Identification

Name
Fosnetupitant
Accession Number
DB14019
Type
Small Molecule
Groups
Approved
Description

In April 2018, the U.S. Food and Drug Administration (FDA) and the Swiss company Helsinn approved the intravenous formulation of AKYNZEO® (NEPA, a fixed antiemetic combination of fosnetupitant, 235mg, and palonosetron, 0.25mg) as an alternative treatment option for patients experiencing chemotherapy-induced nausea and vomiting [3]. Fosnetupitant is the pro-drug form of netupitant [FDA Label].

Generally, 25% to 30% of patients with a diagnosis of cancer receive chemotherapy as a treatment modality and 70% to 80% of these patients undergoing chemotherapy treatment may experience nausea and vomiting as major side effects. Considered one of the most distressing side effects of chemotherapy, nausea and vomiting has an immense impact on the quality of life of patients receiving certain antineoplastic therapies [1].

Structure
Thumb
Synonyms
Not Available
External IDs
07-PNET
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
AkynzeoFosnetupitant (260 mg/1) + Palonosetron hydrochloride (.28 mg/1)InjectionIntravenousHelsinn Therapeutics (U.S.), Inc2018-04-20Not applicableUs
Categories
UNII
T672P80L2S
CAS number
1703748-89-3
Weight
Average: 688.608
Monoisotopic: 688.224926219
Chemical Formula
C31H35F6N4O5P
InChI Key
HZIYEEMJNBKMJH-UHFFFAOYSA-N
InChI
InChI=1S/C31H35F6N4O5P/c1-20-8-6-7-9-24(20)25-17-27(40-10-12-41(5,13-11-40)19-46-47(43,44)45)38-18-26(25)39(4)28(42)29(2,3)21-14-22(30(32,33)34)16-23(15-21)31(35,36)37/h6-9,14-18H,10-13,19H2,1-5H3,(H-,43,44,45)
IUPAC Name
4-(5-{2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethylpropanamido}-4-(2-methylphenyl)pyridin-2-yl)-1-[(hydrogen phosphonooxy)methyl]-1-methylpiperazin-1-ium
SMILES
CN(C(=O)C(C)(C)C1=CC(=CC(=C1)C(F)(F)F)C(F)(F)F)C1=CN=C(C=C1C1=CC=CC=C1C)N1CC[N+](C)(COP(O)([O-])=O)CC1

Pharmacology

Indication

Indicated in combination palonosetron (as the drug Akynzeo) and dexamethasone in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy [FDA Label].

The following are indications listed on the EMA label [8]:

Prevention of acute and delayed nausea and vomiting associated with highly emetogenic cisplatin-based cancer chemotherapy [8].

Prevention of acute and delayed nausea and vomiting associated with moderately emetogenic cancer chemotherapy [8].

Structured Indications
Not Available
Pharmacodynamics

In the combination drug, Akynzeo, palonosetron prevents nausea and vomiting during the acute phase and fosnetupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy [FDA Label].

Neurokinin-1 (NK-1) inhibitor drugs, such as netupitant, possess unique anxiolytic, antidepressant, and antiemetic properties [6].

Mechanism of action

The fosnetupitant in this drug combination is a selective P/neurokinin-1 (NK-1) receptor antagonist [FDA Label].

Netupitant, the prodrug of fosnetupitant, is a selective neurokinin 1 (NK1) receptor antagonist with antiemetic activity. Netupitant competitively binds to and blocks the activity of the human substance P/NK1 receptors in the central nervous system (CNS), inhibiting NK1-receptor binding of the endogenous tachykinin neuropeptide substance P (SP), which results in the prevention of chemotherapy-induced nausea and vomiting (CINV). Substance P is found in neurons of vagal afferent fibers innervating the brain-stem nucleus tractus solitarii and the area postrema, which contains the chemoreceptor trigger zone (CTZ), and may be present at high levels in response to chemotherapy. The NK-receptor is a G-protein receptor coupled to the inositol phosphate signal-transduction pathway and is found in both the nucleus tractus solitarii and the area postrema [7].

Netupitant demonstrated 92.5% NK1 receptor occupancy at 6 hours, with 76% occupancy at 96 hours [5].

TargetActionsOrganism
ANeurokinin-1 Receptor (NK1R)
antagonist
Human
Absorption

Following single intravenous doses of Akynzeo for injection in patients (235 mg fosnetupitant and 0.25 mg palonosetron infused in 30 minutes) or fosnetupitant in healthy subjects (235 mg fosnetupitant infused in 30 minutes), maximum concentration of fosnetupitant was achieved at the end of the 30-minute infusion [FDA Label].

