Meta Information
ID:d3-k2-liposomal
Name:Vitamin D3 + K2 (Liposomal)
Schema Version:2.4_uniform_evidence_2026_06_18
Created
2026-07-02T15:09:16Z
Model
phase-c-combo-claude-opus-4.8
Derived From
- vitamin-d
- vitamin-k2
Provenance Note
Liposomal D3/K2 combo; interactions inherited from vitamin-d and vitamin-k2 (deduped). Note vitamin-k2 antagonises warfarin — retained from component.
Interactions
Target id:
/intervention/weight-bearing-exercise
Target name:
Weight-Bearing Exercise
Severity:
major
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Exercise signals bones to get stronger, and Vitamin D provides the necessary calcium to do so.
Actionable advice:
These should be combined for optimal bone health.
Validation status:
validated_via_class_inference
Evidence tier:
tier_c
Evidence basis:
class_inference_summary
Evidence anchors:
Source url:
Established mechanism / class pharmacology (no single primary source quoted)
Exact phrase from label:
Supportive-care synergy (class inference): weight-bearing exercise stimulates bone formation while vitamin D supports the intestinal calcium absorption needed for mineralization - complementary for bone health, not a pharmacologic interaction.
Label source:
Class inference
Action type:
informational_none
Target id:
/intervention/denosumab
Target name:
Denosumab
Severity:
major
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Adequate Vitamin D is required to prevent severe low blood calcium, a side effect of this drug.
Actionable advice:
Adequate Vitamin D and calcium should be maintained.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Advise these patients to have their serum calcium
measured weekly for the first month after Prolia administration and monthly thereafter [see Dosage and
Administration (2.2), Warnings and Precautions (5.1), Use in Specific Populations (8.6)]
Drug Products with Same Active Ingredient
Advise patients that if they receive Prolia, they should not receive other denosumab products
concomitantly [see Warnings and Precautions (5.2)].
Label source:
Action type:
informational_none
Target id:
/intervention/bisphosphonates
Target name:
Bisphosphonates
Severity:
major
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Adequate Vitamin D is necessary for this osteoporosis medication class to work effectively and safely.
Actionable advice:
Adequate Vitamin D and calcium should be maintained.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
It is recommended to ensure adequate 25-OH vitamin D level and calcium supplementation before administering zoledronate.
Label source:
PubMed: Bariatric surgery and skeletal health: A narrative review and position statement for management by the European Calcified Tissue Society (ECTS). (PMID 34688942)
Action type:
informational_none
Target id:
/intervention/digoxin
Target name:
Digoxin
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
High Vitamin D can raise calcium levels, increasing the risk of serious digoxin heart toxicity.
Actionable advice:
Calcium and digoxin levels should be monitored closely.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
there was a modest but statistically significant increase in plasma calcium levels, from 9.32-9.68 mg/dL (P = 0.0277).
Label source:
PubMed: Fundamental & clinical pharmacology (2012)
Source url:
Exact phrase from label:
Moreover, the incubation with ouabain and digoxin increased the rate of (45)Ca(2+) uptake, indicating that the effect of 1,25D(3) may also result from Na(+)/K(+)-ATPase inhibition.
Label source:
PubMed: Biochemistry (2011)
Source url:
Exact phrase from label:
We examined data on 1) renal Trpv5 (transient receptor potential cation channel, subfamily V member 5) and Trpv6 and intestinal Trpv6 (calcium channels) for calcium absorption; 2) liver 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (Hmgcr) and cytochrome 7α-hydroxylase (Cyp7a1) for cholesterol synthesis and degradation, respectively; and 3) renal and brain Mdr1 (multidrug-resistance protein that encodes the P-glycoprotein) for digoxin disposition after repetitive intraperitoneal doses of 120 pmol 1,25(OH)2D3
Label source:
PubMed: Drug metabolism and disposition: the biological fate of chemicals (2018)
Action type:
monitor
Target id:
/intervention/calcium-akg
Target name:
Calcium Alpha-Ketoglutarate
Severity:
major
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Vitamin D significantly enhances the absorption of calcium, making them work better together for bone health.
Actionable advice:
Often recommended to be taken together.
