment recommendations. Mast Cell Activation Syndrome is a complex condition requiring individualized care from a qualified specialist. Do not start, stop, or modify any medication without direct supervision from your treating physician. Many of the medications discussed here are used off-label, can cause significant side effects, and may interact with other treatments. If you suspect you have MCAS, seek evaluation from a mast cell specialist, allergist/immunologist, or hematologist with experience in this condition.

Introduction: Why This Matters in My Practice

In my decades of caring for patients with endometriosis, recurrent pregnancy loss, and unexplained infertility, I have learned to recognize a pattern that hides in plain sight. Many of these patients carry a second, often unrecognized diagnosis: Mast Cell Activation Syndrome (MCAS). They tell me about food sensitivities that worsened after a viral illness, flushing episodes around their menstrual cycle, hives triggered by stress, GI symptoms that no gastroenterologist could pin down, and a constellation of seemingly unrelated complaints that span multiple organ systems.

MCAS is not a fringe diagnosis. It sits at the crossroads of immunology, allergy, and chronic inflammation, and in my reproductive immunology practice it appears with striking frequency alongside endometriosis, hypermobile Ehlers-Danlos syndrome (hEDS), and POTS — the so-called “trifecta”. When MCAS is unrecognized and untreated, surgical outcomes suffer, IVF cycles fail, and patients endure years of unnecessary suffering.

This article is intended as an educational resource for patients and clinicians who want to understand how MCAS is treated. It is structured around the stepwise escalation protocol most experienced mast cell specialists follow, drawn from the work of Dr. Lawrence Afrin, Dr. Cem Akin, Dr. Gerhard Molderings, Dr. Theoharis Theoharides, and the consensus literature. Throughout, I have added clinical commentary based on what I see in my own patients.

A note from Dr. Vidali: I want to emphasize at the outset: the medications discussed in this article are listed because they appear in the published treatment literature for MCAS. None of this is a substitute for working with a physician who knows your case. MCAS patients often react paradoxically to medications, and even helpful drugs need to be introduced one at a time, slowly, so we can tell what is working and what is not. Patience is the most underrated tool in this protocol.

Part 1: Foundational Concepts

What MCAS Is, Briefly

Mast cells are tissue-resident immune cells that sit at every interface between the body and the environment — skin, gut lining, airways, blood vessels, the genitourinary tract. When they are appropriately activated, they release a powerful cocktail of chemical mediators that fight infection, drive inflammation, and recruit other immune cells. In MCAS, mast cells release these mediators inappropriately, repeatedly, and across multiple organ systems, producing chronic multisystem symptoms that wax and wane.

Unlike systemic mastocytosis, where there is an actual proliferation of abnormal mast cells, MCAS patients usually have a normal number of mast cells that simply do not behave normally. This makes the diagnosis harder, because routine biopsies and a single tryptase level often appear unremarkable.

The Three Therapeutic Targets

Every MCAS medication works through one or more of three mechanisms. Understanding which target a drug hits is the key to building a rational combination.

Table 1. The three pharmacologic targets in MCAS therapy.

Target	Mechanism	Example Drugs
Block released mediators	Bind to receptors that mediators activate, preventing downstream effect	H1 antihistamines, H2 antihistamines, leukotriene antagonists, aspirin
Stabilize the mast cell	Prevent the mast cell from degranulating in the first place	Cromolyn sodium, ketotifen, quercetin, omalizumab
Reduce mast cell numbers / signaling	Inhibit the KIT pathway or reduce mast cell population	Tyrosine kinase inhibitors (imatinib, midostaurin, avapritinib), hydroxyurea

Clinical insight: When a patient is doing poorly on antihistamines alone, it is usually because we have only addressed target #1. Adding a stabilizer (target #2) often changes the picture entirely. The mediators have already been released by the time an H1 blocker reaches the receptor — preventing the release upstream is a different battle.

Diagnostic Framework (in Brief)

Two major sets of diagnostic criteria are in use. The “consensus-1” criteria (Valent, Akin, Metcalfe and colleagues) are stricter and require objective laboratory evidence of mediator elevation during a flare, plus response to anti-mediator therapy. The “consensus-2” criteria (Afrin, Molderings and colleagues) are broader and allow for patients in whom mediator testing is repeatedly negative despite a clinical picture strongly suggesting mast cell activation.

