Supreh Bee Venom Arthritis Pain Relieving Cream

Dosage for Apis Mellifera Venom is highly individualized and follows a strict protocol divided into two main phases: the 'Build-up' (or Induction) phase and the 'Maintenance' phase.

Build-up Phase

In a conventional schedule, the starting dose is extremely low, often ranging from 0.01 mcg to 0.1 mcg. Doses are gradually increased at weekly intervals. The goal is to reach a target maintenance dose, which is typically 100 mcg of venom protein. This phase usually lasts 10 to 20 weeks. In 'Rush' or 'Cluster' protocols, the build-up occurs over several days or weeks under close inpatient or outpatient supervision to reach the maintenance dose faster.

Maintenance Phase

Once the 100 mcg target is reached, the interval between injections is increased. Initially, injections are given every 4 weeks. Over several years of treatment, this interval may be extended to every 6 or 8 weeks, depending on the patient's tolerance and the clinician's judgment. Maintenance therapy typically continues for 3 to 5 years.

Apis Mellifera Venom immunotherapy is approved for use in children, generally starting at age 5, although younger children with severe reactions may be considered. The dosing protocol for children is remarkably similar to the adult protocol, as the goal is to reach the same 100 mcg maintenance dose. Clinical studies have shown that children often tolerate VIT better than adults and achieve high levels of protection. However, pediatric patients must be monitored even more closely for subtle signs of systemic reactions.

Renal Impairment

No specific dose adjustments are typically required for patients with renal impairment, as the venom is administered in microgram quantities. However, overall health status should be evaluated, as the ability to tolerate a potential systemic reaction may be compromised in severe kidney disease.

Hepatic Impairment

There are no established guidelines for dose adjustment in hepatic impairment. Since the venom is metabolized by proteases rather than liver-specific enzymes, the pharmacokinetic profile remains largely unchanged.

Elderly Patients

Elderly patients (over 65) require cautious dosing. While the dose itself may not change, the risk of cardiovascular complications during a systemic reaction is much higher in this population. A thorough evaluation of cardiac health is necessary before starting therapy.

Apis Mellifera Venom is administered exclusively by subcutaneous injection, usually in the upper arm. It should NEVER be self-administered by the patient at home.

• Administration: The injection is given by a trained healthcare professional (usually an allergist or immunologist).
• Observation: Patients must remain in the medical office for at least 30 to 60 minutes after every injection. This is the period when most serious systemic reactions occur.
• Site Care: Do not rub or massage the injection site after the procedure, as this can increase the rate of absorption and the risk of a reaction.
• Storage: The lyophilized powder and reconstituted solutions must be stored under refrigeration (2°C to 8°C or 36°F to 46°F). Do not freeze.

If a dose is missed during the build-up phase, the next dose may need to be reduced or the previous dose repeated, depending on how much time has passed. If a maintenance dose is missed by more than 2 to 3 weeks, the dose is often reduced to ensure safety when resuming. Your doctor will follow a specific 'back-off' schedule to prevent reactions after a lapse in treatment.

An overdose in the context of venom immunotherapy refers to an injection that exceeds the patient's current tolerance level. Signs of overdose are identical to a severe allergic reaction:

• Generalized hives (urticaria)
• Swelling of the throat or tongue
• Difficulty breathing or wheezing
• Rapid pulse or drop in blood pressure (fainting)

In the event of an accidental overdose or severe reaction, emergency measures include the immediate administration of epinephrine (adrenaline), oxygen, intravenous fluids, and antihistamines.

> Important: Follow your healthcare provider's dosing instructions. Do not adjust your dose or skip appointments without medical guidance, as this can significantly increase your risk of a dangerous reaction.

The most frequent side effects of Apis Mellifera Venom are local reactions at the site of the injection. These occur in the majority of patients at some point during therapy.

• Local Swelling: A 'Large Local Reaction' (LLR) is defined as swelling greater than 10 cm in diameter. This may feel like a firm, warm, and itchy lump around the injection site.
• Redness (Erythema): The skin around the injection site may turn bright red or pink.
• Pruritus (Itching): Intense itching at the site is common and usually begins within minutes of the injection.
• Pain or Tenderness: A mild aching sensation in the arm where the shot was given.

These local reactions typically peak 24 to 48 hours after the injection and may last for several days. They are generally managed with cold compresses and oral antihistamines.

Systemic reactions that are not life-threatening may occur in approximately 5-15% of patients during the build-up phase.

• Generalized Pruritus: Itching that occurs all over the body, not just at the injection site.
• Urticaria (Hives): Raised, itchy welts appearing on various parts of the body.
• Angioedema: Swelling of the deeper layers of the skin, often around the eyes or lips.
• Nausea: A feeling of stomach upset or mild abdominal cramping.
• Fatigue: Some patients report feeling unusually tired for a few hours after their injection.