Validation status:
validated_via_class_inference
Evidence tier:
tier_c
Evidence basis:
class_inference_summary
Evidence anchors:
Source url:
Established mechanism / class pharmacology (no single primary source quoted)
Exact phrase from label:
Established physiology (class inference): vitamin D promotes intestinal calcium absorption, so adequate vitamin D enhances the bone benefit of supplemental calcium. Core ODS-level fact; complementary supportive care.
Label source:
Class inference
Action type:
informational_none
Target id:
/intervention/calcium-citrate
Target name:
Calcium Citrate
Severity:
major
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Vitamin D significantly enhances the absorption of calcium, making them work better together for bone health.
Actionable advice:
Often recommended to be taken together.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
While vitamin D has multiple effects on bone and calcium metabolism, the regulation of intestinal calcium (Ca) absorption efficiency is a critical function for vitamin D.
Label source:
PubMed: Vitamin D-Mediated Regulation of Intestinal Calcium Absorption. (PMID 36014856)
Action type:
informational_none
Target id:
/intervention/teriparatide
Target name:
Teriparatide
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Both substances increase blood calcium levels, raising the risk of hypercalcemia (too much calcium) when combined.
Actionable advice:
Blood calcium levels should be monitored regularly.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
5.5 Risk of Digoxin Toxicity Hypercalcemia may predispose patients to digitalis toxicity because Teriparatide injection transiently increases serum calcium.
Label source:
Action type:
monitor
Target id:
/class/bile-acid-sequestrants
Target name:
Bile Acid Sequestrants (e.g., Cholestyramine)
Severity:
major
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
4
Hours after target:
1
Description:
These medications bind to bile acids in the gut, which prevents the proper absorption of fat-soluble vitamins like Vitamin K2.
Actionable advice:
Vitamin K2 should be taken at least 1 hour before or 4 hours after bile acid sequestrants.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Because cholestyramine binds bile acids, QUESTRAN may interfere with normal fat digestion
and absorption and thus may prevent absorption of fat-soluble vitamins such as A, D, E and
K.
Label source:
Action type:
separate
Target id:
/intervention/vitamin-k2
Target name:
Vitamin K2
Severity:
minor
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Vitamin K2 helps direct the calcium absorbed by Vitamin D into bones, away from soft tissues.
Actionable advice:
Vitamin D and K2 work together for bone and vascular health and are fine to take together; no special action needed.
Validation status:
validated_via_expert_review
Evidence tier:
tier_c
Evidence basis:
expert_review_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
osteocalcin (OC), matrix Gla protein (MGP)... facilitate bone mineralization, inhibit vessel wall calcification... This review updates vitamin D and K skeletal and cardiovascular benefits and evidence for their synergy of action.
Label source:
Kidd (2010), Altern Med Rev, PMID 21155624 (narrative review -> expert-review tier). Supports K2 directing calcium into bone via osteocalcin/MGP and vitamin D-K synergy.
Action type:
informational_none
Target id:
/intervention/menopausal-hrt
Target name:
Menopausal HRT
Severity:
major
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Both hormone therapy and Vitamin D help maintain bone density, providing a combined benefit for bone health.
Actionable advice:
Adequate Vitamin D should be maintained during HRT.
Validation status:
validated_via_class_inference
Evidence tier:
tier_c
Evidence basis:
class_inference_summary
Evidence anchors:
Source url:
Established mechanism / class pharmacology (no single primary source quoted)
Exact phrase from label:
Supportive-care synergy (class inference): menopausal HRT and vitamin D each independently support bone-mineral density, so combined use is complementary for bone health. Not a pharmacologic interaction; the cited PMID 38798836 was not retrievable this pass.
Label source:
Class inference
Action type:
informational_none
Target id:
/intervention/strontium
Target name:
Strontium
Severity:
major
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
3
Hours after target:
3
Description:
Strontium and calcium (whose absorption is boosted by Vitamin D) compete for absorption in the gut.
Actionable advice:
Doses should be separated by at least 2-3 hours.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Vitamin D increases intestinal calcium and phosphate absorption. Not so well known, however, is that vitamin D stimulates the co-absorption of other essential minerals like magnesium, iron, and zinc; toxic metals including lead, cadmium, aluminum, and cobalt; and radioactive isotopes such as strontium and cesium.
Label source:
PubMed: Journal of the American College of Nutrition (1994)
Source url:
Exact phrase from label:
Calcium (Ca) and strontium (Sr) have common chemical features and are absorbed by the same pathways. Vitamin D has a main role in calcium intestinal absorption. The aim of this study was to investigate whether vitamin D status is a determinant of strontium ranelate absorption.
