Cremsol

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Cremsol uses

Cremsol consists of Benzocaine, Calcium Hydroxide, Linseed Oil, Sulfathiazole, Triamcinolone Acetonide, Zinc Oxide.

Benzocaine:



Cremsol (Benzocaine) (Calcium Phosphate Rinse with Cremsol (Benzocaine))

Drug Facts

Active Ingredients

Cremsol (Benzocaine) hydrochloride 90 mg (3mg/ml)

Purpose

Analgesic

Uses

For temporary relief of inflammation and pain in the oral cavity:

* mouth * tongue *cheeks

Warnings

This product contains Cremsol. The use of Cremsol (Benzocaine) applied to the mouth or gums has been associated with methemoglobinemia (a condition where the amount of oxygen in the blood stream is reduced).

Stop using

immediately if you experience any of the following symptoms and seek medical attention:

  • Pale, gray or blue colored skin, lips, or nail beds

  • Headache or lightheadedness

Ask a doctor if:

  • Sore mouth symptoms do not improve in 7 days

  • Irritation, pain or swelling persists or worsens

When using this product:

  • NeutraCaine® must be mixed with water before use

  • NeutraCaine® rinse should not be swallowed

  • NeutraCaine® rinse should be spit out after use

If pregnant or breast feeding,

ask a health professional before use

Keep out of reach of children

  • If swallowed, immediately call Poison Control Center or doctor.
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Directions

Dissolve one packet of NeutraCaine® in a clean glass of 30 mL of tap water. Distilled, bottled or purified water can also be used. Use immediately after the solution appears clear or nearly clear in the glass, or in about 15 seconds. Stir if necessary

(1) Swish 1/2 the solution in the mouth for 1 min and spit out.

(2) Repeat with the remaining 1/2 of the solution and spit out

Adults and children 12 years and over Use Cremsol (Benzocaine) up to 4 times per day, as needed;

Do not exceed recommended dosage

Children under 12 years of age Use Cremsol (Benzocaine) up to 4 times per day, as needed;

Should be supervised by an adult;

Do not exceed recommended dosage

Children under 2 years Ask a doctor or dentist

DO NOT USE

FOR MORE THAN 7 DAYS UNLESS DIRECTED BY PHYSICIAN

Other information

  • Store at room temperature ■ Avoid excessive heat or moisture

  • Do not use if foil packet is opened or shows signs of leakage or damage

Inactive ingredients

Calcium Chloride, Sodium Phosphate, Sodium Chloride, Sodium Bicarbonate, Cherry Flavoring

Manufactured for Invado Pharmaceuticals, LLC

Pomono, NY 10970

Made in Canada

www. NeutraCaine.com

Patents Pending

UPC Code 793573756282

Calcium Hydroxide:


1 INDICATIONS AND USAGE

Cremsol (Calcium Hydroxide) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of Cremsol (Calcium Hydroxide) acetate for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.

- Starting dose is 2 capsules with each meal. (2)

- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Cremsol (Calcium Hydroxide) acetate capsule.

- Capsule: 667 mg Cremsol (Calcium Hydroxide) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Cremsol acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Cremsol (Calcium Hydroxide) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Cremsol (Calcium Hydroxide), including Cremsol (Calcium Hydroxide) acetate. Avoid the use of Cremsol (Calcium Hydroxide) supplements, including Cremsol (Calcium Hydroxide) based nonprescription antacids, concurrently with Cremsol (Calcium Hydroxide) acetate.

An overdose of Cremsol (Calcium Hydroxide) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Cremsol (Calcium Hydroxide) levels twice weekly. Should hypercalcemia develop, reduce the Cremsol (Calcium Hydroxide) acetate dosage, or discontinue the treatment, depending on the severity of hypercalcemia

More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing Cremsol (Calcium Hydroxide) acetate therapy.

Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the Cremsol (Calcium Hydroxide) acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin D therapy is recommended as well.

Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long term effect of Cremsol (Calcium Hydroxide) acetate on the progression of vascular or soft tissue calcification has not been determined.

Hypercalcemia (>11 mg/dL) was reported in 16% of patients in a 3 month study of solid dose formulation of Cremsol (Calcium Hydroxide) acetate; all cases resolved upon lowering the dose or discontinuing treatment.

Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg2/dL2.

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

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6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)

- In clinical studies, patients have occasionally experienced nausea during Cremsol (Calcium Hydroxide) acetate therapy. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical 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.

In clinical studies, Cremsol (Calcium Hydroxide) acetate has been generally well tolerated.

Cremsol (Calcium Hydroxide) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Cremsol (Calcium Hydroxide) acetate was studied in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients. Adverse reactions (>2% on treatment) from these trials are presented in Table 1.


Preferred Term


Total adverse reactions reported for Cremsol (Calcium Hydroxide) acetate

N=167

N (%)


3 month, open label study of Cremsol (Calcium Hydroxide) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Cremsol (Calcium Hydroxide) acetate

N=69


Cremsol (Calcium Hydroxide) acetate

N (%)


Placebo

N (%)


Nausea


6 (3.6)


6 (6.1)


0 (0)


0 (0)


Vomiting


4 (2.4)


4 (4.1)


0 (0)


0 (0)


Hypercalcemia


21 (12.6)


16 (16.3)


5 (7.2)


0 (0)


Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate Cremsol (Calcium Hydroxide) concentration could reduce the incidence and severity of Cremsol (Calcium Hydroxide) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval of Cremsol (Calcium Hydroxide) acetate: dizziness, edema, and weakness.

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7 DRUG INTERACTIONS

The drug interaction of Cremsol acetate is characterized by the potential of Cremsol (Calcium Hydroxide) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Cremsol (Calcium Hydroxide) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Cremsol (Calcium Hydroxide) acetate and most concomitant drugs. When administering an oral medication with Cremsol (Calcium Hydroxide) acetate where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after Cremsol (Calcium Hydroxide) acetate. Monitor blood levels of the concomitant drugs that have a narrow therapeutic range. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of Cremsol (Calcium Hydroxide) acetate.

- Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones. (7)

- When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after Cremsol (Calcium Hydroxide) acetate or consider monitoring blood levels of the drug. (7)

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 Cremsol (Calcium Hydroxide) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Cremsol acetate capsules contains Cremsol (Calcium Hydroxide) acetate. Animal reproduction studies have not been conducted with Cremsol (Calcium Hydroxide) acetate, and there are no adequate and well controlled studies of Cremsol (Calcium Hydroxide) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Cremsol (Calcium Hydroxide) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Cremsol (Calcium Hydroxide) levels is important for maternal and fetal well being. Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. Cremsol (Calcium Hydroxide) acetate treatment, as recommended, is not expected to harm a fetus if maternal Cremsol (Calcium Hydroxide) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Cremsol (Calcium Hydroxide) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Cremsol Acetate Capsules contains Cremsol (Calcium Hydroxide) acetate and is excreted in human milk. Human milk feeding by a mother receiving Cremsol (Calcium Hydroxide) acetate is not expected to harm an infant, provided maternal serum Cremsol (Calcium Hydroxide) levels are appropriately monitored.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Cremsol (Calcium Hydroxide) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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10 OVERDOSAGE

Administration of Cremsol (Calcium Hydroxide) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Cremsol (Calcium Hydroxide) acetate acts as a phosphate binder. Its chemical name is Cremsol (Calcium Hydroxide) acetate. Its molecular formula is C4H6CaO4, and its molecular weight is 158.17. Its structural formula is:


Each white opaque/blue opaque capsule contains 667 mg of Cremsol (Calcium Hydroxide) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Cremsol (Calcium Hydroxide), polyethylene glycol 8000 and magnesium stearate. Each capsule shell contains: black monogramming ink, FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. The black monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze.