• Vasovagal Reactions: Fainting or lightheadedness due to anxiety or the physical sensation of the needle, rather than the venom itself.
• Lymphadenopathy: Swelling of the lymph nodes in the armpit (axilla) of the injected arm.
• Persistent Nodules: Small, hard lumps at the injection site that may persist for weeks.

> Warning: Stop taking Apis Mellifera Venom and call your doctor immediately or seek emergency care if you experience any of these symptoms of anaphylaxis.

• Respiratory Distress: Wheezing, chest tightness, or a sensation of the throat closing up. This indicates a severe narrowing of the airways.
• Hypotension (Low Blood Pressure): Feeling extremely dizzy, fainting, or a sudden sense of 'impending doom.'
• Laryngeal Edema: Severe swelling of the vocal cords making it difficult to speak or breathe.
• Cardiac Arrhythmia: A racing or irregular heartbeat.
• Generalized Seizures: Though extremely rare, severe systemic reactions can lead to neurological symptoms if oxygen levels drop.

Long-term side effects of Apis Mellifera Venom immunotherapy are rare. Most patients tolerate the 3-to-5-year course well. However, because the venom is classified as an Estrogen and Androgen Receptor Agonist, there is theoretical concern regarding prolonged hormonal modulation. While no clinical evidence currently links VIT to long-term endocrine disruption, patients with hormone-sensitive conditions should be monitored. There is no evidence that VIT increases the risk of cancer or autoimmune diseases; in fact, it often improves the patient's quality of life by removing the fear of stings.

Apis Mellifera Venom extracts carry a significant warning regarding the risk of severe systemic reactions.

Summary of Warning:

• Anaphylaxis Risk: This product can cause severe, life-threatening allergic reactions, including anaphylaxis.
• Clinical Setting: It must only be administered by healthcare providers experienced in the treatment of Hymenoptera allergy and the management of anaphylaxis.
• Emergency Equipment: The facility must be equipped with emergency supplies, including epinephrine, oxygen, and airway management tools.
• Patient Status: Patients with unstable asthma or significant cardiovascular disease are at a much higher risk of fatal outcomes if a reaction occurs.

Report any unusual symptoms or delayed reactions (occurring hours after you leave the clinic) to your healthcare provider immediately.

Apis Mellifera Venom is a potent biological agent. Its use is strictly reserved for individuals with a confirmed, high-risk allergy to honey bee stings. It is not a general 'vaccine' and should not be used by the general public. Every patient undergoing this therapy must carry a personal epinephrine auto-injector (e.g., EpiPen) at all times, as the therapy does not provide 100% protection, especially during the build-up phase.

No FDA black box warnings for Apis Mellifera Venom. However, it carries 'Strong Warnings and Precautions' in the professional labeling that function similarly to a black box warning. These focus on the risk of fatal anaphylaxis and the requirement for administration in a controlled medical environment. The labeling emphasizes that the risk of a systemic reaction is higher with honey bee venom than with other Hymenoptera venoms (like yellow jacket or wasp).

• Allergic Reactions / Anaphylaxis Risk: The most significant risk is a systemic allergic reaction. This can occur even if the patient has tolerated previous doses perfectly.
• Asthma: Patients with poorly controlled or severe asthma are at a significantly higher risk of a severe, potentially fatal bronchospasm during a venom-induced reaction. Asthma must be stabilized before an injection is given.
• Cardiovascular Disease: Patients with a history of heart disease, hypertension, or arrhythmias may not be able to tolerate the physiological stress of a systemic reaction or the effects of the epinephrine required to treat it.
• Beta-Blocker Therapy: Patients taking beta-blockers (medications for blood pressure or heart rate) may be resistant to the effects of epinephrine, making a systemic reaction much harder to treat.
• ACE Inhibitors: There is evidence that patients taking ACE inhibitors (e.g., lisinopril) may be at an increased risk of more severe, 'flush' type systemic reactions during VIT.

Before starting therapy, your doctor may order several tests:

• Baseline Tryptase: A blood test to measure mast cell activity. High baseline tryptase levels can indicate a condition called mastocytosis, which significantly increases the risk of severe reactions to both stings and immunotherapy.
• Lung Function Tests (Spirometry): To ensure asthma is well-controlled.
• Cardiac Evaluation: Including an EKG if the patient has a history of heart issues.
• Observation Log: Patients are often asked to keep a log of any delayed local reactions (swelling that occurs after leaving the office).