Label source:
PubMed: European journal of endocrinology (2014)
Source url:
Exact phrase from label:
The effect of calcium concentration and vitamin B3 25 OHD3 and 1.25 diOHD3 upon intestinal strontium transport was studied in vitamin D deficient rats with duodenal perfusion in situ. When the calcium concentration was increased, the strontium passive absorption was decreased.
Label source:
PubMed: Comptes rendus des seances de la Societe de biologie et de ses filiales (1976)
Action type:
separate
Target id:
/intervention/saint-johns-wort
Target name:
Saint John's Wort
Severity:
moderate
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
This herb can speed up the breakdown of Vitamin D in the body, potentially lowering its levels.
Actionable advice:
Vitamin D levels are best monitored with long-term use.
Validation status:
validated_via_class_inference
Evidence tier:
tier_c
Evidence basis:
class_inference_summary
Evidence anchors:
Source url:
Established mechanism / class pharmacology (no single primary source quoted)
Exact phrase from label:
Mechanistic inference: St. John's Wort is a potent PXR/CYP3A4 inducer and can accelerate vitamin D catabolism (via CYP24A1/CYP3A4), modestly lowering 25(OH)D levels. Plausible, established-direction interaction; the cited PMC5623087 was not retrievable this pass to quote verbatim.
Label source:
Class inference
Action type:
monitor
Target id:
/intervention/ipriflavone
Target name:
Ipriflavone
Severity:
moderate
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
This supplement may work with Vitamin D and calcium to improve bone density and prevent bone loss.
Actionable advice:
Often used in combination for bone health.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Women receiving the placebo showed only a limited bone loss during the treatment period, probably due to calcium supplement; however, a significant between-treatment difference was obtained in both studies.
Label source:
PubMed: Efficacy of ipriflavone in established osteoporosis and long-term safety. (PMID 9263613)
Action type:
informational_none
Target id:
/intervention/magnesium
Target name:
Magnesium
Severity:
moderate
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Magnesium is essential for activating Vitamin D, so adequate levels are needed for it to work properly.
Actionable advice:
Adequate magnesium intake is a good idea for efficacy.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Not so well known, however, is that vitamin D stimulates the co-absorption of other essential minerals like magnesium, iron, and zinc; toxic metals including lead, cadmium, aluminum, and cobalt; and radioactive isotopes such as strontium and cesium.
Label source:
PubMed: The role of vitamin D in toxic metal absorption: a review. (PMID 7706586)
Action type:
informational_none
Target id:
/intervention/boron
Target name:
Boron
Severity:
moderate
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Boron may help increase Vitamin D levels in the body and supports its role in bone health.
Actionable advice:
May enhance Vitamin D status.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Pilot clinical studies suggest that this effect may be mediated, in whole or in part, by an increase in serum 25-hydroxyvitamin D.
Label source:
PubMed: Up-regulatory impact of boron on vitamin D function -- does it reflect inhibition of 24-hydroxylase? (PMID 15504575)
Action type:
informational_none
Target id:
/class/sglt2-inhibitors
Target name:
SGLT2 Inhibitors
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
This drug class may increase fracture risk; adequate Vitamin D is crucial to support bone health.
Actionable advice:
It is a good idea to maintain adequate Vitamin D and calcium intake.
Validation status:
validated_via_class_inference
Evidence tier:
tier_c
Evidence basis:
class_inference_summary
Evidence anchors:
Source url:
Established mechanism / class pharmacology (no single primary source quoted)
Exact phrase from label:
Mechanistic inference: some SGLT2 inhibitors modestly affect calcium/phosphate handling and fracture risk; vitamin D supports calcium homeostasis, so monitoring bone/mineral status is reasonable. Weak/indirect link, monitoring-level.
Label source:
Class inference
Action type:
informational_none
Target id:
/intervention/high-fiber-diet
Target name:
High-Fiber Diet
Severity:
minor
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
2
Hours after target:
2
Description:
Very high fiber intake, especially from phytates, can slightly reduce absorption of Vitamin D and calcium.
Actionable advice:
This and high-phytate meals are best separated if there is concern.