Oral bioavailability in each species varied substantially between animals, with 42-105%, 34-83% and 37-62% in rats, dogs, and monkeys. The large variation is most likely due to the low numbers of animals used in the studies [8].

Volume of distribution

The mean SD volume of distribution of fosnetupitant in healthy subjects and in patients was 124 +/- 76 L and 296 +/- 535 L, respectively [FDA Label].

Protein binding

Netupitant is highly bound (>99%) to plasma proteins in all species [8].

Metabolism

Fosnetupitant is the prodrug of netupitant [FDA Label].

Netupitant is a moderate inhibitor and substrate of CYP3A4 [FDA Label].

Akynzeo should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4 systems. One dose of netupitant 300 mg significantly inhibits CYP3A4 for about 6 days. It is avisable to avoid concomitant use of drugs that are CYP3A4 substrates for one week. If not possible, consider dose reduction of CYP3A4 substrates [FDA Label].

In the human, rat, dog, minipig and marmoset liver microsomal incubations, two major metabolites, an N-demethylation product (M1) _and an _N-oxidation product (M2), in addition to hydroxylation products (M3), were identified in all species. CYP3A4 was found to be responsible for the oxidation of netupitant to the same metabolites observed also in the incubations with human liver microsomes. Metabolism was extensive, with the metabolites generally achieving greater concentrations than parent drug witin 24 hours. M1 and M2 exposure was similar in rat to humans, but higher in dogs, however M3 was lower in both species than in humans [8].

Route of elimination

After one oral dose of [14C]­netupitant, approximately one-half of the administered radioactivity was measured in the urine and feces within 120 hours of the dose. The total of 3.95% and 70.7% of the radioactive dose was measured in the urine and feces collected over 336 hours, respectively, and the average fraction of an oral dose of netupitant excreted unchanged in urine is under 1%, implying that renal clearance is not a significant route of elimination for the netupitant-related entities [FDA Label].

About 86.5% and 4.7% of administered radioactivity was estimated to be excreted via the feces and urine within 30 days post-dose [FDA Label].

Half life

Netupitant is eliminated from the body in a multi-exponential fashion, with an apparent elimination half-life in cancer patients of 80 ± 29 hours (mean ± SD) [FDA Label].

Clearance

Netupitant has a mean estimated systemic clearance of 0.3 ± 9.2 L/h (mean ± SD) after a single oral dose of Akynzeo [FDA Label].

Toxicity

Most common adverse reactions (≥3%) for AKYNZEO capsules are headache, asthenia, dyspepsia, fatigue, constipation and erythema [5].

The safety profile of Akynzeo for injection is generally similar to that seen with Aynzeo capsules [FDA Label], [5].