Both frameworks share three pillars:

1. Chronic, episodic, multisystem symptoms typical of mast cell activation.

2. Objective evidence of mast cell mediator release.

3. Response to mast cell-directed therapy.

The third pillar is essentially a therapeutic trial — which brings us to the escalation protocol.

Part 2: The Stepwise Escalation Protocol

There is no single MCAS treatment regimen that works for everyone. What experienced mast cell physicians do instead is follow a tiered escalation: start with the safest, cheapest, best-tolerated agents; add layers one at a time; trial each new addition for four to eight weeks before judging efficacy; and escalate to more potent or specialized agents only when simpler combinations fail.

The MCAS treatment pyramid, read bottom-up. Most patients achieve adequate control within tiers 1–4. Higher tiers are reserved for refractory disease.

 

Tier	Class	Representative Agents
7 — Specialized	TKIs / cytoreduction	Avapritinib, midostaurin, imatinib, hydroxyurea, cladribine
6 — Biologics	Anti-IgE	Omalizumab
5 — Adjuncts	Symptom-specific add-ons	Benzodiazepines, doxepin, LDN, gabapentinoids, DAO
4 — Prostaglandin	COX inhibitors	Low-dose aspirin (under supervision)
3 — Leukotriene	LTRA / 5-LO inhibitor	Montelukast, zafirlukast, zileuton
2 — Stabilizers	Mast cell stabilizers	Cromolyn sodium, ketotifen, quercetin
1 — Foundation	Antihistamines (H1 + H2)	Cetirizine, fexofenadine, famotidine

Tier 1: H1 + H2 Antihistamines (The Foundation)

Every MCAS protocol begins here. Histamine is one of the most clinically active mast cell mediators, and blocking it at both H1 and H2 receptors covers a large fraction of typical symptoms. Importantly, an H2 antihistamine is not interchangeable with a proton pump inhibitor — they hit different receptors, and the H2 effect is part of the mast cell stabilization strategy.

• Recommended approach: Start with a second-generation H1 (less sedating) plus an H2.

• Standard adult starting combination: cetirizine 10 mg twice daily plus famotidine 20–40 mg twice daily.

• If partial response, the H1 can typically be increased up to four times the standard dose, mirroring the chronic urticaria treatment guidelines.

• If one H1 is poorly tolerated or ineffective, switch to a different one — patient response is highly idiosyncratic.

• Add a sedating H1 (hydroxyzine, diphenhydramine, doxepin) at night for breakthrough symptoms or sleep.

Table 2. H1 and H2 antihistamines commonly used in MCAS. (Doses are illustrative ranges from the published literature; always individualize.)

Drug	Class	Typical adult dose range	Notes
Cetirizine (Zyrtec)	2nd gen H1	10 mg once to four times daily	Mildly sedating in some; partially crosses BBB
Levocetirizine (Xyzal)	2nd gen H1	5 mg once to four times daily	Active enantiomer of cetirizine
Fexofenadine (Allegra)	2nd gen H1	180 mg once to four times daily	Least sedating; minimal CNS effects
Loratadine (Claritin)	2nd gen H1	10 mg once to four times daily	Generally well tolerated, sometimes less potent
Hydroxyzine (Atarax/Vistaril)	1st gen H1	10–25 mg every 6–8 hours	Sedating; useful at night and for anxiety
Diphenhydramine (Benadryl)	1st gen H1	25–50 mg as needed	Sedating; useful for breakthrough/rescue
Doxepin	TCA / potent H1+H2	10–25 mg at bedtime	Powerful H1 blocker; helps sleep and neuropathic pain
Famotidine (Pepcid)	H2	20–40 mg twice daily	Best-tolerated H2; first-line H2 in MCAS
Cimetidine (Tagamet)	H2	200–400 mg twice daily	Many drug interactions (CYP450); use cautiously
Nizatidine	H2	150–300 mg twice daily	Alternative when famotidine is poorly tolerated

Why both H1 and H2 — always: “I sometimes see patients on Zyrtec alone whose physician told them ‘famotidine is a stomach drug, you don’t need it.’ This is a misunderstanding. H2 receptors sit on mast cells themselves and on cardiovascular tissue, so blocking H2 contributes to overall stabilization, not just to acid suppression. A PPI cannot replace this function.”