Validation status:
validated_via_class_inference
Evidence tier:
tier_c
Evidence basis:
class_inference_summary
Evidence anchors:
Source url:
Established mechanism / class pharmacology (no single primary source quoted)
Exact phrase from label:
Mechanistic inference: very high fiber/phytate intake can modestly reduce absorption of calcium and fat-soluble vitamins; the effect on vitamin D specifically is small and indirect. Standard nutrition guidance, rendered as class inference.
Label source:
Class inference
Action type:
separate
Target id:
/class/proton-pump-inhibitors
Target name:
Proton Pump Inhibitors
Severity:
minor
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Long-term use may reduce calcium absorption, which is crucial for Vitamin D's function in bone health.
Actionable advice:
Adequate calcium intake and monitoring may help.
Validation status:
validated_via_class_inference
Evidence tier:
tier_c
Evidence basis:
class_inference_summary
Evidence anchors:
Source url:
Established mechanism / class pharmacology (no single primary source quoted)
Exact phrase from label:
Mechanistic inference: PPIs can reduce acid-dependent calcium absorption and are associated with long-term fracture risk, so adequate vitamin D/calcium status is relevant; vitamin D absorption itself is largely pH-independent. Monitoring-level, indirect.
Label source:
Class inference
Action type:
monitor
Target id:
/class/statins
Target name:
Statins
Severity:
minor
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Statins may slightly interfere with the body's ability to synthesize Vitamin D from cholesterol precursors.
Actionable advice:
Vitamin D levels may be worth monitoring if there is concern.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Both molecules intersect metabolically at 7-dehydrocholesterol, raising interest in their potential interactions. While theoretical concerns exist about statins impairing vitamin D synthesis, clinical studies suggest a neutral or modestly positive effect on circulating 25(OH)D levels.
Label source:
PubMed: Biomedicines (2025)
Source url:
Exact phrase from label:
We also highlight the results that cannot be explained with our current knowledge of molecular mechanisms: (i) vitamin D supplementation mitigates the side-effects of statin therapy; (ii) statin therapy does not impact upon vitamin D status; and critically (iii) vitamin D supplementation does not improve cardiovascular outcomes, despite improving cardiovascular risk factors.
Label source:
PubMed: Cells (2021)
Source url:
Exact phrase from label:
Across RCTs, treatment with statins was associated a significant increase in serum vitamin D concentrations [weighted mean difference (WMD) 2·71 ng/mL, 95% CI 0·19-5·24, I2 62·1%). Across studies of non-RCT design, statins treatment was associated with a decrease in vitamin D concentrations (WMD -0·70 ng/mL, 95% CI -1·20 to -0·20, I2 56·3%).
Label source:
PubMed: European journal of clinical investigation (2017)
Action type:
monitor
Target id:
/class/thiazide-diuretics
Target name:
Thiazide Diuretics
Severity:
moderate
Interaction type:
adverse
Nature:
conditional
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Thiazide diuretics decrease urinary calcium excretion, which can combine with high-dose vitamin D supplementation to cause hypercalcemia.
Actionable advice:
Have serum calcium monitored periodically if combining thiazides with vitamin D supplementation.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Greater urine calcium reductions after thiazide treatment are observed among those with higher baseline urine calcium, and higher thiazide dose led to a larger reduction.
Label source:
PubMed: Baseline Urinary Calcium and the Efficacy of Thiazide Diuretics for Kidney Stone Prevention. (PMID 41894644)
Action type:
monitor
Target id:
/intervention/calcipotriene-topical
Target name:
Calcipotriene / Calcipotriol (Topical Vitamin D Analog)
Severity:
moderate
Interaction type:
adverse
Nature:
conditional
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Topical synthetic vitamin D analogs such as calcipotriene/calcipotriol are used for plaque psoriasis. Combining them with high-dose oral vitamin D may increase the risk of hypercalcemia.
Actionable advice:
If using topical calcipotriene/calcipotriol, discuss oral vitamin D dose with your prescriber and have calcium checked.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
First line management of chronic plaque psoriasis is with topical treatments, including vitamin D analogues, topical corticosteroids, tar-based preparations, dithranol, salicylic acid and topical retinoids.
Label source:
PubMed: Topical treatments for chronic plaque psoriasis. (PMID 19370616)
Action type:
informational_none
Target id:
/intervention/cholestyramine
Target name:
Cholestyramine (Bile Acid Sequestrant)
Severity:
moderate
Interaction type:
adverse
Nature:
conditional
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Cholestyramine binds fat-soluble vitamins in the gut and can reduce absorption of vitamin D.