Currently a repeated dose safety study is ongoing in patients receiving anthracycline plus cyclophosphamide to further establish the safety profile in this setting [3].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
Acetyl sulfisoxazoleThe metabolism of Fosnetupitant can be decreased when combined with Acetyl sulfisoxazole.Approved, Vet Approved
AmiodaroneThe metabolism of Fosnetupitant can be decreased when combined with Amiodarone.Approved, Investigational
ApalutamideThe serum concentration of Fosnetupitant can be decreased when it is combined with Apalutamide.Approved, Investigational
AprepitantThe serum concentration of Fosnetupitant can be increased when it is combined with Aprepitant.Approved, Investigational
AsunaprevirThe serum concentration of Asunaprevir can be increased when it is combined with Fosnetupitant.Approved, Investigational, Withdrawn
AtazanavirThe metabolism of Fosnetupitant can be decreased when combined with Atazanavir.Approved, Investigational
AtomoxetineThe metabolism of Fosnetupitant can be decreased when combined with Atomoxetine.Approved
AtorvastatinThe risk or severity of adverse effects can be increased when Fosnetupitant is combined with Atorvastatin.Approved
BoceprevirThe metabolism of Fosnetupitant can be decreased when combined with Boceprevir.Approved, Withdrawn
BortezomibThe metabolism of Fosnetupitant can be decreased when combined with Bortezomib.Approved, Investigational
BosentanThe serum concentration of Fosnetupitant can be decreased when it is combined with Bosentan.Approved, Investigational
BosutinibThe serum concentration of Bosutinib can be increased when it is combined with Fosnetupitant.Approved
BromocriptineThe risk or severity of adverse effects can be increased when Bromocriptine is combined with Fosnetupitant.Approved, Investigational
CabergolineThe risk or severity of adverse effects can be increased when Cabergoline is combined with Fosnetupitant.Approved
CarbamazepineThe metabolism of Fosnetupitant can be increased when combined with Carbamazepine.Approved, Investigational
CeritinibThe serum concentration of Fosnetupitant can be increased when it is combined with Ceritinib.Approved
CerivastatinThe serum concentration of Cerivastatin can be increased when it is combined with Fosnetupitant.Approved, Withdrawn
ClarithromycinThe metabolism of Fosnetupitant can be decreased when combined with Clarithromycin.Approved
ClemastineThe metabolism of Fosnetupitant can be decreased when combined with Clemastine.Approved, Investigational
ClotrimazoleThe metabolism of Fosnetupitant can be decreased when combined with Clotrimazole.Approved, Vet Approved
CobicistatThe metabolism of Fosnetupitant can be decreased when combined with Cobicistat.Approved
ConivaptanThe serum concentration of Conivaptan can be increased when it is combined with Fosnetupitant.Approved, Investigational
CrizotinibThe metabolism of Fosnetupitant can be decreased when combined with Crizotinib.Approved
CyclosporineThe metabolism of Fosnetupitant can be decreased when combined with Cyclosporine.Approved, Investigational, Vet Approved
DabrafenibThe serum concentration of Fosnetupitant can be decreased when it is combined with Dabrafenib.Approved, Investigational
DarunavirThe metabolism of Fosnetupitant can be decreased when combined with Darunavir.Approved
DasatinibThe serum concentration of Fosnetupitant can be increased when it is combined with Dasatinib.Approved, Investigational
DeferasiroxThe serum concentration of Fosnetupitant can be decreased when it is combined with Deferasirox.Approved, Investigational
DelavirdineThe metabolism of Fosnetupitant can be decreased when combined with Delavirdine.Approved
DihydroergocornineThe risk or severity of adverse effects can be increased when Dihydroergocornine is combined with Fosnetupitant.Approved
DihydroergocristineThe risk or severity of adverse effects can be increased when Dihydroergocristine is combined with Fosnetupitant.Approved, Experimental
DihydroergocryptineThe risk or severity of adverse effects can be increased when Dihydroergocryptine is combined with Fosnetupitant.Experimental
DihydroergotamineThe risk or severity of adverse effects can be increased when Dihydroergotamine is combined with Fosnetupitant.Approved, Investigational
DiltiazemThe metabolism of Fosnetupitant can be decreased when combined with Diltiazem.Approved, Investigational
DoxycyclineThe metabolism of Fosnetupitant can be decreased when combined with Doxycycline.Approved, Investigational, Vet Approved
DronedaroneThe metabolism of Fosnetupitant can be decreased when combined with Dronedarone.Approved
EnzalutamideThe serum concentration of Fosnetupitant can be decreased when it is combined with Enzalutamide.Approved
ErgonovineThe risk or severity of adverse effects can be increased when Ergonovine is combined with Fosnetupitant.Approved
ErgotamineThe risk or severity of adverse effects can be increased when Ergotamine is combined with Fosnetupitant.Approved
ErythromycinThe metabolism of Fosnetupitant can be decreased when combined with Erythromycin.Approved, Investigational, Vet Approved
FluconazoleThe metabolism of Fosnetupitant can be decreased when combined with Fluconazole.Approved, Investigational
FluvastatinThe serum concentration of Fluvastatin can be increased when it is combined with Fosnetupitant.Approved
FluvoxamineThe metabolism of Fosnetupitant can be decreased when combined with Fluvoxamine.Approved, Investigational
FosamprenavirThe metabolism of Fosnetupitant can be decreased when combined with Fosamprenavir.Approved
FosaprepitantThe serum concentration of Fosnetupitant can be increased when it is combined with Fosaprepitant.Approved
FosphenytoinThe metabolism of Fosnetupitant can be increased when combined with Fosphenytoin.Approved, Investigational
Fusidic AcidThe serum concentration of Fosnetupitant can be increased when it is combined with Fusidic Acid.Approved, Investigational
IbrutinibThe serum concentration of Ibrutinib can be increased when it is combined with Fosnetupitant.Approved
IdelalisibThe metabolism of Fosnetupitant can be decreased when combined with Idelalisib.Approved
ImatinibThe metabolism of Fosnetupitant can be decreased when combined with Imatinib.Approved
IndinavirThe metabolism of Fosnetupitant can be decreased when combined with Indinavir.Approved
IsavuconazoleThe serum concentration of Fosnetupitant can be increased when it is combined with Isavuconazole.Approved, Investigational
IsavuconazoniumThe metabolism of Fosnetupitant can be decreased when combined with Isavuconazonium.Approved, Investigational
IsradipineThe metabolism of Fosnetupitant can be decreased when combined with Isradipine.Approved, Investigational
ItraconazoleThe metabolism of Fosnetupitant can be decreased when combined with Itraconazole.Approved, Investigational
IvacaftorThe serum concentration of Fosnetupitant can be increased when it is combined with Ivacaftor.Approved