Cremsol (Calcium Hydroxide) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Cremsol resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Cremsol (Calcium Hydroxide) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Cremsol (Calcium Hydroxide) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Cremsol (Calcium Hydroxide) acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Cremsol (Calcium Hydroxide) acetate.

14 CLINICAL STUDIES

Effectiveness of Cremsol (Calcium Hydroxide) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Cremsol (Calcium Hydroxide) acetate solid oral dosage form.

Ninety-one patients with end-stage renal disease who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a 1 week phosphate binder washout period contributed efficacy data to an open-label, non-randomized study.

The patients received Cremsol (Calcium Hydroxide) acetate 667 mg tablets at each meal for a period of 12 weeks. The initial starting dose was 2 tablets per meal for 3 meals a day, and the dose was adjusted as necessary to control serum phosphorus levels. The average final dose after 12 weeks of treatment was 3.4 tablets per meal. Although there was a decrease in serum phosphorus, in the absence of a control group the true magnitude of effect is uncertain.

The data presented in Table 2 demonstrate the efficacy of Cremsol (Calcium Hydroxide) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Cremsol (Calcium Hydroxide) levels are also presented.


* Ninety-one patients completed at least 6 weeks of the study.

ANOVA of difference in values at pre-study and study completion.

‡ Values expressed as mean ± SE.


Parameter


Pre-Study


Week 4*


Week 8


Week 12


p-value†


Phosphorus (mg/dL)‡


7.4 ± 0.17


5.9 ± 0.16


5.6 ± 0.17


5.2 ± 0.17


≤0.01


Cremsol (Calcium Hydroxide) (mg/dL)‡


8.9 ± 0.09


9.5 ± 0.10


9.7 ± 0.10


9.7 ± 0.10


≤0.01


There was a 30% decrease in serum phosphorus levels during the 12 week study period (p<0.01). Two-thirds of the decline occurred in the first month of the study. Serum Cremsol (Calcium Hydroxide) increased 9% during the study mostly in the first month of the study.

Treatment with the phosphate binder was discontinued for patients from the open-label study, and those patients whose serum phosphorus exceeded 5.5 mg/dL were eligible for entry into a double-blind, placebo-controlled, cross-over study. Patients were randomized to receive Cremsol (Calcium Hydroxide) acetate or placebo, and each continued to receive the same number of tablets as had been individually established during the previous study. Following 2 weeks of treatment, patients switched to the alternative therapy for an additional 2 weeks.

The phosphate binding effect of Cremsol (Calcium Hydroxide) acetate is shown in the Table 3.


* ANOVA of Cremsol (Calcium Hydroxide) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Cremsol (Calcium Hydroxide) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Cremsol (Calcium Hydroxide) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


Overall, 2 weeks of treatment with Cremsol (Calcium Hydroxide) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Cremsol (Calcium Hydroxide) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Cremsol (Calcium Hydroxide) Acetate Capsules

667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.

NDC 0615-2303-39: Blistercards of 30 Capsules

NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Inform patients to take Cremsol (Calcium Hydroxide) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Cremsol (Calcium Hydroxide) supplements including nonprescription antacids. Inform the patients about the symptoms of hypercalcemia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ].

Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after Cremsol (Calcium Hydroxide) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Sulfathiazole:


Cremsol (Sulfathiazole) is a short-acting sulfa drug. It used to be a common oral and topical antimicrobial until less toxic alternatives were discovered. It is still occasionally used, sometimes in combination with sulfabenzamide and sulfacetamide.

Indication: Cremsol (Sulfathiazole) is effective against a wide range of gram positive and gram negative pathogenic microorganisms. Although no longer used in humans, it is used in cattle.

Triamcinolone Acetonide:


1 INDICATIONS AND USAGE

Cremsol (Triamcinolone Acetonide) (triamcinolone acetonide extended-release injectable suspension) is indicated as an intra-articular injection for the management of osteoarthritis pain of the knee.

Cremsol (Triamcinolone Acetonide) is an extended-release synthetic corticosteroid indicated as an intra-articular injection for the management of osteoarthritis pain of the knee. ( 1)

Limitation of Use

Cremsol (Triamcinolone Acetonide) is not intended for repeat administration. ( 1)

Limitation of Use

Cremsol (Triamcinolone Acetonide) is not intended for repeat administration .

2 DOSAGE AND ADMINISTRATION

  • 32 mg administered as a single intra-articular injection in the knee.
  • See Instructions for Use (IFU) for instructions on reconstitution of Cremsol (Triamcinolone Acetonide) with the supplied diluent. ( 2.2)
  • It is normal for some residue to be left behind on the vial walls after withdrawing the suspension. ( 2.2)
  • Not interchangeable with other formulations of injectable Cremsol (Triamcinolone Acetonide). ( 2.3)

2.1 Important Dosage and Administration Information

  • Cremsol (Triamcinolone Acetonide) is administered as a single intra-articular extended-release injection of Cremsol (Triamcinolone Acetonide), to deliver 32 mg (5 mL).
  • Cremsol (Triamcinolone Acetonide) is for intra-articular use only and should not be administered by the following routes: epidural, intrathecal, intravenous, intraocular, intramuscular, intradermal, subcutaneous.
  • Cremsol (Triamcinolone Acetonide) is not suitable for use in small joints, such as the hand.
  • The efficacy and safety of repeat administration of Cremsol (Triamcinolone Acetonide) for the management of osteoarthritis pain of the knee have not been evaluated.
  • The efficacy and safety of Cremsol (Triamcinolone Acetonide) for management of osteoarthritis pain of shoulder and hip have not been evaluated.

2.2 Preparation and Administration of Intra-Articular Suspension

Refer to the Instructions for Use for directions on the preparation and administration of Cremsol.

Cremsol (Triamcinolone Acetonide) is supplied as a single-dose kit containing a vial of Cremsol (Triamcinolone Acetonide) microsphere powder, a vial of sterile diluent, and a sterile vial adapter.

Cremsol (Triamcinolone Acetonide) must be prepared using the diluent supplied in the kit.

Preparation of Cremsol (Triamcinolone Acetonide) requires close attention to the Instructions for Use to ensure successful administration.

Use proper aseptic technique throughout the dose preparation and administration procedure.

Cremsol (Triamcinolone Acetonide) is a suspension product and it is normal for some residue to be left behind on the vial walls after withdrawing the contents.