Tier 2: Mast Cell Stabilizers

When antihistamines alone do not provide adequate control, the next step is to add a stabilizer — a drug that prevents mast cells from degranulating in the first place. The two main agents are cromolyn sodium and ketotifen. Both can take four to eight weeks to reach full effect, and both should be titrated up slowly because hypersensitive MCAS patients sometimes react to the stabilizer itself or to its excipients.

• Cromolyn sodium: Cromolyn is poorly absorbed from the gut, which is actually an advantage: high local concentrations are delivered directly to the GI mucosa where many MCAS symptoms originate. Standard dosing is 200 mg four times daily, taken 30 minutes before meals and at bedtime. A common practical titration schedule starts at 100–200 mg twice daily in the first week and increases by 200–400 mg per week as tolerated.

• Ketotifen: Ketotifen is both an H1 antihistamine and a mast cell stabilizer. It is not approved as an oral medication in the United States but is widely used in compounded form. Typical dosing starts at 1 mg twice daily and titrates up to 2–6 mg per dose, up to four times daily. Sedation is the main dose-limiting side effect.

• Natural stabilizers: Several flavonoids — quercetin, luteolin, and rutin — have demonstrated mast cell stabilizing activity in laboratory studies and are used adjunctively. Quercetin is the most studied, typically at 250–500 mg twice daily. Vitamin C, vitamin D repletion, and omega-3 fatty acids may also play supporting roles.

Table 3. Mast cell stabilizers and supportive nutrients used in MCAS protocols.

Stabilizer	Typical dose	Mechanism / role
Cromolyn sodium (oral)	100 mg titrating to 200 mg QID, 30 min before meals	Prevents degranulation; not absorbed — best for GI symptoms
Cromolyn (nasal/ocular/inhaled)	Per product label	Local action for sinus, eye, airway symptoms
Ketotifen	1 mg BID titrating to 2–6 mg up to QID	Dual H1 + stabilizer; compounded in U.S.
Quercetin	250–500 mg BID	Flavonoid stabilizer; often combined with bromelain for absorption
Luteolin	100–200 mg BID	Crosses blood-brain barrier; may help neuro symptoms
Vitamin C	500–1000 mg/day, divided	Antihistamine effect; cofactor for DAO
Vitamin D	Repletion to 50–80 ng/mL	Modulates mast cell activation; deficiency common in MCAS

Tier 3: Leukotriene Pathway Blockade

Leukotrienes are mast cell mediators that drive bronchoconstriction, vascular permeability, and GI smooth-muscle cramping. Blocking the leukotriene pathway is a logical addition for patients whose symptoms include respiratory tightness, asthma overlap, sinus congestion, or visceral cramping that persists despite antihistamines and stabilizers.

Table 4. Leukotriene-modifying agents.

Drug	Class	Typical adult dose	Notes
Montelukast (Singulair)	Leukotriene receptor antagonist	10 mg once daily (sometimes BID)	FDA boxed warning regarding neuropsychiatric effects — monitor for mood changes
Zafirlukast (Accolate)	Leukotriene receptor antagonist	20 mg twice daily	Take on empty stomach; hepatic monitoring
Zileuton (Zyflo)	5-lipoxygenase inhibitor	600 mg four times daily (or 1200 mg ER BID)	Blocks leukotriene synthesis; requires LFT monitoring

Tier 4: Prostaglandin Coverage with Aspirin

Prostaglandin D2 (PGD2) is a potent vasodilator released by mast cells; it drives flushing, presyncope, headache, and some neuropsychiatric symptoms. Low-dose aspirin can be highly effective for these symptoms by inhibiting prostaglandin synthesis through COX-1 and COX-2.

This step is approached carefully and only under physician supervision. Some MCAS patients have aspirin- or NSAID-induced reactions, so the first dose is typically given in a monitored setting. When tolerated, doses range from 81 mg up to 325 mg one or two times daily.

