Hyaluronate derivatives, often referred to as hyaluronic acid derivatives, are modified forms of hyaluronic acid (HA). Hyaluronic acid is a natural substance found in the human body and is known for its ability to retain water, which contributes to the skin's hydration and elasticity. In the context of derivatives, modifications are made to the hyaluronic acid molecule to enhance its properties for various applications, particularly in the fields of medicine, cosmetics, and pharmaceuticals.

Hyaluronate and derivatives (available as Juvederm and other brands) are widely distributed in the extracellular matrix. They are used as an intraarticular injection for osteoarthritis, intradermally for wrinkles, and for cheek augmentation.

Hyaluronate derivatives Uses:

• Intradermal:
  • All formulations of Juvederm (apart from Volbella XC and Voluma XC), Perlane, Restylane, Restylane Defyne, Restylane Lyft, Restylane-L, and Restylane Refyne:
    • These products are intended to treat mild to severe facial creases and wrinkles.
  • Juvederm in every form
    • Perioral rhytides can be treated by persons older than 21 with Juvederm Volbella XC and Restylane Silk.
• Intra-articular injection:
  • It is suggested for the treatment of pain in patients with knee osteoarthritis who do not respond to nonpharmacologic pain relief, basic analgesics, or nonsteroidal anti-inflammatory medications (NSAIDs).
• Subcutaneous:
  • Restylane Lyft: It's utilized to treat dorsal hand volume loss in persons older than 21.
• Topical cream, gel:
  • Atopic dermatitis, allergic contact dermatitis, and radiodermatitis are a few examples of dermatoses that can be treated and relieved of their symptoms, which include burning, itching, and pain. Management of skin ulcers and wounds (Bionect, Therapevo); (Therapevo)
• Subcutaneous/ subperiosteal:
  • Juvederm Voluma XC, Restylane Lyft:
    • Adults over the age of 21 who have a volume deficit due to aging may have their cheeks augmented via deep injections under the skin or supra-periosteal injections.
• Ophthalmic:
  • Retinal attachment surgery (Amvisc, Amvisc Plus)
  • Intraocular lens implantation (Amvisc, Amvisc Plus, Biolon, Provisc)
  • Surgical aid in cataract extraction (Amvisc, Amvisc Plus, Biolon, Provisc)
  • Corneal transplant (Amvisc, Amvisc Plus)
  • Glaucoma filtration (Amvisc, Amvisc Plus)
  • Anterior segment surgery (Biolon, Healon [all formulations])
• Submucosal:
  • Adults above the age of 21 who get lip augmentation (Restylane, Restylane-L, Restylane Silk, Juvederm Ultra XC, Juvederm Volbella XC).
• Off Label Use of Hyaluronate in Adults:
  • Interstitial cystitis that is resistant

Hyaluronate Dose in Adults

Hyaluronate Dose for Cheek Augmentation: Supraperiosteal/Subcutaneous

In adults over 21 years old:

• Juvederm Voluma XC:
  • Inject the product as needed to achieve the desired cosmetic result.
  • Typically, small amounts (0.1 to 0.2 mL) are injected in different spots over a wide area to add volume and shape to the cheeks.
  • You might need more than one treatment to get the look you want.
  • The maximum amount you can use in a year is 20 mL for every 60 kg of body weight.
• Restylane Lyft:
  • The most you can use in one treatment is 6 mL.

Hyaluronate Dose in the therapy of Dermatoses:

Therapevo Gel:

• Apply the gel generously to the affected area.
• Use it 2 to 3 times a day.

Hyaluronate Dose in the therapy of Facial wrinkles/folds: Intradermal:

When using hyaluronate derivatives for the treatment of facial wrinkles and folds through intradermal injection, the recommended doses vary depending on the specific formulation. Here are the guidelines for different products:

• Juvederm (all formulations except Voluma XC):
  • Inject as needed to achieve the desired cosmetic result.
  • A typical treatment usually requires 1.6 to 1.7 mL per treatment site.
  • For repeat treatments, the typical volume is 0.56 to 0.7 mL per treatment site.
  • The maximum amount you can use in a year is 20 mL for every 60 kg of body weight.
• Perlane, Restylane Lyft:
  • Inject as needed into the deep dermis or superficial subcutis for the desired cosmetic result.
  • The median total dose is 3 mL for Perlane.
  • The maximum amount for each treatment is 6 mL.
• Restylane, Restylane-L:
  • Inject as needed to achieve the desired cosmetic result.
  • The median total dose is 3 mL.
  • The maximum amount for each treatment is 6 mL.
• Restylane Defyne:
  • Inject as needed for the cosmetic result.
  • A typical treatment is generally around 1.4 mL per treatment site.
  • For repeat treatments, the typical volume is about 0.7 mL per treatment site.
• Restylane Refyne:
  • Inject as needed for the cosmetic result.
  • A typical treatment is generally around 1.5 mL per treatment site.
  • For repeat treatments, the typical volume is about 1 mL per treatment site.

Hyaluronate Dose in the Hand augmentation: Subcutaneous:

With Restylane Lyft, the recommended dose for adults over 21 years old is as follows:

• Restylane Lyft:
  • Inject small amounts (boluses) in the subcutaneous plane on the dorsum (back) of the hand.
  • The maximum amount you can use per hand in one treatment session is 3 mL.

Hyaluronate Dose in the treatment of Interstitial cystitis, refractory (off-label):

• Dose:
  • 40 mg of the hyaluronate derivative in 50 mL saline is administered intravesically.
  • The solution should be retained in the bladder for at least 30 minutes.
• Frequency:
  • Administer once weekly for the first 4 weeks.
  • After the initial 4-week period, continue with monthly administrations for up to 1 year in patients who show an initial positive response.

This information is based on a specific study from 1996 (Morales 1996) and reflects an off-label use of hyaluronate derivatives for interstitial cystitis.

Hyaluronate Dose in the Lip augmentation: Submucosal:

For adults over 21 years old are as follows:

• Juvederm Ultra XC:
  • Approximately 2.2 mL is administered to the lips and perioral area.
  • Correct to 100% of the desired volume effect without overcorrection.
  • Repeat treatment is generally 1.5 mL.
  • The maximum amount for each treatment session is 20 mL for every 60 kg of body weight in a year.
• Juvederm Volbella XC:
  • Approximately 2.6 mL is administered to the lips and perioral area.
  • Correct to 100% of the desired volume effect without overcorrection.
  • Repeat treatment is generally 1.6 mL.
  • The maximum amount for each treatment session is 20 mL for every 60 kg of body weight in a year.
• Restylane, Restylane-L, Restylane Silk:
  • The maximum amount for each lip (upper or lower) in one treatment session is 1.5 mL.

Hyaluronate Dose in the treatment of Osteoarthritis of the knee: Intra-articular:

• Durolane:
  • Inject 60 mg (3 mL) once.
• Euflexxa:
  • Inject 20 mg (2 mL) once weekly for 3 weeks (total of 3 injections).
• Gel-One:
  • Inject 30 mg (3 mL) once.
• Gelsyn-3:
  • Inject 16.8 mg (2 mL) once weekly for 3 weeks (total of 3 injections).
• GenVisc 805, Supartz, Supartz FX:
  • Inject 25 mg (2.5 mL) once weekly for 5 weeks (total of 5 injections); some patients may benefit from a total of 3 injections.
• Hyalgan:
  • Inject 20 mg (2 mL) once weekly for 5 weeks (total of 5 injections); some patients may benefit from a total of 3 injections.
• Hymovis:
  • Inject 24 mg (3 mL) once weekly for 2 weeks (total of 2 injections).
• Monovisc:
  • Inject 88 mg (4 mL) once.
• Orthovisc:
  • Inject 30 mg (2 mL) once weekly for 3 to 4 weeks (total of 3 to 4 injections).
• Synvisc:
  • Inject 16 mg (2 mL) once weekly for 3 weeks (total of 3 injections).
• Synvisc-One:
  • Inject 48 mg (6 mL) once.
• TriVisc:
  • Inject 25 mg (2.5 mL) once weekly for 3 weeks (total of 3 injections).
• Visco-3:
  • Inject 25 mg (2.5 mL) once weekly for 3 weeks (total of 3 injections).

Hyaluronate Dose in the therapy of Perioral rhytids: Intradermal:

For adults over 21 years old are as follows:

• Restylane Silk:
  • The maximum amount for each correction in one treatment session is 1 mL.
• Juvederm Volbella XC:
  • For perioral rhytids, it is recommended to refer to the dosing guidelines for lip augmentation. This implies that the dosing for Juvederm Volbella XC in the context of perioral rhytids should follow the lip augmentation dosing guidelines provided for adults over 21 years.