Actionable advice:
Vitamin D administration and cholestyramine should be separated by at least 4 hours; higher doses may be warranted with long-term cholestyramine.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Large doses of cholestyramine (greater than 32 g/day) may be associated with malabsorption of fat-soluble vitamins.
Label source:
PubMed: Adverse effects of hypolipidaemic drugs. (PMID 3547004)
Action type:
separate
Target id:
/intervention/mineral-oil
Target name:
Mineral Oil
Severity:
moderate
Interaction type:
adverse
Nature:
conditional
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Mineral oil can reduce absorption of both vitamin D and calcium.
Actionable advice:
Chronic mineral oil use is best avoided with vitamin D supplementation; if needed, the two are best separated by several hours.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Mineral oil will alter the absorption of fat-soluble vitamins and reduces the tube light.
Label source:
PubMed: Nutricion hospitalaria (2014)
Source url:
Exact phrase from label:
There have been concerns regarding the interference in the absorption of fat-soluble vitamins in long-term treatment with mineral oil; however, there is no clear evidence in the literature to support this claim.
Label source:
PubMed: Clinical pediatrics (2006)
Source url:
Exact phrase from label:
The utilization of indigestible oils, however, may have unforeseen nutritional consequences, such as the reduction of vitamin bioavailability.
Label source:
PubMed: Food research international (Ottawa, Ont.) (2019)
Action type:
separate
Target id:
/intervention/phenytoin
Target name:
Phenytoin
Severity:
moderate
Interaction type:
adverse
Nature:
conditional
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Phenytoin increases hepatic metabolism of vitamin D to inactive compounds, thereby reducing calcium absorption.
Actionable advice:
Patients on long-term phenytoin may require higher vitamin D doses; have 25(OH)D and calcium monitored.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Current evidence indicates that these drugs derange bone metabolism, both through induction of increased hepatic catabolism of vitamin D and its biologically active products, as well as by direct effects on membrane cation transport systems.
Label source:
PubMed: Drugs (1976)
Source url:
Exact phrase from label:
The effect of these drugs appears to be the acceleration of the metabolism of vitamin D and an increase in the excretion of polar metabolites. This may result in reduced levels of 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol which are necessary for normal absorption of calcium.
Label source:
PubMed: The Journal of clinical endocrinology and metabolism (1975)
Source url:
Exact phrase from label:
He was finally diagnosed with vitamin D deficiency associated with low sunlight exposure and long-term phenytoin use for symptomatic epilepsy: phenytoin is shown to accelerate catabolism of 25-hydroxyvitamin D.
Label source:
PubMed: Case reports in nephrology (2019)
Action type:
adjust_with_prescriber
Target id:
/intervention/phenobarbital
Target name:
Phenobarbital
Severity:
moderate
Interaction type:
adverse
Nature:
conditional
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Phenobarbital increases hepatic metabolism of vitamin D to inactive compounds, thereby reducing calcium absorption.
Actionable advice:
Patients on long-term phenobarbital may require higher vitamin D doses; have 25(OH)D and calcium monitored.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
When activated by antiseizure medications, such as phenobarbital, or environmental chemicals, such as perfluoroalkyl substances, CAR induces hepatic enzymes, including UDP-glucuronosyltransferases (UGTs), which increase the clearance of THs and raise thyroid-stimulating hormone levels.
Label source:
PubMed: Role of constitutive androstane receptor in developmental toxicology: linking chemical exposure, nutrition, and disease susceptibility. (PMID 41733502)
Action type:
adjust_with_prescriber
Target id:
/condition/sarcoidosis
Target name:
Sarcoidosis (and other Granulomatous Diseases)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
In sarcoidosis, tuberculosis, and histoplasmosis, vitamin D metabolism is disturbed and can produce hypercalcemia even at modest supplemental doses.
Actionable advice:
Vitamin D supplementation should be avoided in active granulomatous disease (sarcoidosis, TB, histoplasmosis) unless a specialist directs otherwise, and calcium should be monitored closely.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
These abnormalities of calcium metabolism are due to dysregulated production of 1,25-(OH2)D3 (calcitriol) by activated macrophages trapped in pulmonary alveoli and granulomatous inflammation.