An important caution: “Patients should never self-initiate aspirin for MCAS. I have seen aspirin be transformative for some patients with prominent flushing and dysautonomia, and I have seen others react badly. The decision belongs in your physician’s office with appropriate monitoring.”

Tier 5: Symptom-Specific Adjuncts

These agents are layered onto the foundation depending on which symptoms remain dominant after tiers 1–4.

Table 5. Symptom-specific adjuncts added to the foundation regimen.

Adjunct	Used for	Mechanism / rationale
Benzodiazepines (clonazepam, lorazepam)	Anxiety, insomnia, neuropsychiatric symptoms, skin burning	Mast cells express benzodiazepine receptors; direct stabilizing effect beyond anxiolysis
Doxepin (low dose)	Itching, sleep, neuropathic pain	Most potent H1 blocker known; also H2 active
Low-dose naltrexone (LDN)	Inflammation, pain, autoimmune overlap	Modulates microglial activation; off-label in MCAS
Gabapentin / pregabalin	Neuropathic pain, neurogenic itching	Useful for neuro-dominant disease
Diamine oxidase (DAO)	Food-triggered histamine reactions	Replaces deficient enzyme that breaks down dietary histamine
Ondansetron (Zofran)	Nausea, vomiting	5-HT3 antagonist; sublingual form for breakthrough
Topical cromolyn / doxepin cream	Localized skin symptoms	Local mast cell stabilization
Pentosan polysulfate	Bladder pain (interstitial cystitis overlap)	Restores GAG layer of bladder
Tranexamic acid	Severe angioedema	Antifibrinolytic; useful in bradykinin overlap

Tier 6: Omalizumab — The Main Biologic Step

Omalizumab (Xolair) is a monoclonal antibody that binds free IgE and downregulates the high-affinity IgE receptor on mast cells and basophils. Originally approved for severe allergic asthma and chronic spontaneous urticaria, it is now the most studied biologic for refractory MCAS.

In a 2024 systematic review of refractory MCAS patients treated with omalizumab, dosing ranged from 150 mg every four weeks to 300 mg every two to three weeks. Roughly 60% of patients achieved a partial response and an additional 18% achieved a complete response. Importantly, omalizumab has reduced anaphylaxis frequency and allowed several patients to come off chronic systemic corticosteroids.

Table 6. Omalizumab in MCAS — key clinical parameters.

Aspect	Detail
Typical dose range	150 mg every 4 weeks up to 300–375 mg every 2 weeks
Time to response	Often 3–6 months for full effect
Approximate response rate	~60% partial response; ~18% complete response
Special use cases	Recurrent idiopathic anaphylaxis; severe chronic urticaria; allows venom immunotherapy
Important safety note	Can itself cause delayed anaphylaxis; first 3 doses observed for 2 hours; patient must carry epinephrine
Discontinuation	Symptoms typically return; long-term therapy is the norm

Tier 7: Cytoreduction and KIT-Targeted Therapy

This tier is reserved for severe, refractory disease and for patients whose evaluation reveals systemic mastocytosis (a related but distinct mast cell proliferative disorder). These therapies require specialist oversight, typically by a hematologist familiar with mast cell disease.

Table 7. Cytoreductive and KIT-targeted agents.

Drug	Indication	Typical dose / monitoring
Avapritinib (Ayvakit)	Indolent and advanced systemic mastocytosis (FDA-approved); refractory MCAS off-label	25 mg daily (ISM) up to 200 mg daily (advanced); CBC and cognition monitoring
Midostaurin (Rydapt)	Advanced systemic mastocytosis	100 mg twice daily; significant GI side effects
Imatinib (Gleevec)	Mast cell disease without KIT D816V (rare subtypes)	100–400 mg daily; not effective in classic D816V-positive disease
Hydroxyurea	Cytoreduction in proliferative disease	500–2000 mg daily; weekly CBC initially
Cladribine, interferon-α	Aggressive systemic mastocytosis	Specialist-managed; significant immunosuppression

Emergency / Anaphylaxis Protocol

Every MCAS patient should have a written emergency action plan signed by their physician and should carry two epinephrine auto-injectors at all times. Anaphylaxis in MCAS can present atypically, can be biphasic, and can occasionally be refractory in patients on beta-blockers — in which case glucagon may be required.