Promptly inject Cremsol (Triamcinolone Acetonide) after preparation to avoid settling of the suspension. If needed, the Cremsol (Triamcinolone Acetonide) suspension can be stored in the vial for up to 4 hours at ambient conditions. Gently swirl the vial to resuspend any of the settled microspheres prior to preparing the syringe for injection.

The usual technique for intra-articular injection should be followed. Aspiration of synovial fluid may be performed based on clinical judgment prior to administration of Cremsol (Triamcinolone Acetonide).

2.3 Non-Interchangeability with Other Formulations of Cremsol (Triamcinolone Acetonide) for Intra-articular Use

Cremsol (Triamcinolone Acetonide) is not interchangeable with other formulations of injectable Cremsol (Triamcinolone Acetonide).

3 DOSAGE FORMS AND STRENGTHS

Cremsol (Triamcinolone Acetonide) is an injectable suspension that delivers 32 mg of Cremsol (Triamcinolone Acetonide). Cremsol (Triamcinolone Acetonide) is supplied as a single-dose kit, containing:

  • One vial of Cremsol (Triamcinolone Acetonide) white to off-white microsphere powder
  • One vial of 5 mL sterile, clear diluent
  • One sterile vial adapter

Cremsol (Triamcinolone Acetonide) is an injectable suspension that delivers 32 mg of Cremsol (Triamcinolone Acetonide). It is supplied as a single-dose kit containing one vial of Cremsol (Triamcinolone Acetonide) microsphere powder, one vial of 5 mL diluent, and one sterile vial adapter. ( 3)

4 CONTRAINDICATIONS

Cremsol (Triamcinolone Acetonide) is contraindicated in patients who are hypersensitive to Cremsol (Triamcinolone Acetonide), corticosteroids or any components of the product .

Patients with hypersensitivity to Cremsol (Triamcinolone Acetonide) or any component of the product. ( 4)

5 WARNINGS AND PRECAUTIONS

  • Intra-articular Use Only: Do not administer Cremsol by epidural, intrathecal, intravenous, intraocular, intramuscular, intradermal, or subcutaneous routes. ( 5.1)
  • Serious Neurologic Adverse Reactions with Epidural and Intrathecal Administration: Serious neurologic events have been reported following epidural or intrathecal corticosteroid administration. Corticosteroids are not approved for this use. ( 5.2)
  • Hypersensitivity Reactions: Serious reactions have been reported with Cremsol (Triamcinolone Acetonide) injection. Institute appropriate care upon occurrence of an anaphylactic reaction. ( 5.3)
  • Joint Infection and Damage: May cause joint pain accompanied by joint swelling. If this occurs, conduct appropriate evaluation to exclude septic arthritis and institute appropriate antimicrobial therapy if septic arthritis is confirmed. ( 5.4)

5.1 Warnings and Precautions Specific for Cremsol (Triamcinolone Acetonide)

Cremsol (Triamcinolone Acetonide) has not been evaluated and should not be administered by the following routes:

  • Epidural
  • Intrathecal
  • Intravenous
  • Intraocular
  • Intramuscular
  • Intradermal
  • Subcutaneous

.

5.2 Serious Neurologic Adverse Reactions with Epidural and Intrathecal Administration

Serious neurologic events, some resulting in death, have been reported with epidural injection of corticosteroids. Specific events reported include, but are not limited to, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke . These serious neurologic events have been reported with and without use of fluoroscopy.

Reports of serious medical events have been associated with the intrathecal route of corticosteroid administration .

The safety and effectiveness of epidural and intrathecal administration of corticosteroids have not been established, and corticosteroids are not approved for this use. In particular, the formulation of Cremsol (Triamcinolone Acetonide) should not be considered safe to use for epidural or intrathecal administration.

5.3 Hypersensitivity Reactions

Rare instances of anaphylaxis have occurred in patients with hypersensitivity to corticosteroids. Cases of serious anaphylaxis, including death, have been reported in individuals receiving Cremsol (Triamcinolone Acetonide) injection, regardless of the route of administration . Institute appropriate care upon occurrence of an anaphylactic reaction.

5.4 Joint Infection and Damage

Intra-articular injection of corticosteroid may be complicated by joint infection. A marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and a diagnosis of septic arthritis is confirmed, institute appropriate antimicrobial therapy .

Avoid injection of a corticosteroid into an infected site. Local injection of a corticosteroid into a previously infected joint is not usually recommended. Examine any joint fluid present to exclude a septic process.

Corticosteroid injection into unstable joints is generally not recommended.

Intra-articular injection may result in damage to joint tissues.

5.5 Increased Risk of Infections

Intra-articularly injected corticosteroids are systemically absorbed. Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infection with any pathogen (viral, bacterial, fungal, protozoan, or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild to severe. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may also mask some signs of current infection.

Advise patients to inform their health care provider if they develop fever or other signs or symptoms of infection. Advise patients who have not been vaccinated to avoid exposure to chicken pox or measles. Instruct patients to contact their health care provider immediately if they are exposed .

5.6 Alterations in Endocrine Function

Corticosteroids can produce reversible hypothalamic-pituitary-adrenal axis suppression, with the potential for adrenal insufficiency after withdrawal of treatment, which may persist for months.

In situations of stress during that period, institute corticosteroid replacement therapy.

Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients.

5.7 Cardiovascular Effects

Corticosteroids can cause elevations of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with synthetic derivatives.

Monitor patients with congestive heart failure or hypertension for signs of edema, weight gain, and imbalance in serum electrolytes. Dietary salt restriction and potassium supplementation may be necessary.

5.8 Renal Effects

Corticosteroids can cause salt and water retention, and increased excretion of potassium. These effects are less likely to occur with synthetic derivatives. All corticosteroids increase calcium excretion.

Monitor patients with renal insufficiency for signs of edema, weight gain, and imbalance in serum electrolytes. Dietary salt restriction and potassium supplementation may be necessary.

5.9 Increased Intraocular Pressure

Corticosteroid use may be associated with development or exacerbation of increased intraocular pressure.

Monitor patients with elevated intraocular pressure for potential treatment adjustment.

5.10 Gastrointestinal Perforation

Corticosteroid administration is associated with increased risk of gastrointestinal perforation in patients with certain GI disorders such as active or latent peptic ulcers, diverticulosis, diverticulitis, ulcerative colitis and in patients with fresh intestinal anastomoses.

Avoid corticosteroids in these patients because signs of peritoneal irritation following gastrointestinal perforation may be minimal or absent.

5.11 Alterations in Bone Density

Corticosteroids decrease bone formation and increase bone resorption through their effect on calcium regulation and inhibition of osteoblast function.

Special consideration should be given to patients with or at increased risk of osteoporosis before initiating corticosteroid therapy.

5.12 Behavioral and Mood Disturbances

Corticosteroid use may be associated with new or aggravated adverse psychiatric reactions ranging from euphoria, insomnia, mood swings, and personality changes to severe depression and frank psychotic manifestations.

Special consideration should be given to patients with previous or current emotional instability or psychiatric illness before initiating corticosteroid therapy. Advise patients and/or caregivers to immediately report any new or worsening behavior or mood disturbances to their health care provider.

