Drug Monograph

Hydroxy B12 0.07%/ Calcipotriene 50mcg/gm
Topical Cream + Cardio B Capsules

DESCRIPTION

Combining Cardio B (Folic Acid, B12, B6) with topical B12 (hydroxycobalamin) and a potent Vitamin D analog (Calcipotriene) offers a pharmaceutically comprehensive approach to the pathogenesis of psoriasis.

HOW SUPPLIED
Cardio B

Pyridoxine Hydrochloride 50mg
Folate 8,500mcg DFE (5,000mcg Folic Acid)
Vitamin B12 (as Methylcobalamin) 1000mcg
Betaine 500mg

Hydroxycobalamin/Cacipotriene is commonly compounded as a 0.07%/50mcg/gm topical cream

CLINICAL PHARMACOLOGY

Psoriasis is caused by a complex interplay among the immune system, genetic background, autoantigens, and environmental factors.

Recent studies have demonstrated that patients with psoriasis have a significantly higher serum homocysteine (Hcy) level and a higher prevalence of hyperhomocysteinaemia (HHcy). Insufficiency of folic acid and vitamin B12 can be a cause of HHcy and resulting pathophysiology in psoriasis. Moreover, hyperhomocysteinemia is a risk factor for cardiovascular disease, hence, psoriasis is associated with an increased risk of CVD and mortality.

Coenzymes methylene tetrahydrofolate, methylcobalamin, and pyridoxal phosphate are essential for three of the enzymes involved in the metabolism of homocysteine and are dependent on folate, vitamins B12 and B6. Hence in patients with severe psoriasis who have large areas of rapid skin turnover and increased keratinocyte activity, there is excessive consumption of folate. This in turn results in reduced breakdown and elevated serum levels of Hcy with all of its adverse effects.

Moreover, Hcy may promote the immuno-inflammatory process in the pathogenesis of psoriasis by activating Th1 and Th17 cells and neutrophils, while suppressing regulatory T cells. Hcy can drive the immuno-inflammatory process by enhancing the production of the pro-inflammatory cytokines in related to psoriasis. Case in point, Hcy can induce nuclear factor kappa B activation, which is critical in the immunopathogenesis of psoriasis.

The proinflammatory cytokines involved in psoriasis stimulate the expression of inducible nitric oxide synthase (iNOS) in keratinocytes and other cell types. High levels of iNOS have been detected in psoriatic lesions and in skin affected by atopic dermatitis and are shown to be associated with a greatly increased release of nitric oxide (NO). NO has been found to be implicated in the pathogenesis of atopic eczema and psoriasis. Application of a NO synthase inhibitor leads to a clear decrease in pruritus and erythema in atopic dermatitis.

Methyl-B12

Cobinamide, a cobalamin (vitamin B12) precursor binds to NO with high affinity and has been shown to be a potent NO-scavenger in biologic systems.

Systemic administration of vitamin B12 has been reported to decrease the immunological factors responsible for skin inflammation and cell proliferation, producing a significant improvement of symptoms and positive impact on psoriatic patients. Since the important renal excretion (nearly 90%) after parenteral administration, vitamin B12 requires high blood concentrations to reach peripheral targets which can be associated with toxicity. To avoid the possible concentration-related adverse events, transdermal application was recently considered the most appropriate way of administration.

Calcipotriene

Vitamin D analogs are known to enhance the expression of keratins (K10 and K6) in the keratinocyte population in psoriasis plaques in vivo, which correlates with their clinical improvement. Furthermore, it has been shown that vitamin D analogs acts as an immunomodulator in the skin as a potent inhibitor of T-cell proliferation and of several inflammatory mediators including interleukins-1, -6, and -8.

Folic Acid (5-MethyltTHF)

Recent case control studies have demonstrated the patients with psoriasis have lower levels of folate in comparison to normal controls.

Postulated mechanisms include the following:

(1) Decreased Gut Absorption. Alterations in gut absorption of folate due to microscopic inflammatory changes seen in the bowel mucosa of patients with active psoriasis and psoriatic arthritis.