Standard anaphylaxis steps:

• Inject epinephrine 0.3 mg intramuscularly into the lateral thigh. Repeat every 5–10 minutes if symptoms are not improving.

• Call emergency services.

• Lay the patient flat with legs elevated unless breathing is compromised.

• Administer additional H1 + H2 antihistamines if available.

• Corticosteroids (e.g., methylprednisolone) for prolonged or biphasic reactions.

• IV fluids for hypotension.

• Bronchodilator (albuterol) for wheezing.

• If on a beta-blocker and refractory: glucagon 1–5 mg IV.

Part 3: Tailoring the Protocol to Symptom Patterns

In practice, MCAS rarely presents as a uniform syndrome. Most patients have a dominant symptom domain — GI, neurologic, cardiovascular, dermatologic, or respiratory — that drives quality-of-life impairment. The escalation framework above remains the same, but the order of layering and the choice of adjuncts shifts depending on the dominant pattern.

Table 8. Tailoring the protocol by dominant symptom pattern.

Dominant pattern	Foundation	Key adjuncts to prioritize	Notes
GI-dominant	H1 + H2 + cromolyn (full dose, before meals)	Ketotifen, ondansetron, DAO, prokinetics if motility issues	Cromolyn shines here because it is not absorbed
Neuropsychiatric	H1 (BBB-crossing) + H2	Clonazepam, doxepin, LDN, luteolin, gabapentinoids	Avoid sedating agents during the day if cognition is the issue
Cardiovascular / POTS overlap	H1 + H2 + cromolyn	Aspirin (early), ivabradine, midodrine, fludrocortisone, salt/volume	Caution with beta-blockers re: anaphylaxis response
Skin-dominant	H1 maxed (4×) + H2	Doxepin, omalizumab earlier, topical cromolyn	Omalizumab approved for chronic urticaria — easier insurance approval
Respiratory	H1 + H2 + montelukast	Inhaled cromolyn (where available), inhaled steroid + LABA, intranasal therapies	Omalizumab approved for severe asthma — earlier access

Triggers and Drugs to Avoid

Equally important to what we add is what we remove. Many medications and exposures can degranulate mast cells directly. Common offenders include:

• Opioids — particularly morphine and codeine; fentanyl and hydromorphone are generally safer when an opioid is necessary.

• NSAIDs other than carefully titrated aspirin.

• Vancomycin (rapid infusion causes “red man syndrome” via direct degranulation).

• Iodinated radiocontrast — premedicate if exposure is unavoidable.

• Succinylcholine and atracurium during anesthesia.

• Alcohol, especially red wine and aged spirits.

• High-histamine and histamine-liberating foods (aged cheese, fermented foods, leftovers, certain shellfish).

• Excipients and dyes in tablets — compounded dye-free formulations rescue many “treatment-resistant” patients.

• Extreme temperatures and rapid temperature changes.

• Significant emotional stress (a real, biological trigger — not a character flaw).

Perioperative Considerations

This is where my surgical practice intersects directly with MCAS care. Patients with MCAS undergoing surgery — including endometriosis excision — require thoughtful planning to prevent intraoperative or postoperative mast cell crises.

Table 9. Standard perioperative premedication framework. (Always individualize with anesthesia and the surgical team.)

Timing	Intervention	Purpose
1–2 weeks before	Optimize daily MCAS regimen; ensure adequate baseline control	Stable baseline reduces flare risk
24 hours before	Prednisone 20–50 mg PO + H1 + H2 antihistamines	Premedication
12 hours before	Repeat H1 + H2; second prednisone dose	Sustained blockade
1 hour before	IV diphenhydramine + IV famotidine + IV hydrocortisone or methylprednisolone	Peak coverage during induction
Intraoperative	Avoid known degranulators; prefer propofol-based anesthesia; minimize opioid use; avoid latex	Reduce intraoperative triggers
Postoperative	Continue scheduled antihistamines; resume cromolyn early; have epinephrine immediately available	Catch and treat any flare promptly

From my operating room: “When I operate on a patient with known MCAS, we coordinate as a team — anesthesia, nursing, and surgery all know the plan in advance. Drug selection matters more than the exact dose of premedication. A propofol-based anesthetic with carefully chosen muscle relaxants and minimal opioid avoids most of the common pitfalls. Postoperatively, we resume the patient’s home regimen as quickly as possible.”