Label source:
PubMed: Hypercalcemia in granulomatous disorders: a clinical review. (PMID 10958237)
Action type:
avoid
Target id:
/condition/chronic-excessive-vitamin-d-intake
Target name:
Chronic Excessive Vitamin D Intake
Severity:
major
Interaction type:
adverse
Nature:
conditional
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Vitamin D is Possibly Unsafe when used orally in excessive doses, long-term — primarily because of the risk of hypercalcemia.
Actionable advice:
Prescribed doses should not be exceeded long-term without 25(OH)D monitoring; safe upper limits for most adults are well below toxicity thresholds.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Confusion, apathy, recurrent vomiting, abdominal pain, polyuria, polydipsia, and dehydration are the most often noted clinical symptoms of vitamin D toxicity (VDT; also called vitamin D intoxication or hypervitaminosis D). VDT and its clinical manifestation, severe hypercalcemia, are related to excessive long-term intake of vitamin D, malfunctions of the vitamin D metabolic pathway, or the existence of coincident disease that produces the active vitamin D metabolite locally.
Label source:
PubMed: Frontiers in endocrinology (2018)
Source url:
Exact phrase from label:
While vitamin D supplementation is generally safe within recommended limits, excessive intake may cause hypercalcemia or nephrolithiasis, emphasizing the need for personalized strategies.
Label source:
PubMed: Frontiers in nutrition (2025)
Source url:
Exact phrase from label:
Vitamin D is a toxic compound, and excessive amounts can cause soft-tissue calcification. We have suggested a mechanism by which this calcification might occur. There is a narrow leeway between the amount required and that initiating tissue damage.
Label source:
PubMed: Journal of the American College of Nutrition (1983)
Action type:
monitor
Target id:
/intervention/orlistat
Target name:
Orlistat
Severity:
moderate
Interaction type:
adverse
Nature:
conditional
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Orlistat reduces absorption of fat-soluble vitamins including vitamin D.
Actionable advice:
Vitamin D and orlistat doses should be separated by at least 2 hours; a higher vitamin D dose may be warranted with long-term orlistat.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Mean vitamin D levels were significantly reduced compared with baseline (p<0.02) after 1 month of orlistat, despite multivitamin supplementation.
Label source:
PubMed: Pharmacotherapy (2002)
Source url:
Exact phrase from label:
Orlistat interferes with the absorption of many drugs (such as warfarin, amiodarone, ciclosporin and thyroxine as well as fat-soluble vitamins), affecting their bioavailability and effectiveness.
Label source:
PubMed: Drug safety (2008)
Source url:
Exact phrase from label:
sucrose polyesters (Olestra) and tetrahydrolipstatin (orlistat) probably diminish vitamin D absorption
Label source:
PubMed: Critical reviews in food science and nutrition (2015)
Action type:
separate
Target id:
/condition/pregnancy
Target name:
Pregnancy
Severity:
minor
Interaction type:
adverse
Nature:
conditional
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Vitamin D is Likely Safe when used orally and appropriately in pregnancy. Excessive doses are not recommended.
Actionable advice:
Vitamin D is generally best used at recommended pregnancy doses (typically 600–4,000 IU/day per clinician guidance), and mega-doses are best avoided.
Validation status:
unvalidatable
Evidence tier:
tier_e
Evidence basis:
unvalidatable
Evidence anchors:
Source url:
Scientific literature support not found
Exact phrase from label:
Label source:
NatMed Professional Monograph: Vitamin D
Action type:
avoid
Target id:
/class/cns-depressants
Target name:
CNS Depressants
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
null
Description:
General caution when combined with other active therapeutic agents.
Actionable advice:
It is important to talk to a physician before combining this with other medications.
Validation status:
unvalidatable
Evidence tier:
tier_e
Evidence basis:
unvalidatable
Evidence anchors:
Source url:
Scientific literature support not found
Exact phrase from label:
Label source:
Generic placeholder row: the text is non-specific ('general caution') and there is no established CNS-depressant interaction for this agent. No validatable interaction claim - marked unvalidatable (candidate for removal).
Action type:
informational_none
Target id:
/intervention/warfarin
Target name:
Warfarin (Coumadin)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Vitamin K directly opposes the anticoagulant effect of warfarin by promoting the synthesis of clotting factors, which can lead to therapeutic failure and increased risk of blood clots.