Hyaluronate Dose in the treatment of Skin ulcers and wounds: Topical:

• Bionect cream, gel:
  • Apply a thin layer to the clean and disinfected wound or ulcer.
  • Apply 2 to 3 times daily.
• Therapevo gel:
  • Apply the gel liberally to the clean and dried wound or ulcer and the surrounding area.
  • Apply once daily.

Hyaluronate Dose in the therapy of Surgical aid:

• When using hyaluronate derivatives as a surgical aid for eye procedures, such as in products like Amvisc, Amvisc Plus, Biolon, Healon, and Provisc, the amount used depends on the specific surgical procedure.
• The general instruction is to slowly introduce a sufficient quantity of the hyaluronate derivative into the eye.
• The goal is to provide the necessary support and maintain the right conditions during the surgery.

• It's crucial for the surgeon to determine the appropriate amount based on the nature of the eye procedure being performed.
• This ensures the best possible outcome and safety for the patient.

Use in Children:

Not indicated.

Pregnancy Risk Category: C

• In studies with animals, no harmful effects were seen during pregnancy.
• However, it's not clear if it's safe for pregnant women since specific research on this hasn't been done yet.
• More studies are needed to understand if there are any risks or if it's safe for pregnant women to use.

Use during breastfeeding:

• It's uncertain whether hyaluronic acid derivatives are present in breast milk.
• Manufacturers advise caution when giving these derivatives to breastfeeding women.
• This means that there's not enough information to confirm whether these substances pass into breast milk or if they could affect a nursing baby.

Dose in Kidney Disease:

• The information from the manufacturer's labeling indicates that there are no recommended changes in dosage for individuals with renal impairment.
• This means that, according to the manufacturer's instructions, the usual dosage of the product should be followed regardless of any kidney-related issues.

Dose in Liver disease:

• The manufacturer's labeling indicates that there are no recommended changes or dosage adjustments for individuals with hepatic (liver) impairment.
• This suggests that, according to the manufacturer's instructions, the usual dosage of the product should be followed regardless of any liver-related issues.

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Depending on the formulation and the application or injection site, local reactions can take different forms. Lidocaine is mentioned concurrently in some reports.

Common Side Effects of Hyaluronate (Juvederm):

• Neuromuscular & Skeletal:
  • Arthralgia
  • Joint Swelling
  • Joint Effusion
• Central Nervous System:
  • Headache
• Hematologic & Oncologic:
  • Bruise
• Dermatologic:
  • Skin Discoloration At Injection Site
• Local:
  • Muscle Rigidity At Injection Site
  • Hematoma At Injection Site
  • Erythema At Injection Site
  • Induration At Injection Site
  • Swelling At Injection Site
  • Tenderness At Injection Site
  • Bruising At Injection Site
  • Pain At Injection Site
  • Residual Mass At Injection Site
  • Itching At Injection Site
• Miscellaneous:
  • Swelling

Less Common Side Effects Of Hyaluronate (Juvederm):