While Apis Mellifera Venom does not directly cause sedation, a systemic reaction or the administration of antihistamines/epinephrine can impair your ability to drive. It is often recommended that patients do not drive themselves home immediately after an injection if they feel at all unwell.

Alcohol should be avoided for at least 24 hours after an injection. Alcohol causes vasodilation (widening of blood vessels), which can increase the rate of venom absorption and potentially trigger or worsen a systemic allergic reaction.

Discontinuing Apis Mellifera Venom immunotherapy should only be done in consultation with an allergist. If stopped prematurely (before 3-5 years), the patient remains at high risk for life-threatening reactions to future stings. There is no 'withdrawal syndrome,' but the loss of immunological protection is a serious consequence.

> Important: Discuss all your medical conditions, especially heart or lung problems, with your healthcare provider before starting Apis Mellifera Venom.

There are few absolute contraindications for drug combinations, but the following are considered highly dangerous:

• Non-Selective Beta-Blockers (e.g., Propranolol): These drugs block the receptors that epinephrine needs to act upon. If a patient has an anaphylactic reaction to the venom, epinephrine may fail to reverse the airway obstruction or low blood pressure, leading to a fatal outcome. This combination is generally avoided unless the benefit of VIT clearly outweighs the risk and no alternative heart medication exists.

• Selective Beta-Blockers (e.g., Metoprolol, Atenolol): While slightly safer than non-selective versions, they still pose a risk of interfering with emergency treatment. Close monitoring and possible medication adjustment are required.
• ACE Inhibitors (e.g., Lisinopril, Enalapril): These medications interfere with the body's ability to break down bradykinin, a substance involved in allergic reactions. This can lead to more severe or unusual systemic reactions during venom injections.
• MAO Inhibitors (e.g., Phenelzine): These can interfere with the metabolism of epinephrine, potentially leading to a hypertensive crisis if emergency epinephrine is administered.

• NSAIDs (e.g., Ibuprofen, Naproxen): In some sensitive individuals, NSAIDs can lower the threshold for an allergic reaction, though this is more commonly associated with food allergies than venom.
• Hormonal Therapies: Since Apis Mellifera Venom is an Estrogen and Androgen Receptor Agonist, it may theoretically compete with or enhance the effects of hormone replacement therapy (HRT) or hormonal contraceptives. While not a standard contraindication, patients should report any changes in hormonal symptoms.

• Alcohol: As mentioned, alcohol increases blood flow to the skin and can accelerate venom absorption, increasing reaction risk.
• Spicy Foods: Large amounts of spicy food can sometimes trigger histamine release, which might complicate the assessment of a mild reaction to the venom.
• Caffeine: Excessive caffeine can increase heart rate, which may complicate the monitoring of a patient's vital signs during the 30-minute observation period.

• St. John's Wort: May affect the metabolism of various co-administered medications, though its direct interaction with bee venom is unknown.
• Ginkgo Biloba: Has mild anti-platelet effects; while not a direct interaction, it should be noted if the patient experiences significant bruising at the injection site.
• Kava/Valerian: These sedative herbs may mask the early signs of a systemic reaction (such as anxiety or 'impending doom').

• Serum Tryptase: The venom injection itself can cause a transient rise in tryptase if a systemic reaction occurs. This is used diagnostically to confirm a reaction.
• Skin Testing: If a patient is currently undergoing VIT, skin tests for bee venom will likely become less reactive over time, which is an expected result of the therapy.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking. A complete list is vital for your safety during immunotherapy.

Apis Mellifera Venom must NEVER be used in the following circumstances:

• Acute Infection: Patients with an active fever or systemic infection should delay their injection. An active immune system may be more 'primed' for a systemic reaction.
• Severe, Uncontrolled Asthma: If the FEV1 (a measure of lung function) is consistently below 70% of the predicted value despite treatment, the risk of a fatal reaction is too high.
• Recent Myocardial Infarction (Heart Attack): Within the last 3-6 months, the heart is too vulnerable to the stress of a potential reaction.
• History of Severe Reaction to Previous VIT: If a patient has had a life-threatening reaction to the immunotherapy itself that could not be managed, the therapy may be deemed too dangerous to continue.

These conditions require a careful risk-benefit analysis by the specialist:

• Autoimmune Diseases: There is a theoretical concern that stimulating the immune system could worsen conditions like Lupus or Rheumatoid Arthritis, though evidence for this is weak.
• Malignancy: Patients with active cancer may have altered immune responses.
• Beta-Blocker Use: As discussed, this makes treating a reaction difficult.
• Pregnancy (Initiation): It is generally recommended not to start VIT during pregnancy due to the risk of anaphylaxis-induced fetal hypoxia (lack of oxygen).