Actionable advice:
Vitamin K2 supplements should not be taken while on warfarin unless specifically instructed and closely monitored by the prescribing physician.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
6 Aluminum Lake
10 mg: Dye-free
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Warfarin acts by inhibiting the synthesis of vitamin K-dependent clotting factors, which include
Factors II, VII, IX, and X, and the anticoagulant proteins C and S.
Label source:
Action type:
avoid
Target id:
/dietary/high-fat-meal
Target name:
Meal Containing Dietary Fat
Severity:
major
Interaction type:
requirement
Nature:
temporal
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
As a fat-soluble vitamin, Vitamin K2 requires dietary fats for proper absorption from the small intestine into the bloodstream.
Actionable advice:
Vitamin K2 should be taken with a meal that contains some healthy fat (e.g., olive oil, avocado, nuts).
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
The oral bioavailability of lipid-soluble vitamin K was influenced by the fat content of a meal, although the increase in bioavailability seemed to reach a peak when the lipid content of the meal was > 35 g.
Label source:
PubMed: Journal of pharmaceutical sciences (1996)
Source url:
Exact phrase from label:
It is concluded that the bioavailability of membrane-bound phylloquinone is extremely poor and may depend on other food components, notably fat.
Label source:
PubMed: The British journal of nutrition (1996)
Source url:
Exact phrase from label:
The vitamin K2 uptake into buccal and intestinal cells was increased via micellization.
Label source:
PubMed: Nutrients (2025)
Action type:
informational_none
Target id:
/biomarker/inr
Target name:
INR (Prothrombin Time)
Severity:
major
Interaction type:
assay_interference
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Vitamin K2 supplementation directly opposes the effect of warfarin, causing a lower INR reading which indicates a reduced level of anticoagulation and increased clotting risk.
Actionable advice:
Vitamin K2 should not be taken while monitoring INR for warfarin therapy, unless under strict medical supervision.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
The vitamin K supplement was discontinued and his warfarin dose was increased by 14.3%.
Label source:
PubMed: Elevated international normalized ratio from vitamin K supplement discontinuation. (PMID 21205949)
Action type:
monitor
Target id:
/intervention/vitamin-d
Target name:
Vitamin D3
Severity:
moderate
Interaction type:
synergistic
Nature:
temporal
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Vitamin D promotes the synthesis of proteins (e.g., osteocalcin, MGP) that Vitamin K2 then activates to properly regulate calcium placement in the body, enhancing bone and cardiovascular health.
Actionable advice:
Vitamin K2 and Vitamin D3 are best taken together with a fatty meal for optimal effect.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Exact phrase from label:
vitamin D promotes the production of vitamin K-dependent proteins, which require vitamin K for carboxylation in order to function properly
Label source:
Primary literature: https://pmc.ncbi.nlm.nih.gov/articles/PMC5613455/
Action type:
informational_none
Target id:
/intervention/vitamin-e
Target name:
Vitamin E (High Doses)
Severity:
moderate
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
High supplemental doses of Vitamin E (>800 IU/day) can antagonize the effects of Vitamin K, particularly its role in blood clotting, and may impair its absorption.
Actionable advice:
Very high doses of Vitamin E are best not taken with Vitamin K2 unless directed by a physician.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Clinicians should assess patient supplementation status pre-treatment to optimize outcomes and minimize complications, particularly advising against high-dose vitamin E peri-procedurally.
Label source:
PubMed: Botulinum Toxin Effects and Its Association with Vitamin and Mineral Supplementation: A Narrative Review. (PMID 41683312)
Action type:
avoid
Target id:
/intervention/vitamin-a
Target name:
Vitamin A (High Doses)
Severity:
moderate
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
High supplemental doses of Vitamin A (>10,000 IU/day) can compete with Vitamin K for intestinal absorption, potentially leading to reduced Vitamin K status.
Actionable advice:
High doses of Vitamin A are best not taken with Vitamin K2 unless medically supervised.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Vitamin A also significantly decreased the uptake of the other FSVs but, conversely, its uptake was not impaired by vitamins D and K and even promoted by vitamin E.
Label source:
PubMed: Food chemistry (2015)
Source url:
Exact phrase from label:
The fat-soluble vitamins are vitamins A, D, E, and K. Each vitamin has unique characteristics and contributes to the overall health of an individual. These vitamins have complex absorption, metabolism, and distribution elements that provide protection to the cells in the body as well as many organs.