Part 4: Practical Pearls from Clinical Practice

• Add one drug at a time: Adding two or three medications simultaneously almost guarantees confusion. If the patient gets better, you do not know which drug helped; if they get worse, you do not know which to discontinue. A four to eight week trial of each new addition is the convention

• Stabilize before you subtract: Patients on a working combination should not have medications removed until they have been stable for at least six months. Recurrence after withdrawal can be more difficult to control than the original presentation.

• Hormonal cycling matters: Many female patients flare premenstrually. Estrogen and progesterone both modulate mast cell activity. Tracking symptoms across the cycle and adjusting medications accordingly can be transformative — and is one of the reasons MCAS care intersects so naturally with reproductive endocrinology.

• The infection-flare connection: New onset or worsening of MCAS frequently follows viral infection (post-COVID, post-EBV, post-Lyme are common patterns). Any infection treatment plan should account for the increased reaction risk — and the threshold for restarting a stabilizer should be low.

• Compounding pharmacies: Find a compounding pharmacy that can prepare dye-free, filler-free formulations. This single change rescues many patients labeled “treatment-resistant” who were actually reacting to the excipients in commercial tablets.

• The MCAS–endometriosis–POTS triad: In my reproductive immunology practice, I see this triad — MCAS, hypermobile EDS, and POTS — overlap with endometriosis with a frequency that cannot be coincidence. When patients with endometriosis fail standard treatments, fail multiple IVF cycles, or have disproportionate pain, MCAS evaluation belongs on the differential. Treating the MCAS component often improves both the surgical outcome and the fertility trajectory.

A final word from Dr. Vidali: “MCAS is a marathon, not a sprint. Most of my patients who have done well with this condition share three traits: they found a physician who took them seriously, they tracked their symptoms and medications carefully, and they were patient enough to give each tier of treatment time to work. The escalation protocol exists not because we are guessing — it exists because we are systematically narrowing in on what your particular mast cells are doing wrong. Stay the course.”

Quick Reference: The Complete Escalation Map

Table 10. The complete escalation map — a synthesis of the published literature and clinical practice.

Step	Action	Decision point: escalate if…
1	Trigger identification + dietary modification (low-histamine if relevant)	Symptoms persist after 4 weeks
2	Add H1 antihistamine (e.g., cetirizine 10 mg BID)	Inadequate control at 4–8 weeks
3	Add H2 antihistamine (e.g., famotidine 20–40 mg BID)	Inadequate control
4	Up-titrate H1 to 4× standard dose; trial alternate H1	Inadequate control
5	Add cromolyn sodium (titrate to 200 mg QID before meals)	Inadequate control after 8 weeks
6	Add ketotifen or quercetin	Inadequate control
7	Add montelukast (or other leukotriene blocker)	Inadequate control
8	Trial low-dose aspirin under physician supervision	Inadequate control
9	Add symptom-specific adjuncts (benzodiazepine, doxepin, LDN, etc.)	Inadequate control
10	Initiate omalizumab	Inadequate control
11	Reevaluate for clonal disease (KIT D816V, bone marrow biopsy)	Indication for KIT-targeted therapy
12	Initiate KIT-targeted therapy or cytoreduction	Specialist-managed

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Selected References

The following references provide the scientific foundation for the concepts and protocols described in this article. Patients are encouraged to share these with their treating physicians.

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3. Afrin LB. Presentation, diagnosis, and management of mast cell activation syndrome. In: Murray DB, ed. Mast Cells: Phenotypic Features, Biological Functions and Role in Immunity. Nova Science Publishers; 2013:155–232.

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FINAL DISCLAIMER: The information in this article reflects published literature and clinical experience as of the date of writing. It is intended as a general educational resource for patients and clinicians and is NOT medical advice. MCAS treatment decisions must be individualized and made in partnership with a qualified healthcare provider. Dosing ranges, drug selection, and escalation timing all vary based on the patient’s complete clinical picture, comorbidities, and other medications. No physician-patient relationship is established by reading this material. If you have a medical emergency, call your local emergency number immediately