(2) Accelerated Keratinocyte Turnover. Accelerated keratinocyte turnover as seen in patients with psoriasis results in excessive consumption of folate used to methylate DNA in these actively dividing cells thus lowering folate levels.

(3) MTHFR Polymorphism. Folic acid is converted into its metabolically active form, 5-MTHF, by the enzyme methyltetrahydrofolate reductase (MTHFR). 5-MTHF donates its methyl group to vitamin B12 (cobalamin), forming methylcobalamin. Methylcobalamin helps convert the problematic amino acid metabolite homocysteine into the amino acid methionine. As mentioned above, decrease in methylcobalamin may increase the immunoinflammatory response of higher levels of Hcy and decrease its activity as a NO scavenge, affecting the clinical picture of psoriasis.

CLINICAL EVIDENCE
Study 1 – Vit B12 Ointment1

24 patients with mild to moderate plaque psoriasis were enrolled in a 12-week randomized, controlled, single-blind study, followed by a 4-week observational washout period. Patients were administered either Vitamin B12 ointment containing 0.07% cyanocobalamin with 20% avocado oil (M-treatment) and a glycerol-petrolatum emollient cream (C-treatment) twice daily to the affected skin areas on contralateral sides of their bodies.

After 14 days, there was a statistically highly significant decrease in PASI scores in all M-treated body sides, whereas only small decrease in C-treated sides. The M-treated PASI scores remained lower than the C-treated body scores throughout the study, as well as the washout period.

Study 2 – Vit B122

A total of 12 patients (8 males and 4 females, 21–86 years old) with manifest and treatment-resistant psoriasis (moderate to severe) were included and treated for 12 weeks.

All patients were assigned to twice-daily treatment with a newly developed topical combination containing plant-based extracts traditionally used in skin disease as black cumin, olive oil, tea tree oil, cocoa butter completed by vitamin A and vitamin B12.

Treatment success was determined by the Psoriasis Area and Severity Index (PASI) score, the body surface area, and the dermatology life index.

PASI reduction of >75% in 10 of the 12 treated patients (83%). The remaining two patients showed a PASI reduction of ≤50%. In 5 of the patients PASI reduction was achieved <12 weeks (between week 3–11).

Study 3 – Vit B12 vs Calcipotriol (Vit D3 Analog)3

In this randomized, prospective clinical trial, the effects of the vitamin D3 analog calcipotriol were evaluated in a trial population of 13 patients (10 men, 3 women) against those of a recently developed vitamin B12 cream containing avocado oil in an intraindividual right/left-side comparison for an observation period of 12 weeks.

There was a more rapid development of beneficial effects with the use of calcipotriol in the initial 8 weeks, although differences in effects were significant only at the time point of therapy week 8 (p < 0.05). After 12 weeks, neither the PASI score nor 20-MHz sonography showed significant differences between the two treatments. While the efficacy of the calcipotriol preparation reached a maximum in the first 4 weeks and then began to subside, the effects of the vitamin B12 cream containing avocado oil remained at a constant level over the whole observation period.

Study 4 – Folic Acid 4-7mg4

The daily intake of FA of 5% Americans age 50 and over and in one study of psoriatic American women is about 1 mg. A patient with plaque psoriasis on 10 mg lisinopril did not improve on oral vitamins B12 and B6 alone. When folic acid 5 mg daily was added, PASI improved 50%.

Three cases of plaque psoriasis flared when given 1-2 mg folic acid (FA), 100 mg vitamin B6 and 1000 mcg B12 daily. When daily FA was increased to 4 to 7 mg daily, all three cases improved their disease.

Study 5 - Folic acid combined with Vit B125

A combination of folic acid and vitamin B12 is more effective for lowering Hcy than is folic acid alone. A randomized, double-blind study with 150 women aged 20-34 years showed Hcy was significantly reduced in all treatment groups after 4 weeks compared to baselines Hcy values.

INDICATIONS AND USAGE

The use of oral folic acid, topical B12 0.07% cream, and topical calcipotriene 50mcg/gm cream have been clinically studied for the use in mild to moderate chronic plaque psoriasis.1-5

DOSING AND ADMINISTRATION

Take 1 serving of Cardio B daily.