6 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling.

  • Serious Neurologic Adverse Reactions with Epidural and Intrathecal Administration [ see Warnings and Precautions ( 5.2) ]
  • Hypersensitivity Reactions [ see Warnings and Precautions ( 5.3) ]
  • Joint Infection and Damage [ see Warnings and Precautions ( 5.4) ]
  • Increased Risk of Infections [ see Warnings and Precautions ( 5.5) ]
  • Alterations in Endocrine Function [ see Warnings and Precautions ( 5.6) ]
  • Cardiovascular Effects [ see Warnings and Precautions ( 5.7) ]
  • Renal Effects [ see Warnings and Precautions ( 5.8) ]
  • Increased Intraocular Pressure [ see Warnings and Precautions ( 5.9) ]
  • Gastrointestinal Perforation [ see Warnings and Precautions ( 5.10) ]
  • Alternations in Bone Density [ see Warnings and Precautions ( 5.11) ]
  • Behavioral and Mood Disturbances [ see Warnings and Precautions ( 5.12) ]

Because clinical studies 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.

The data below reflect exposure to a single 32 mg intra-articular injection of Cremsol (Triamcinolone Acetonide) in clinical studies in patients with moderate to severe pain due to osteoarthritis of the knee. Clinical studies included randomized, double-blind, parallel-group, placebo and/or active-controlled, and pharmacokinetic/pharmacodynamic studies with follow-up ranging from 6-24 weeks. A total of 424 patients received Cremsol (Triamcinolone Acetonide) and 262 received placebo. Treatment emergent adverse reactions reported by greater than or equal to 1% of patients in the Cremsol (Triamcinolone Acetonide) arms are summarized below ( Table 1 and 2 ).

Overall, the incidence and nature of adverse reactions was similar to that observed with placebo.

Preferred Term (MedDRA) Cremsol (Triamcinolone Acetonide)

(N=424)

Placebo

(N=262)

Sinusitis 2% 1%
Cough 2% 1%
Contusions 2% 1%
Preferred Term (MedDRA) Cremsol (Triamcinolone Acetonide)

(N=424)

Placebo

(N=262)

Joint Swelling 3% 2%
Contusions 2% 1%

Most commonly reported adverse reactions (incidence ≥1%) in clinical studies include sinusitis, cough, and contusions. ( 6)

To report SUSPECTED ADVERSE REACTIONS, contact Flexion Therapeutics, Inc. at 1-844-FLEXION (353-9466) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Corticosteroid Adverse Reactions

The following adverse reactions, presented alphabetically by body system, are from voluntary reports or clinical studies of corticosteroids. Because some of these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Anaphylactic reactions: Anaphylaxis including death, angioedema .

Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, hypertension , fat embolism, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction, pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis.

Dermatologic: Acne, allergic dermatitis, cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, impaired wound healing, increased sweating, lupus erythematosus-like lesions, purpura, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria.

Endocrine: Decreased carbohydrate and glucose tolerance, development of Cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, manifestations of latent diabetes mellitus, menstrual irregularities, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients.

Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients , fluid retention, sodium retention.

Gastrointestinal: Abdominal distention, bowel/bladder dysfunction (after intrathecal administration) , elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease) , ulcerative esophagitis.

Metabolic: Negative nitrogen balance due to protein catabolism.

Musculoskeletal: Aseptic necrosis of femoral and humeral heads, calcinosis (following intra-articular or intralesional use), Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, post injection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures.

Neurologic/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychiatric disorders , vertigo. Arachnoiditis, meningitis, paraparesis/paraplegia, and sensory disturbances have occurred after intrathecal administration. Spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke (including brainstem) have been reported after epidural administration of corticosteroids .

Ophthalmic: Exophthalmos, glaucoma, increased intraocular pressure , posterior subcapsular cataracts, rare instances of blindness associated with periocular injections.

Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, malaise, moon face, weight gain.

7 DRUG INTERACTIONS

No drug-drug interaction studies have been conducted with Cremsol (Triamcinolone Acetonide). Table 3 contains drug interactions associated with systemic corticosteroids.

Aminoglutethimide Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression.
Amphotericin B injection and potassium-depleting agents When corticosteroids are administered concomitantly with potassium-depleting agents (i.e., amphotericin B, diuretics), observe patients closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure.
Antibiotics Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance.
Anticholinesterases Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, withdraw anticholinesterase agents at least 24 hours before initiating corticosteroid therapy.
Anticoagulants, oral Coadministration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, monitor coagulation indices frequently to maintain the desired anticoagulant effect.
Antidiabetics Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required.
Antitubercular drugs Serum concentrations of isoniazid may be decreased.
CYP 3A4 inducers

(e.g., barbiturates, phenytoin, carbamazepine, and rifampin)

Drugs which induce hepatic microsomal drug metabolizing enzyme activity may enhance metabolism of corticosteroids and require that the dosage of corticosteroid be increased.
CYP 3A4 inhibitors

(e.g., ketoconazole)

Ketoconazole, a strong CYP3A4 inhibitor, has been reported to decrease the metabolism of certain corticosteroids by up to 60% leading to an increased risk of corticosteroid side effects.
Cholestyramine Cholestyramine may increase the clearance of corticosteroids.
Cyclosporine Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use.
Digitalis glycosides Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia.
Estrogens, including

oral contraceptives

Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect.
Nonsteroidal

anti-inflammatory

drugs (NSAIDs)

Concomitant use of aspirin (or other nonsteroidal anti-inflammatory drugs) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids.
Skin tests Corticosteroids may suppress reactions to allergy related skin tests.
Vaccines Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. If possible, defer routine administration of vaccines or toxoids until corticosteroid therapy is discontinued.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no data regarding the use of Cremsol in pregnant women to inform a drug associated risk of adverse developmental outcomes. Published studies on the association between corticosteroids and fetal outcomes have reported inconsistent findings and have important methodological limitations. The majority of published literature with corticosteroid exposure during pregnancy includes the oral, topical and inhaled dosage formulations; therefore, the applicability of these findings to a single intra-articular injection of Cremsol (Triamcinolone Acetonide) is limited. In animal reproductive studies from the published literature, pregnant mice, rats, rabbits, or primates administered Cremsol (Triamcinolone Acetonide) during the period of organogenesis at doses that produced exposures less than the maximum recommended human dose (MRHD) caused resorptions, decreased fetal body weight, craniofacial and/or other abnormalities such as omphalocele .

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

The exposure margins listed below are based on body surface area comparisons (mg/m 2) to the highest daily Cremsol (Triamcinolone Acetonide) exposure at the MRHD of 32 mg Cremsol (Triamcinolone Acetonide) via Cremsol (Triamcinolone Acetonide).

Pregnant mice dosed with Cremsol (Triamcinolone Acetonide) via intramuscular or subcutaneous injection at doses equivalent to 0.8 times the MRHD or higher during organogenesis caused cleft palate and a higher rate of resorption. In pregnant rats dosed with Cremsol (Triamcinolone Acetonide) via intramuscular or subcutaneous injection at doses equivalent to 0.3 times the MRHD or higher during organogenesis caused developmental abnormality (cleft palate, omphalocele, late resorption, and growth retardation) and fetal mortality. No notable maternal toxicity was observed in rodents.