• Cardiovascular:
  • Increased Blood Pressure
  • Edema
  • Presyncope
  • Hypertension
• Infection:
  • Influenza
  • Infection
  • Herpes Zoster Infection
• Central Nervous System:
  • Paresthesia
  • Sciatica
  • Malaise
  • Tingling In The Lips
  • Falling
  • Dizziness
  • Hyperesthesia
  • Hypoesthesia
  • Fatigue
• Gastrointestinal:
  • Diarrhea
  • Dyspepsia
  • Oral Herpes Simplex Infection
  • Toothache
  • Abdominal Pain
  • Nausea
• Dermatologic:
  • Papule Of Skin
  • Rash At Injection Site
  • Cheilosis
  • Fine Wrinkling
  • Local Acneiform Eruptions
  • Ecchymoses
  • Hyperpigmentation
  • Exfoliation Of Skin
  • Local Dryness
  • Skin Tightness
• Genitourinary:
  • Urinary Tract Infection
• Neuromuscular & Skeletal:
  • Arthropathy
  • Connective Tissue Disease
  • Lower Extremity Pain
  • Back Pain
  • Limb Pain
  • Puffiness Of Cheeks
  • Musculoskeletal Disease
  • Musculoskeletal Pain
  • Localized Osteoarthritis
  • Muscle Strain
  • Osteoarthritis
  • Tendonitis
  • Joint Stiffness
• Local:
  • Local Skin Exfoliation
  • Injection Site Infection
  • Injection Site Nodule
  • Injection Site Numbness
  • Bleeding At Injection Site
  • Injection Site Reaction
• Ophthalmic:
  • Cystoid Macular Edema
  • Opacity Of Ocular Lens Capsule
  • Conjunctivitis
  • Increased Intraocular Pressure
  • Punctate Keratitis
  • Superficial Keratitis
  • Corneal Injury
  • Injury To Eye Region
  • Corneal Edema
  • Corneal Erosion
  • Uveitis
• Miscellaneous:
  • Laceration
  • Accidental Injury
  • Fever
  • Soft Tissue Injury
  • Wound
• Respiratory:
  • Bronchitis
  • Rhinitis
  • Sinusitis
  • Nasopharyngitis
  • Oropharyngeal Pain
  • Respiratory Tract Infection
  • Upper Respiratory Tract Infection
  • Flulike Symptoms
  • Cough

Frequency of side effects not defined:

• Ophthalmic:
  • Ophthalmic inflammation (postoperative; iritis, hypopyon)
• Central nervous system:
  • Tingling sensation

Contraindications to Hyaluronate (Juvederm):

• If someone has a strong reaction or allergy to hyaluronate or any part of the product, they should avoid using it. This is known as hypersensitivity.

Submucosal and Intradermal:

• For injections under the skin or in certain tissues, there are some situations where it's not recommended.
• These include a history of severe allergic reactions or anaphylaxis, the presence of multiple severe allergies, bleeding disorders, a history of strong sensitivity to certain bacterial proteins or specific local anesthetics.
• Additionally, it's important to follow the recommended injection sites as per the product instructions.

Intraocular:

• The manufacturer's instructions for intraocular use, involving products like Amvisc, Amvisc Plus, Biolon, Healon (all formulations), and Provisc, do not list any specific situations where the use of these products is not recommended.
• This means that, according to the manufacturer's information, there are no contraindications or reasons why these products cannot be used in the eye for specific procedures.

Intra-articular

• For injections directly into the knee joint, there are certain situations where it's not recommended.
• This includes having an infection in the knee joint, infections or skin diseases at the injection site, hypersensitivity to specific bacterial proteins, and systemic bleeding disorders.

Subcutaneous/Supraperiosteal:

• Numerous severe allergies and a history of anaphylaxis are further contraindications (Juvederm Voluma XC and Restylane Lyft).
• Patients with a history of reactions to proteins from gram-positive bacteria or lidocaine (Juvederm Voluma XC and Restylane Lyft).

Monitoring parameters:

Intraocular Formulations (Eye Use):

• Keep an eye out for changes in intraocular pressure (pressure inside the eye) when using formulations for the eyes.
• Report any unusual symptoms or discomfort to your eye doctor.

Intradermal Formulations (Under the Skin):

• Watch for signs of too much local inflammation or infection at the injection site.
• If you notice any redness, swelling, or other unusual symptoms, let your healthcare provider know promptly.

How to administer Hyaluronate?

Intra-articular:

• Inject directly into the knee joint; avoid injecting outside the joint or into specific tissues.
• Do not use certain disinfectants for skin cleaning before the injection.
• If treating both knees, use separate syringes for each.
• Follow the manufacturer's instructions for injection technique.

Intradermal/Submucosal/Subcutaneous/Supraperiosteal:

• Avoid injecting into blood vessels.
• Massage the area after injection.
• Apply an ice pack if the treated area is swollen.
• Before treatment, avoid certain medications and supplements to reduce the risk of bruising and bleeding.
• Follow the specific injection guidelines for each product.

Ophthalmic:

• Let the product reach room temperature before using.
• If the drug looks cloudy or forms a slight precipitate after administration, it can be removed by irrigation or aspiration.
• Refer to the manufacturer's instructions for procedure-specific details.

Topical (Bionect products):

• Clean and disinfect the wound before applying.
• Avoid certain disinfectants due to the potential for hyaluronic acid precipitation.
• Apply a thin layer without rubbing extensively.
• Cover the area with sterile gauze and, if needed, a compressive bandage.