KetoconazoleThe metabolism of Fosnetupitant can be decreased when combined with Ketoconazole.Approved, Investigational
LisurideThe risk or severity of adverse effects can be increased when Lisuride is combined with Fosnetupitant.Approved, Investigational
LopinavirThe metabolism of Fosnetupitant can be decreased when combined with Lopinavir.Approved
LorpiprazoleThe serum concentration of Fosnetupitant can be increased when it is combined with Lorpiprazole.Approved
LovastatinThe serum concentration of Lovastatin can be increased when it is combined with Fosnetupitant.Approved, Investigational
LuliconazoleThe serum concentration of Fosnetupitant can be increased when it is combined with Luliconazole.Approved
LumacaftorThe metabolism of Fosnetupitant can be increased when combined with Lumacaftor.Approved
Lysergic Acid DiethylamideThe risk or severity of adverse effects can be increased when Lysergic Acid Diethylamide is combined with Fosnetupitant.Illicit, Investigational, Withdrawn
MetergolineThe risk or severity of adverse effects can be increased when Metergoline is combined with Fosnetupitant.Experimental
MethylergometrineThe risk or severity of adverse effects can be increased when Methylergometrine is combined with Fosnetupitant.Approved
MethysergideThe risk or severity of adverse effects can be increased when Methysergide is combined with Fosnetupitant.Approved
MevastatinThe serum concentration of Mevastatin can be increased when it is combined with Fosnetupitant.Experimental
MifepristoneThe serum concentration of Fosnetupitant can be increased when it is combined with Mifepristone.Approved, Investigational
MitotaneThe serum concentration of Fosnetupitant can be decreased when it is combined with Mitotane.Approved
NefazodoneThe metabolism of Fosnetupitant can be decreased when combined with Nefazodone.Approved, Withdrawn
NelfinavirThe metabolism of Fosnetupitant can be decreased when combined with Nelfinavir.Approved
NetupitantThe serum concentration of Fosnetupitant can be increased when it is combined with Netupitant.Approved, Investigational
NevirapineThe metabolism of Fosnetupitant can be increased when combined with Nevirapine.Approved
NicergolineThe risk or severity of adverse effects can be increased when Nicergoline is combined with Fosnetupitant.Approved, Investigational
NilotinibThe metabolism of Fosnetupitant can be decreased when combined with Nilotinib.Approved, Investigational
OlaparibThe metabolism of Fosnetupitant can be decreased when combined with Olaparib.Approved
OsimertinibThe serum concentration of Fosnetupitant can be increased when it is combined with Osimertinib.Approved
PalbociclibThe serum concentration of Fosnetupitant can be increased when it is combined with Palbociclib.Approved, Investigational
PentobarbitalThe metabolism of Fosnetupitant can be increased when combined with Pentobarbital.Approved, Investigational, Vet Approved
PergolideThe risk or severity of adverse effects can be increased when Pergolide is combined with Fosnetupitant.Approved, Investigational, Vet Approved, Withdrawn
PhenobarbitalThe metabolism of Fosnetupitant can be increased when combined with Phenobarbital.Approved, Investigational
PhenytoinThe metabolism of Fosnetupitant can be increased when combined with Phenytoin.Approved, Vet Approved
PitavastatinThe serum concentration of Pitavastatin can be increased when it is combined with Fosnetupitant.Approved
PitolisantThe serum concentration of Fosnetupitant can be decreased when it is combined with Pitolisant.Approved, Investigational
PosaconazoleThe metabolism of Fosnetupitant can be decreased when combined with Posaconazole.Approved, Investigational, Vet Approved
PravastatinThe serum concentration of Pravastatin can be increased when it is combined with Fosnetupitant.Approved
PrimidoneThe metabolism of Fosnetupitant can be increased when combined with Primidone.Approved, Vet Approved
RanolazineThe metabolism of Fosnetupitant can be decreased when combined with Ranolazine.Approved, Investigational
RifabutinThe metabolism of Fosnetupitant can be increased when combined with Rifabutin.Approved, Investigational
RifampicinThe metabolism of Fosnetupitant can be increased when combined with Rifampicin.Approved
RifapentineThe metabolism of Fosnetupitant can be increased when combined with Rifapentine.Approved, Investigational
RilpivirineThe serum concentration of Rilpivirine can be increased when it is combined with Fosnetupitant.Approved
RosuvastatinThe serum concentration of Rosuvastatin can be increased when it is combined with Fosnetupitant.Approved
RucaparibThe metabolism of Fosnetupitant can be decreased when combined with Rucaparib.Approved, Investigational
SaquinavirThe metabolism of Fosnetupitant can be decreased when combined with Saquinavir.Approved, Investigational
SarilumabThe therapeutic efficacy of Fosnetupitant can be decreased when used in combination with Sarilumab.Approved, Investigational
SildenafilThe metabolism of Fosnetupitant can be decreased when combined with Sildenafil.Approved, Investigational
SiltuximabThe serum concentration of Fosnetupitant can be decreased when it is combined with Siltuximab.Approved, Investigational
SimeprevirThe serum concentration of Fosnetupitant can be increased when it is combined with Simeprevir.Approved
SimvastatinThe serum concentration of Simvastatin can be increased when it is combined with Fosnetupitant.Approved
St. John's WortThe serum concentration of Fosnetupitant can be decreased when it is combined with St. John's Wort.Approved, Investigational, Nutraceutical
StiripentolThe serum concentration of Fosnetupitant can be increased when it is combined with Stiripentol.Approved
SulfisoxazoleThe metabolism of Fosnetupitant can be decreased when combined with Sulfisoxazole.Approved, Vet Approved
TelaprevirThe metabolism of Fosnetupitant can be decreased when combined with Telaprevir.Approved, Withdrawn
TelithromycinThe metabolism of Fosnetupitant can be decreased when combined with Telithromycin.Approved
TergurideThe risk or severity of adverse effects can be increased when Terguride is combined with Fosnetupitant.Experimental
TiclopidineThe metabolism of Fosnetupitant can be decreased when combined with Ticlopidine.Approved
TocilizumabThe serum concentration of Fosnetupitant can be decreased when it is combined with Tocilizumab.Approved
TolvaptanThe serum concentration of Tolvaptan can be increased when it is combined with Fosnetupitant.Approved
VemurafenibThe serum concentration of Fosnetupitant can be decreased when it is combined with Vemurafenib.Approved
VenlafaxineThe metabolism of Fosnetupitant can be decreased when combined with Venlafaxine.Approved
VerapamilThe metabolism of Fosnetupitant can be decreased when combined with Verapamil.Approved
VoriconazoleThe metabolism of Fosnetupitant can be decreased when combined with Voriconazole.Approved, Investigational
ZiprasidoneThe metabolism of Fosnetupitant can be decreased when combined with Ziprasidone.Approved
Food Interactions
Not Available