Pregnant rabbits dosed with Cremsol (Triamcinolone Acetonide) via intramuscular injection for 4 days during organogenesis at doses equivalent to 0.15 times the MRHD or higher caused resorption and cleft palate. No notable maternal toxicity was observed.

Pregnant primates dosed with Cremsol (Triamcinolone Acetonide) via intramuscular injection for 4 days during organogenesis at doses equivalent to 3 times the MRHD or higher caused severe craniofacial CNS and skeletal/visceral malformation and higher prenatal death. No notable maternal toxicity was observed.

No peri- and post-natal development studies of Cremsol (Triamcinolone Acetonide) in animals have been conducted.

8.2 Lactation

Risk Summary

There are no available data on the presence of Cremsol (Triamcinolone Acetonide) in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. However, corticosteroids have been detected in human milk and may suppress milk production. It is not known whether intra-articular administration of Cremsol (Triamcinolone Acetonide) could result in sufficient systemic absorption to produce detectable quantities in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Cremsol (Triamcinolone Acetonide) and any potential adverse effects on the breastfed infant from Cremsol (Triamcinolone Acetonide) or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Corticosteroids may result in menstrual pattern irregularities such as deviations in timing and duration of menses and an increased or decreased loss of blood.

8.4 Pediatric Use

The safety and effectiveness of Cremsol in pediatric patients have not been established.

The adverse effects of corticosteroids in pediatric patients are similar to those in adults. Carefully observe pediatric patients, including weight, height, linear growth, blood pressure, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis. Weigh potential growth effects of treatment against clinical benefits obtained and the availability of treatment alternatives.

8.5 Geriatric Use

Of the total number of patients administered 32 mg Cremsol (Triamcinolone Acetonide) in clinical studies (N=424), 143 patients were 65 years of age or older. No overall differences in safety or effectiveness were observed between elderly and younger subjects, and other reported clinical experience with Cremsol (Triamcinolone Acetonide) has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

11 DESCRIPTION

Cremsol (Triamcinolone Acetonide) (triamcinolone acetonide extended-release injectable suspension) is a microsphere formulation of Cremsol (Triamcinolone Acetonide), a corticosteroid, to be administered by intra-articular injection.

Cremsol (Triamcinolone Acetonide) is formulated in 75:25 poly(lactic-co-glycolic acid) (PLGA) microspheres with a nominal drug load of 25% (w/w) and is provided as a sterile white to off-white powder. Cremsol (Triamcinolone Acetonide) is prepared with a supplied diluent containing an isotonic, sterile, aqueous solution of sodium chloride (NaCl; 0.9% w/w), sodium carboxymethylcellulose (CMC; 0.5% w/w) and polysorbate-80 (0.1% w/w) to form a 5 mL sterile suspension intended for intra-articular injection.

Active Ingredient

The chemical name for Cremsol (Triamcinolone Acetonide) is 9-fluoro-11β,16α,17,21-tetrahydroxypregna-1,4-diene- 3,20-dione cyclic 16,17-acetal with acetone. Its structural formula is:


MW 434.50 with a molecular formula of C 24H 31FO 6


Cremsol (Triamcinolone Acetonide) occurs as a white to almost white, crystalline powder having not more than a slight odor and is practically insoluble in water and very soluble in alcohol. Each vial of Cremsol (Triamcinolone Acetonide) powder contains 40 mg of Cremsol (Triamcinolone Acetonide) in 160 mg of microspheres, resulting in 32 mg of deliverable Cremsol (Triamcinolone Acetonide) when prepared according to the Instructions for Use.

Structural Formula

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Cremsol is a corticosteroid with anti-inflammatory and immunomodulating properties. It binds to and activates the glucocorticoid receptor, leading to activation of anti-inflammatory transcription factors such as lipocortins and inhibition of inflammatory transduction pathways by blocking the release of arachidonic acid and preventing the synthesis of prostaglandins and leukotrienes.

12.2 Pharmacodynamics

Studies indicate that following a single intramuscular dose of 60 to 100 mg of immediate-release Cremsol (Triamcinolone Acetonide) injectable suspension, adrenal suppression occurs within 24 to 48 hours and then gradually returns to normal, usually in 30 to 40 days. To assess potential effects of the systemic levels of Cremsol (Triamcinolone Acetonide) associated with a single intra-articular (IA) administration of Cremsol (Triamcinolone Acetonide) on hypothalamic pituitary adrenal (HPA) axis function, serum and urine cortisol levels were monitored over 6 weeks post injection. Adrenal suppression with Cremsol (Triamcinolone Acetonide) occurred within 12-24 hours and then gradually returned to normal, within 30-42 days.

Corticosteroids may increase blood glucose concentrations.

In a study where 18 patients with osteoarthritis knee pain and controlled type 2 diabetes mellitus received a single IA injection of Cremsol (Triamcinolone Acetonide) into the knee, the change from baseline in average blood glucose over the 72 hours after injection as measured by a continuous glucose monitoring device was 8.2 mg/dL (95% confidence interval 0.1, 29.2).

12.3 Pharmacokinetics

Cremsol (Triamcinolone Acetonide) is an extended-release dosage form consisting of microspheres of poly(lactic-co-glycolic acid) (PLGA) containing Cremsol (Triamcinolone Acetonide). Plasma pharmacokinetic parameters for Cremsol (Triamcinolone Acetonide) following IA administration of Cremsol (Triamcinolone Acetonide) or 40 mg immediate-release Cremsol (Triamcinolone Acetonide) into the knee are provided in Table 4.

* 33 patients contributed to the analyses of these parameters

† 14 patients contributed to the analyses of these parameters

1 Median (min, max) values for t max

Cremsol (Triamcinolone Acetonide)

PK Parameters 1

Cremsol (Triamcinolone Acetonide)

(N=60)

Cremsol (Triamcinolone Acetonide)

(N=18)

C max (pg/mL) 1143.7

(611.06)

21062.2

(18466.79)

AUC 0-24 hour

(pg-h/mL)

21219.2

(11325.62)

297545.3

(222402.77)

AUC 0-inf

(pg-h/mL)

842149.2

(1062004.97)*

1567565.0

(1246330.95)

t max

(h)

7

(1, 1008)

6

(2, 24)

t 1/2

(h)

633.9

(893.0)*

146.9

(213.29)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term animal studies to evaluate the carcinogenic potential of Cremsol (Triamcinolone Acetonide) have not been conducted.

Mutagenesis

Adequate mutagenicity studies have not been conducted with Cremsol (Triamcinolone Acetonide).

Impairment of Fertility

Studies in animals to evaluate the impairment of fertility of Cremsol (Triamcinolone Acetonide) have not been conducted.