Patients allergic to Apis Mellifera Venom may show cross-reactivity with other members of the Apidae family (like bumblebees). However, there is usually very little cross-reactivity between honey bee venom and 'Vespid' venoms (yellow jackets, hornets, and wasps). A person can be allergic to both, but it is usually due to two separate sensitizations rather than cross-reactivity.

> Important: Your healthcare provider will evaluate your complete medical history and current health status before prescribing Apis Mellifera Venom.

Apis Mellifera Venom is classified as Pregnancy Category C. The primary risk to the fetus is not the venom itself, but the potential for the mother to have a severe anaphylactic reaction. Anaphylaxis can cause a sudden drop in maternal blood pressure, leading to decreased uterine blood flow and fetal hypoxia (oxygen deprivation).

• Maintenance: If a woman is already on a stable maintenance dose and becomes pregnant, therapy is usually continued because the risk of a reaction to a wild sting is higher than the risk of a reaction to a controlled maintenance dose.
• Initiation: Starting VIT during pregnancy is generally avoided.

There is no evidence that the components of Apis Mellifera Venom are excreted into human breast milk in significant quantities. Because the venom consists of proteins that would be digested in the infant's stomach, the risk to the nursing child is considered negligible. The decision to continue VIT while breastfeeding should be made between the patient and her doctor.

VIT is highly effective in children. According to the American Academy of Allergy, Asthma & Immunology (AAAAI), children with only cutaneous (skin) reactions to stings (like hives) generally do not require VIT, as their risk of future severe reactions is low. However, children who have experienced respiratory or cardiovascular symptoms after a sting are prime candidates for therapy. Growth and development do not appear to be affected by long-term VIT.

Patients over age 65 are at the highest risk for fatal reactions to both wild stings and immunotherapy. This is often due to underlying cardiovascular or pulmonary disease. In this population, the decision to use Apis Mellifera Venom must be made with extreme caution. The 'Estrogen Receptor Agonist' properties of the venom should also be considered in post-menopausal women, although clinical data in this area is limited.

In patients with chronic kidney disease, the clearance of peptide fragments may be slightly delayed. While no specific dose adjustments are standardized, these patients should be monitored closely for delayed local or systemic reactions. Dialysis does not significantly clear the immunological 'blocking antibodies' produced by the therapy.

Liver disease does not typically affect the safety or efficacy of Apis Mellifera Venom. However, severe liver disease (Child-Pugh Class C) may be associated with coagulopathies (bleeding disorders), which could increase the risk of hematoma (bruising) at the injection site.

> Important: Special populations require individualized medical assessment to ensure the benefits of preventing a fatal sting outweigh the risks of the therapy.

Apis Mellifera Venom acts through a dual-pathway mechanism. Immunologically, it induces 'immune tolerance.' By presenting the immune system with gradually increasing amounts of venom allergens (such as Api m 1, which is Phospholipase A2), it stimulates the production of IL-10-producing regulatory T-cells. These cells suppress the allergic Th2 response and promote the production of IgG4 antibodies.

Pharmacologically, the venom contains melittin, which is a potent stimulator of phospholipase A2 and can also act as an Estrogen Receptor Agonist and Androgen Receptor Agonist. Melittin can bind to these steroid receptors, potentially modulating gene expression related to inflammation and cell survival. This explains its classification in the Estrogen [EPC] and Androgen [EPC] categories.

The onset of the immunological effect is slow, typically requiring several months of the build-up phase before significant protection is achieved. The duration of effect is long-lasting; many patients remain protected for years after completing a 5-year course. Tolerance development (in the sense of needing more drug for the same effect) does not occur; rather, 'immunological tolerance' (the desired lack of allergic response) is the goal.

| Parameter | Value |

|---|---|

| Bioavailability | High (Subcutaneous) |

| Protein Binding | Variable (Melittin binds albumin) |

| Half-life | 1.5 - 4 hours (Plasma components) |

| Tmax | 30 - 60 minutes |

| Metabolism | Proteolytic degradation (Proteases) |

| Excretion | Renal (primarily as fragments) |

• Molecular Components: Melittin (C131H229N39O31), Phospholipase A2, Apamin, Hyaluronidase.
• Solubility: Highly soluble in water and saline solutions.
• Structure: A complex aqueous mixture of basic peptides, enzymes, and low-molecular-weight compounds like histamine and dopamine.

Apis Mellifera Venom is a Standardized Allergenic Extract. It is related to other venom extracts such as Vespula species (Yellow Jacket) and Polistes species (Wasp) venom, though its biochemical composition is distinct, particularly its high melittin content.