  • Reducing or stopping folic acid (FA) 4-8 mg daily may place patient at risk for comorbid events due to the passage through FA levels that would promote pro-inflammatory side effects.

Apply Methyl-B12 0.07%/ Calcipotriene 50mcg/gm topical cream to affected areas twice daily.

Do not use on the face.

ADVERSE EFFECTS
MethylFolate

- Allergic Reactions
- Abdominal Cramps
- Diarrhea
- Rash
- Sleep Disorders
- Irritability
- Confusion
- Nausea
- Stomach Upset
- Behavior Changes
- Skin Reactions
- Seizures
- Excitability

Methylcobalamin

- Mild transient diarrhea
- Polycythemia
- Itching
- Transitory exanthema
- Edema

Calcipotriene

In controlled clinical trials, the most frequent adverse reactions reported to be related to calcipotriene Scalp Solution, 0.005%, use were transient burning, stinging and tingling, which occurred in approximately 23% of patients. Rash was reported in about 11% of patients. Dry skin, irritation and worsening of psoriasis were reported in 1-5% of patients. Skin atrophy, hyperpigmentation, hypercalcemia, and folliculitis were not observed in these studies, but cannot be excluded.

WARNINGS AND PRECAUTIONS

A mild exacerbation of the skin inflammation may be a common initial response (2-4 days after treatment initiation) with a subsequent consistent improvement of the disease state thereafter.

Calcipotriene
  1. Calcipotriene is not for oral, ophthalmic, or intravaginal use and application to the eyes, lips, or facial skin should be avoided.
  2. Calcipotriene may cause transient irritation of both lesions and surrounding uninvolved skin. If irritation develops, calcipotriene should be discontinued.
  3. Calcipotriene cream is not generally recommended for severe extensive psoriasis. If calcipotriene is used for severe extensive psoriasis, it is important to monitor the serum calcium levels at regular intervals due to the risk of hypercalcemia secondary to excessive absorption of calcipotriene when there is extensive skin involvement. If the serum calcium level becomes elevated, calcipotriene therapy should be discontinued and the serum calcium level monitored in these patients until it returns to normal.
  4. Calcipotriene, when used in combination with ultra-violet radiation (UVR) may enhance the known skin carcinogenic effect of UVR. This potential risk is based on the preclinical finding in mice of a reduced time to tumor formation from long term exposure to UVR and topically applied calcipotriol.
  5. Calcipotriene is not recommended for use on the face since this may give rise to itching and erythema of the facial skin. Patients should be instructed to wash their hands after using calcipotriene to avoid inadvertent transfer to the face from other body parts. Should facial dermatitis develop in spite of these precautions, calcipotriol therapy should be discontinued.
  6. Calcipotriene should be used cautiously in skin folds, where the natural occlusion may give rise to an increase of the irritant effect of calcipotriol.
  7. Reversible elevation of serum calcium has occurred with use of topical calcipotriene. If elevation in serum calcium outside the normal range should occur, discontinue treatment until normal calcium levels are restored.
Folic Acid
  1. Folic acid should be given with caution to drug-treated epileptic patients because seizure control may be affected.
  2. Folic acid may cause neurological injury when given to patients with undiagnosed pernicious anemia.
DRUG INTERACTIONS
Folic Acid
  • Fosphenytoin. Folic acid can increase fosphenytoin metabolism, decreasing its effectiveness in seizure prevention.
  • Methotrexate. Taking folic acid with methotrexate may decrease the effectiveness of methotrexate.
  • Phenobarbitol. Taking folic acid with phenobarbitol can decrease its effectiveness for seizure prevention.
  • Phenytoin. Folic acid may incrEase the metabolism of phenytoin, decreasing its effectiveness for seizure prevention.
  • Primidone. Taking folic acid with primidone may decrease itS effectiveness in preventing seizures.
  • Pyrimethamine. Taking folic acid with pyrimethamine may decrease its effectiveness in treating parasitic infections.
CONTRAINDICATIONS

Calcipotriene is contraindicated in those patients with acute psoraiatic eruoptions or history of hypersensitivity tot he components of the preparation. It should not be used by patients with demonstrated hypercalcemia or evidence of Vitamin D toxicity.