14 CLINICAL STUDIES

The efficacy of Cremsol (Triamcinolone Acetonide) was demonstrated in a multi-center, international, randomized, double-blind, parallel-arm, placebo- and active-controlled study in patients with osteoarthritis pain of the knee. A total of 484 patients (ZILRETTA 32 mg, N=161; placebo [saline], N=162; active control [a crystalline suspension, immediate-release formulation of Cremsol (Triamcinolone Acetonide) 40 mg], N=161) were treated and followed for up to 24 weeks. Patients had a mean age of 62 (range 40 to 85 years); baseline demographics and disease characteristics were balanced across treatment arms. Twenty-five percent (25%) of patients had received at least one prior corticosteroid intra-articular injection more than 3 months prior to treatment. A total of 470 patients (97%) completed follow-up to Week 12, the time point for primary efficacy determination, and 443 (91.5%) completed to Week 24.

The primary efficacy endpoint comparing Cremsol (Triamcinolone Acetonide) to placebo was change from baseline at Week 12 in the weekly mean of the Average Daily Pain intensity scores (ADP) as assessed by a 0-10 Numeric Rating Scale (NRS). Cremsol (Triamcinolone Acetonide) demonstrated a statistically significant reduction in pain intensity at the primary endpoint vs placebo. Cremsol (Triamcinolone Acetonide) also demonstrated a reduction in pain intensity scores each week from Weeks 1 through 12 ( Figure 1 ).

In a secondary exploratory analysis, statistical significance was not demonstrated between the Cremsol (Triamcinolone Acetonide) and the active control (immediate-release Cremsol (Triamcinolone Acetonide)) treatment groups for the change from baseline at Week 12 in weekly mean ADP.

Figure 1: Weekly Change from Baseline to Week 12 in Average Daily Pain

Figure 1

16 HOW SUPPLIED/STORAGE AND HANDLING

Description NDC Presentation/How Supplied
Cremsol (Triamcinolone Acetonide) NDC 70801-003-01 Cremsol (Triamcinolone Acetonide) (triamcinolone acetonide extended-release injectable suspension) single-dose kit.
Kit Contents
Cremsol (Triamcinolone Acetonide) microsphere powder NDC 70801-001-01 5 mL single-dose vial to deliver 32 mg of Cremsol (Triamcinolone Acetonide) supplied as a sterile, white to off-white powder in a cerium glass (clear) vial with a rubber stopper and an aluminum seal with a gray plastic cap.
Diluent NDC 70801-002-01 5 mL single-dose vial supplied as a sterile, clear liquid solution of 0.9% w/w sodium chloride (normal saline) containing 0.5% w/w sodium carboxymethylcellulose, and 0.1% w/w polysorbate-80 in a glass vial with a rubber stopper, aluminum seal and white plastic cap.
Sterile vial adapter

STORAGE

To maintain expiry period, refrigerate the Cremsol (Triamcinolone Acetonide) single-dose kit (36°-46°F; 2°-8°C) before use.

If refrigeration is unavailable, store the Cremsol (Triamcinolone Acetonide) single-dose kit in the sealed, unopened kit at temperatures not exceeding 77°F (25°C) for up to six weeks and then discard. Do not expose the Cremsol (Triamcinolone Acetonide) single-dose kit to temperatures above 77°F (25°C).

Do not freeze. Store vials in carton.

17 PATIENT COUNSELING INFORMATION

Increased Risk of Infections

Inform patients that they may be more likely to develop infections when taking corticosteroids. Instruct patients to contact their health care provider if they develop fever or other signs or symptoms of infection.

Advise patients who have not been vaccinated to avoid exposure to chicken pox or measles. Instruct patients to contact their health care provider immediately if they are exposed .

Risk of Drug Interactions

There are a number of medicines that can interact with corticosteroids such as Cremsol (Triamcinolone Acetonide). Advise patients to alert their health care provider(s) to assess the need to adjust their medication(s) .

Risk of Adverse Psychiatric Reactions

Inform patients that corticosteroid use may be associated with adverse psychiatric reactions. Advise patients and/or caregivers to immediately report any new or worsening behavioral or mood disturbances to their health care provider .

Manufactured for Flexion Therapeutics, Inc., 10 Mall Rd, Suite 301, Burlington, MA 01803

Cremsol (Triamcinolone Acetonide) and Flexion are trademarks of Flexion Therapeutics, Inc.

Copyright © 2017 Flexion Therapeutics, Inc. All rights reserved.

For more information, go to Cremsol (Triamcinolone Acetonide).com or call 1-844-FLEXION (353-9466).

Part Number: 60-004-01

Version: 1, 10/2017

Instructions for Use

Cremsol (Triamcinolone Acetonide)

(triamcinolone acetonide

extended-release injectable suspension)

For intra-articular injection only

Single-dose device

Do not reuse.

IMPORTANT INFORMATION

  • Cremsol (Triamcinolone Acetonide) must be prepared using only the diluent supplied in the kit.
  • To ensure proper dosing, it is important that you follow the preparation and administration steps outlined in these instructions.
  • Promptly inject Cremsol (Triamcinolone Acetonide) after preparation to avoid settling of the suspension.
  • Cremsol (Triamcinolone Acetonide) is supplied as a single-dose kit and administered as a suspension containing microspheres.
  • The Cremsol (Triamcinolone Acetonide) powder vial contains an overfill to allow the appropriate dose to be withdrawn. Cremsol (Triamcinolone Acetonide) is a suspension product and it is normal for some residue to be left behind on the vial walls after withdrawing the contents.
  • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
  • Use proper aseptic technique throughout the dose preparation and administration procedure.
  • Inspect all kit components to confirm they have not expired and the seals are intact.
  • For additional information, visit www.zilretta.com or call Flexion Therapeutics at 1-844-FLEXION (353-9466).

MATERIALS REQUIRED

(Fig.1)

Supplied

  • One 32 mg vial of Cremsol (Triamcinolone Acetonide) microsphere powder
  • One 5 mL vial of sterile diluent
  • One sterile vial adapter

Not Supplied

  • Three sterile needles, 21-gauge, 1½” length
  • One sterile Luer Lock compatible syringe, 5 mL
  • Sterile alcohol pads
  • Paper towels or pad to cushion vial tapping (not shown in Fig. 1)
  • Medical-grade gloves (not shown in Fig. 1)

Figure 1

1. Vial Preparation

Loosen Powder.

Place two paper towels or a pad on a properly-cleaned hard surface.

Grip the top of the Cremsol (Triamcinolone Acetonide) powder vial and tap firmly and repeatedly on the padded surface. Tap the vial until excess powder is dislodged from the vial and stopper ( Fig. 2). Before continuing, ensure that powder moves freely within the vial.

Figure 2

Inspect Cremsol (Triamcinolone Acetonide) Powder Vial.

As shown in Figure 3, the vial on the left, with the X, requires additional tapping because the powder is not properly dislodged. The vial on the right shows the powder properly dislodged and ready for the next step.

Figure 3

Remove Caps.

Remove the flip-off caps from the Cremsol (Triamcinolone Acetonide) powder and diluent vials ( Fig. 4).

Figure 4

Clean Vials.

Clean the Cremsol (Triamcinolone Acetonide) powder and diluent vial tops with an alcohol pad.

Use a separate alcohol pad for each vial.