Topical (Therapevo):

• For wound or ulcer management, clean with normal saline and debride if necessary.
• Apply liberally to the ulcer or wound and surrounding area.
• Cover with non-stick gauze dressing after application.
• For dermatoses, apply directly and liberally to the affected area.

Mechanism of action of Hyaluronate (Juvederm):

• Sodium hyaluronate is a natural substance found throughout the body, especially in connective tissues like the vitreous and aqueous humor of the eyes, synovial fluid, skin, and umbilical cord.
• It creates a solution that acts like a gel in water, making it useful in surgeries involving the eyes and joints.
• Sodium hyaluronate helps lubricate tissues and joints, playing a crucial role in how tissues interact.
• When injected into the skin, it can reduce the depth of facial wrinkles.
• For lip augmentation, injecting it just under the skin's surface can help smooth out wrinkles around the mouth.
• In cheek augmentation, injecting it below the skin's surface can address age-related volume loss.
• In topical applications for wound and ulcer care, sodium hyaluronate provides a protective layer, shielding the skin from friction and abrasion.

Distribution:

• Intravitreous Injection:
  • Diffusion of sodium hyaluronate happens gradually when injected into the vitreous (the jelly-like substance in the eye).

Excretion:

• Ophthalmic:
  • Excretion of sodium hyaluronate occurs through the Canal of Schlemm, a drainage system in the eye. This is the route through which the substance leaves the eye after being used in ophthalmic procedures.

International Brand Names of Hyaluronate:

 

• Bionect
• Durolane
• Healon EndoCoat
• Healon GV
• Euflexxa
• Amvisc
• Amvisc Plus
• Orthovisc
• Perlane
• Perlane-L
• Provisc
• Gel-One
• Gelsyn-3
• GenVisc 850
• Healon
• Healon5
• Hyalgan
• HyGel [DSC]
• Hymovis
• Juvederm Ultra
• Juvederm Ultra Plus
• Juvederm Ultra Plus XC
• Therapevo
• Cystistat
• Durolane
• Juvederm Ultra XC
• Juvederm Voluma XC
• Monovisc
• Restylane Lyft
• Restylane Silk
• Restylane
• Restylane-L
• Supartz FX
• Supartz
• Synvisc
• Synvisc-One
• OrthoVisc
• Suplasyn
• Adant Dispo
• Amvisc
• Aragan
• Aragan Plus
• Artz
• Atri
• Biolon
• Curiosin
• Duovisc
• Durolane
• Eyecon
• Gengigel
• Go-On
• Halubone
• Healon
• Healon GV
• Healonid
• Helo
• Hialid
• Hyal
• Hyal Forte
• Hyalein
• Hyalgan
• Hyalgun
• Hyaludrop
• Hylo-Comod
• Hyronate
• Hyruan
• IAL
• Iolvisc
• Kynex
• Lacure
• Laservis
• Lghyal
• Osflex
• Oxyal
• Provisc
• Suplasyn
• Synvisc
• Synvisc One
• Synvisc-One
• Tearbalance
• Toptear
• Viscoseal
• Visiol
• Vivial

Hyaluronate derivatives Brand Names in Pakistan:

Sodium Hyaluronate Injection 10 Mg/Ml in Pakistan
Hyal	Medisure Laboratories Pakistan (Pvt.) Ltd.
Hyalgan Injection	Matrix Pharma
Hyone	Hoffman Health Pakistan Ltd.
Hyruan	Hoffman Health Pakistan Ltd.
Provisc	Novartis Pharma (Pak) Ltd
Unihylon	Neutro Pharma (Pvt) Ltd.

Sodium Hyaluronate Eye Drops 0.2 %W/V in Pakistan
Hylo Eye Drops	Helix Pharma (Private) Limited

Sodium Hyaluronate Eye Drops 0.18 %W/V in Pakistan
Isvisic Ophthalmic Solution	Isis Pharmaceutical
Solonate	Valor Pharmaceuticals

Sodium Hyaluronate Solution 1 %V/V in Pakistan
Bluyal Ud	Haroon Brothers

Sodium Hyaluronate Gel 50 Mg in Pakistan
Genginil	Zanctok Pharmaceuticals