USE IN SPECIFIC POPULATION
Pregnancy

Calcipotriene is Pregnancy category C

Lactation

There is evidence that maternal 1,25-dihydroxy vitamin D3 (calcitriol) may enter the fetal circulation, but it is not known whether it is excreted in human milk. The systemic disposition of calcipotriene is expected to be similar to that of the naturally occurring vitamin. Because many drugs are excreted in human milk, caution should be exercised when calcipotriol is administered to a nursing woman.

5-Methyl THF is likely safe during lactation.

Pediatric

Safety and effectiveness of calcipotriol in pediatric patients have not been established. Because of a higher ratio of skin surface area to body mass, pediatric patients are at greater risk than adults of systemic adverse effects when they are treated with topical medication.

PHARMACOKINETICS

A pharmacokinetic study of calcipotriene has demonstrated that the apparent systemic absorption of the applied dose of calcipotriol over 12 hours is approximately 5.5% of the dose in normal subjects and in psoriatic patients.

TOXICITY

Hypercalcemia does not occur at the usual dose of calcipotriene. Excessive use (i.e. more than the recommended weekly amount) may cause elevated serum calcium, which rapidly subsides when treatment is discontinued. In such cases, the monitoring of serum calcium levels once weekly until the serum calcium returns to normal levels is recommended.

Oral folic acid is generally regarded as not toxic for humans; however, it may cause neurological injury when given to patients with undiagnosed pernicious anemia.

STORAGE

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

REFERENCES
  1. Del Duca E, Farnetani F, De Carvalho N, Bottoni U, Pellacani G, Nisticò SP. Superiority of a vitamin B12-containing emollient compared to a standard emollient in the maintenance treatment of mild-to-moderate plaque psoriasis. Int J Immunopathol Pharmacol. 2017;30(4):439‐444.
  2. Michalsen A, Eddin O, Salama A. A case series of the effects of a novel composition of a traditional natural preparation for the treatment of psoriasis. J Traditional and Complementary Medicine. 2016 Oct; 6(4) 395-398.
  3. Stucker M, Hoffman U, Hartung J, Altmeyer P. Vitamin B12 Cream Containing Avocado Oil in the Therapy of Plaque Psoriasis. Dermatology 2001;203:141–147.
  4. Aronson PJ (2017) Cases of psoriasis improved by lowering homocysteine using 4-7 mg folic acid, vitamins B6 and B12 previously worsened using 1-2 mg daily folic acid, B6 and B12 folic acid. J Transl Sci 2017; 3(5) 1-6.
  5. Quinlivan EP, McPartlin J, McNulty H, et al. Importance of both folic acid and vitamin B12 in reduction of risk of vascular disease (letter). Lancet 2002; 359(9302) 227-228.
MEDICAL DISCLAIMER

This drug monograph does not provide medical or legal advice. All content found on this drug monograph, including: text, images, audio, or other formats were created for informational purposes only. Viewing this drug monograph, receipt of information contained in this monograph, or the transmission of this information from our pharmacy does not constitute a pharmacist-patient relationship.

The medical information on this monograph is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay seeking it because of something you have read on this drug monograph.

If you think you may have a medical emergency, call your doctor, go to the emergency department, or call 911 immediately. Harbor Compounding Pharmacy does not recommend or endorse any specific tests, physicians, products, procedures, opinions, or other information that may be mentioned on any of our content.

Medical information changes constantly. Therefore the information on our drug monograph(s) should not be considered current, complete or exhaustive, nor should you rely on such information to recommend a course of treatment for you or any other individual. Reliance on any information provided by Harbor Compounding Pharmacy, its employees, contracted writers, or medical professionals presenting content for publication to Harbor Compounding Pharmacy is solely at your own risk.

CONTACT

Harbor Compounding Pharmacy

2000 Harbor Blvd, Suite C100
Costa Mesa, CA 92627