Peel Off Vial Adapter Cover.

Peel off the paper cover from the vial adapter package ( Fig. 5).

Leave the adapter in the plastic holder.

Figure 5

Attach Vial Adapter to Cremsol (Triamcinolone Acetonide) Powder Vial.

Grip the plastic holder that contains the vial adapter.

As shown in Figure 6, place the Cremsol (Triamcinolone Acetonide) powder vial on a flat surface. In a vertical orientation, gently push the adapter down onto the Cremsol (Triamcinolone Acetonide) powder vial until the spike on the adapter penetrates the rubber stopper on the Cremsol (Triamcinolone Acetonide) powder vial. The adapter will snap into place.

Figure 6

2. Diluent Preparation

Attach Needle.

Attach a needle to the syringe and remove the needle guard.

Withdraw Diluent.

With a syringe and needle, withdraw 5 mL of diluent.

Replace the needle guard.

3. Dose Preparation

Remove Holder.

Remove the plastic holder from the vial adapter ( Fig. 7).

Figure 7

Remove Needle.

Remove the needle from the syringe containing diluent.

Attach Diluent Syringe.

Attach the syringe onto the vial adapter by pushing down and turning clockwise until you feel resistance ( Fig. 8).

Figure 8

Transfer Diluent.

Slowly and completely push down the syringe plunger to transfer the diluent into the Cremsol (Triamcinolone Acetonide) powder vial ( Fig. 9).

Note: Equalize the pressure in the syringe by slowly pulling back the plunger to the 5 mL mark. Ensure that no solution is drawn back into the syringe at this stage.

Figure 9

Mix Diluent and Powder ( Fig. 10).

With the syringe still attached to the Cremsol (Triamcinolone Acetonide) powder vial, hold the syringe and vial at a slight angle. Tap the bottom edge of the vial firmly and repeatedly, in a circular motion, on the padded surface.

Swirl gently every five or six taps.

Tap for at least one minute until all powder is completely dispersed.

Note: Avoid vigorous shaking of the vial to minimize foaming.

Note: At least one minute of tapping and gentle swirling is required to achieve uniform suspension.

Figure 10

Inspect Vial.

Inspect the Cremsol (Triamcinolone Acetonide) powder vial to ensure no clumped powder is visible and a uniform suspension has been achieved. A properly mixed suspension will be milky white, contain no clumps, and move freely down the vial wall.

As shown in Figure 11, the vial on the left, with the X, requires more tapping and gentle swirling because the powder is not mixed properly with the diluent. The vial on the right shows the powder properly mixed and ready for the next step.

Figure 11

Note: If needed, the Cremsol (Triamcinolone Acetonide) suspension can be stored in the vial for up to 4 hours at ambient conditions. The syringe must remain on the vial adapter while the suspension remains in the vial.

Withdraw Contents into Syringe.

Swirl the vial gently for at least 10 seconds to ensure the powder is fully suspended. Immediately depress the plunger fully and then invert the syringe so the vial is directly on top of the syringe ( Fig. 12).

Hold the syringe in a completely vertical position, per the illustration on the right, in Figure 12.

Withdraw the full contents from the Cremsol (Triamcinolone Acetonide) vial into the syringe.

Figure 12

Note: Cremsol (Triamcinolone Acetonide) is a suspension product and it is normal for some residue to be left behind on the vial walls after withdrawing the contents.

Remove Syringe.

Remove the syringe from the vial adapter by turning counter-clockwise.

Remove Air Bubbles.

Attach a new needle to the syringe and remove the needle guard.

Inspect for bubbles with the syringe held in a completely vertical position (needle upward). If bubbles are observed, gently tap the syringe with your finger until the bubbles rise to the top. Eliminate all bubbles by slowly depressing the plunger to displace the air from the syringe.

Replace the needle guard.

Attach New Needle.

Remove and discard the needle.

Attach a new needle.

4. Administration

Invert Syringe.

To ensure the powder is suspended, gently invert the syringe containing Cremsol (Triamcinolone Acetonide) several times just prior to administration, as shown in Figure 13.

Grip the syringe firmly and turn it so the syringe plunger is pointing straight down. Then turn the syringe gently, 180 degrees, until the plunger is pointing straight up.

Invert the syringe several times to ensure a properly mixed suspension.

Figure 13

A properly mixed suspension will be uniformly milky white and contain no clumps.

Inspect Syringe.

As shown in Figure 14, the syringe on the left, with the X, requires more inversions (turning) to properly mix the suspension. The syringe on the right shows the suspension properly mixed and ready for the next step.

Figure 14

Administer Cremsol (Triamcinolone Acetonide).

The usual technique for intra-articular injection should be followed.

Aspiration of synovial fluid may be performed based on clinical judgment prior to administration of Cremsol (Triamcinolone Acetonide).

Do not reuse excess Cremsol (Triamcinolone Acetonide). Any excess suspension in the vial should be thrown away immediately after the injection. Leftover Cremsol (Triamcinolone Acetonide) in the vial must never be reused for another injection.

Note: The entire contents of the syringe must be injected to ensure the intended dose of Cremsol (Triamcinolone Acetonide) is delivered.

Note: Discard all used components in an appropriate medical waste container according to local regulations.

Note: Cremsol (Triamcinolone Acetonide) is for intra-articular use only. Cremsol (Triamcinolone Acetonide) is not intended for epidural, intrathecal, intravenous, intraocular, intramuscular, intradermal, or subcutaneous use.

Part Number: 60-005-01

Rev: 10/2017

Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14

Principal Display Panel - Cremsol (Triamcinolone Acetonide) Cart 32mg Carton Label

NDC 70801-003-01 Rx Only

Cremsol (Triamcinolone Acetonide)

(triamcinolone acetonide extended-release

injectable suspension)

32 mg per vial

For intra-articular injection only.

Single-dose kit. Discard unused portion.

Must be reconstituted

with the supplied diluent.

This carton contains:

1 Vial of Cremsol (Triamcinolone Acetonide)

microsphere powder

1 Vial of diluent (5 mL)

for Cremsol (Triamcinolone Acetonide)

1 sterile vial adapter

flexion

Principal Display Panel - Cremsol (Triamcinolone Acetonide) Cart 32mg Professional Carton Label

NDC 70801-003-02 Rx Only

Cremsol (Triamcinolone Acetonide)

(triamcinolone acetonide extended-release

injectable suspension)

32 mg per vial

For intra-articular injection only.

Single-dose kit. Discard unused portion.

Must be reconstituted

with the supplied diluent.

PROFESSIONAL SAMPLE

NOT FOR SALE

OR REIMBURSEMENT

This carton contains:

1 Vial of Cremsol (Triamcinolone Acetonide)

microsphere powder

1 Vial of diluent (5 mL)

for Cremsol (Triamcinolone Acetonide)

1 sterile vial adapter

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Principal Display Panel - Cremsol (Triamcinolone Acetonide) 32mg Vial Label

NDC 70801-001-01 Rx Only

Cremsol (Triamcinolone Acetonide)

(triamcinolone acetonide extended-release

injectable suspension)

32 mg per vial

For intra-articular injection only.