Label source:
PubMed: The Nursing clinics of North America (2021)
Source url:
Exact phrase from label:
Vitamins, like many substances, may be toxic when taken in large quantities, especially the fat-soluble vitamins, and the concept of "more is better" is a common misconception.
Label source:
PubMed: Advances in experimental medicine and biology (1984)
Action type:
avoid
Target id:
/class/antibiotics-long-term
Target name:
Antibiotics (Long-term Use)
Severity:
moderate
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Long-term use of broad-spectrum antibiotics can reduce the gut bacteria that produce some forms of Vitamin K2 (menaquinones), potentially lowering overall vitamin K status.
Actionable advice:
If on long-term antibiotics, ensure consistent intake of Vitamin K2 from supplements or food.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
CONCLUSION: These data provide direct evidence for the absorption of vitamin K2 from the distal small bowel, supporting a definite role for bacterially synthesized vitamin K2 in contributing to the human nutritional requirements of this vitamin.
Label source:
PubMed: The contribution of vitamin K2 (menaquinones) produced by the intestinal microflora to human nutritional requirements for vitamin K. (PMID 8198105)
Action type:
informational_none
Target id:
/condition/hepatic-impairment
Target name:
Severe Liver Disease
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
The liver is the primary site for synthesizing vitamin K-dependent clotting factors; in severe liver disease, this function is compromised, and response to vitamin K is unpredictable.
Actionable advice:
It is important to consult a physician before using Vitamin K2 for those with severe liver disease.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
The Cmax in groups LC and CH were 85.9 and 126.3 nmol/l, respectively, which is significantly reduced compared with that of group N (184.4 nmol/l) (p less than 0.01 and p less than 0.05, respectively).
Label source:
PubMed: Scandinavian journal of gastroenterology (1990)
Source url:
Exact phrase from label:
In this situation abnormalities may be due to deficient synthesis of coagulation factors in hepatocellular failure, by failure of vitamin K absorption, and also by disseminated intravascular coagulation (DIC).
Label source:
PubMed: Clinics in haematology (1985)
Source url:
Exact phrase from label:
Vitamin K-dependent carboxylase is found in the liver, where it is involved in the synthesis of four blood coagulation factors and protein C.
Label source:
PubMed: Haematologia (1985)
Action type:
informational_none
Target id:
/condition/renal-impairment
Target name:
Chronic Kidney Disease
Severity:
minor
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Vitamin K2 may help prevent vascular calcification, a common and serious complication in chronic kidney disease, by activating matrix Gla protein (MGP).
Actionable advice:
It is a good idea to talk to a nephrologist; Vitamin K2 may be beneficial but requires coordination with other treatments.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Herein, we focus on another prominent action of vitamin K, in particular vitamin K2 (namely, the activation of matrix γ-carboxyglutamic acid protein, the most potent inhibitor of cardiovascular calcifications).
Label source:
PubMed: Kidney international (2021)
Source url:
Exact phrase from label:
Matrix Gla Protein (MGP), the most potent inhibitor of VC, requires vitamin K as a co-factor to become biologically active.
Label source:
PubMed: Current vascular pharmacology (2022)
Source url:
Exact phrase from label:
Vitamin K plays different roles, including in activating vitamin K-dependent proteins (VKDPs) and in modulating bone metabolism and contributing to the inhibition of VC.
Label source:
PubMed: International journal of molecular sciences (2022)
Action type:
informational_none
Target id:
/dietary/hot-foods-beverages
Target name:
Hot Foods or Beverages
Severity:
moderate
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Liposomal vitamin D3/K2 relies on a heat-sensitive phospholipid bilayer to protect and deliver its payload. Stirring it into a hot beverage (coffee, tea, soup) can melt or rupture the liposomes, destroying the enhanced-absorption advantage that is the entire point of the liposomal form.
Actionable advice:
Liposomal vitamin D3/K2 should not be added to hot drinks or food. It should be taken with cool or room-temperature liquid to keep the liposomes intact.
Validation status:
validated_via_class_inference
Evidence tier:
tier_c
Evidence basis:
class_inference_summary
Evidence anchors:
Source url:
Mechanism / liposome thermal stability
Exact phrase from label:
Phospholipid liposomal delivery systems are thermally labile and lose bilayer integrity when exposed to hot liquids, negating the absorption advantage of the liposomal format.
Label source:
Mechanistic inference
Action type:
avoid