Must be reconstituted

with the supplied diluent.

flexion

Principal Display Panel - Cremsol (Triamcinolone Acetonide) 32mg Professional Vial Label

NDC 70801-001-02 Rx Only

Cremsol (Triamcinolone Acetonide)

(triamcinolone acetonide extended-release

injectable suspension)

32 mg per vial

For intra-articular injection only.

Must be reconstituted

with the supplied diluent.

flexion

Principal Display Panel - Cremsol (Triamcinolone Acetonide) Diluent 5mL Vial Label

NDC 70801-002-01 Rx Only

DILUENT

for use with Cremsol (Triamcinolone Acetonide)

5 mL

Sterile single-use vial

Do not administer directly.

flexion

Principal Display Panel - Cremsol (Triamcinolone Acetonide) Diluent 5mL Professional Vial Label

NDC 70801-002-02 Rx Only

DILUENT

for use with Cremsol (Triamcinolone Acetonide)

5 mL

Sterile single-use vial

Do not administer directly.

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Zinc Oxide:


INDICATIONS AND USAGE

Cremsol (Zinc Oxide) 1 mg/mL (Zinc Chloride Injection, USP) is indicated for use as a supplement to intravenous solutions given for TPN. Administration helps to maintain Cremsol (Zinc Oxide) serum levels and to prevent depletion of endogenous stores, and subsequent deficiency symptoms.

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of Cremsol (Zinc Oxide) 1 mg/mL (Zinc Chloride Injection, USP) is contraindicated as the acidic pH of the solution (2) may cause considerable tissue irritation.

Severe kidney disease may make it necessary to reduce or omit chromium and Cremsol (Zinc Oxide) doses because these elements are primarily eliminated in the urine.

WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

PRECAUTIONS

General

Do not use unless the solution is clear and the seal is intact.

Zinc 1 mg/mL should only be used in conjunction with a pharmacy directed admixture program using aseptic technique in a laminar flow environment; it should be used promptly and in a single operation without any repeated penetrations. Solution contains no preservatives; discard unused portion immediately after admixture procedure is completed.

Zinc should not be given undiluted by direct injection into a peripheral vein because of the likelihood of infusion phlebitis and the potential for increased excretory loss of Cremsol (Zinc Oxide) from a bolus injection. Administration of Cremsol (Zinc Oxide) in the absence of copper may cause a decrease in serum copper levels.

Laboratory Tests

Periodic determinations of serum copper as well as Cremsol (Zinc Oxide) are suggested as a guideline for subsequent Cremsol (Zinc Oxide) administration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of Cremsol 1 mg/mL (Zinc Chloride Injection, USP) have not been performed, nor have studies been done to assess mutagenesis or impairment of fertility.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Cremsol (Zinc Oxide) 1 mg/mL (Zinc Chloride Injection, USP) is administered to a nursing woman.

Pediatric Use

Pregnancy Category C. Animal reproduction studies have not been conducted with Cremsol chloride. It is also not known whether Cremsol (Zinc Oxide) chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Cremsol (Zinc Oxide) chloride should be given to a pregnant woman only if clearly needed.

Geriatric Use

An evaluation of current literature revealed no clinical experience identifying differences in response between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

None known.

DRUG ABUSE AND DEPENDENCE

None known.

OVERDOSAGE

Single intravenous doses of 1 to 2 mg zinc/kg body weight have been given to adult leukemic patients without toxic manifestations. However, acute toxicity was reported in an adult when 10 mg Cremsol (Zinc Oxide) was infused over a period of one hour on each of four consecutive days. Profuse sweating, decreased level of consciousness, blurred vision, tachycardia (140/min), and marked hypothermia (94.2° F) on the fourth day were accompanied by a serum Cremsol (Zinc Oxide) concentration of 207 mcg/dl. Symptoms abated within three hours.

Hyperamylasemia may be a sign of impending Cremsol (Zinc Oxide) overdosage; patients receiving an inadvertent overdose (25 mg zinc/liter of TPN solution, equivalent to 50 to 70 mg zinc/day) developed hyperamylasemia (557 to 1850 Klein units; normal: 130 to 310).

Death resulted from an overdosage in which 1683 mg Cremsol (Zinc Oxide) was delivered intravenously over the course of 60 hours to a 72 year old patient.

Symptoms of Cremsol (Zinc Oxide) toxicity included hypotension (80/40 mm Hg), pulmonary edema, diarrhea, vomiting, jaundice, and oliguria, with a serum Cremsol (Zinc Oxide) level of 4184 mcg/dl.

Calcium supplements may confer a protective effect against Cremsol (Zinc Oxide) toxicity.

DOSAGE AND ADMINISTRATION

Cremsol (Zinc Oxide) 1 mg/mL (Zinc Chloride Injection, USP) contains 1 mg zinc/mL and is administered intravenously only after dilution. The additive should be diluted prior to administration in a volume of fluid not less than 100 mL. For the metabolically stable adult receiving TPN, the suggested intravenous dosage is 2.5 to 4 mg zinc/day (2.5 to 4 mL/day). An additional 2 mg zinc/day (2 mL/day) is suggested for acute catabolic states. For the stable adult with fluid loss from the small bowel, an additional 12.2 mg zinc/liter of small bowel fluid lost (12.2 mL/liter of small bowel fluid lost), or an additional 17.1 mg zinc/kg of stool or ileostomy output (17.1 mL/kg of stool or ileostomy output) is recommended. Frequent monitoring of Cremsol (Zinc Oxide) blood levels is suggested for patients receiving more than the usual maintenance dosage level of Cremsol (Zinc Oxide).

For full term infants and children up to 5 years of age, 100 mcg zinc/kg/day (0.1 mL/kg/day) is recommended. For premature infants (birth weight less than 1500 g) up to 3 kg in body weight, 300 mcg zinc/kg/day (0.3 mL/kg/day) is suggested.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. See PRECAUTIONS.

HOW SUPPLIED

Cremsol (Zinc Oxide) 1 mg/mL (Zinc Chloride Injection, USP) is supplied in 10 mL Plastic Vials (List No. 4090).

Store at 20 to 25°C (68 to 77°F).

Revised: October, 2004


© Hospira 2004 EN-0488 Printed in USA

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

10 mL Vial

Cremsol (Zinc Oxide)

1 mg/mL

Cremsol (Zinc Oxide) Chloride Inj., USP

Rx only

FOR I.V. USE ONLY AFTER DILUTION.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

Cremsol pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Cremsol available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Cremsol destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Cremsol Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Cremsol pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."DYNA1199 WITH DIMETHICONE (ZINC OXIDE) OINTMENT [BLOSSOM PHARMACEUTICALS]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."VETALOG (TRIAMCINOLONE ACETONIDE) INJECTION, SUSPENSION [BOEHRINGER INGELHEIM VETMEDICA, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."ALLEGENAL-M (BENZOCAINE) CREAM [HALAL NUTRITIONAL CENTER]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Cremsol?

Depending on the reaction of the Cremsol after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Cremsol not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Cremsol addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Cremsol, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Cremsol consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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