References

General References
  1. Coyne JW: The First Oral Fixed-Dose Combination of Netupitant and Palonosetron for the Treatment of Chemotherapy-Induced Nausea and Vomiting. J Adv Pract Oncol. 2016 Jan-Feb;7(1):66-70. Epub 2016 Jan 1. [PubMed:27713845]
  2. Navari RM: Profile of netupitant/palonosetron (NEPA) fixed dose combination and its potential in the treatment of chemotherapy-induced nausea and vomiting (CINV). Drug Des Devel Ther. 2014 Dec 17;9:155-61. doi: 10.2147/DDDT.S76158. eCollection 2015. [PubMed:25552904]
  3. Helsinn Group announces the FDA approval of the IV formulation of AKYNZEO® (fosnetupitant/palonosetron) in the United States [Link]
  4. Safety Data Sheet, Netupitant [Link]
  5. Akynzeo.com [Link]
  6. Antiemetic, Neurokinin-1 Receptor Blockers [Link]
  7. Netupitant, PubChem [Link]
  8. EMA label [File]
External Links
ChemSpider
44208829
FDA label
Download (1 MB)
MSDS
Download (72.3 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
InjectionIntravenous
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility1.4 mg/mL at acidic PH (2) and Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.000216 mg/mLALOGPS
logP2.57ALOGPS
logP0.8ChemAxon
logS-6.5ALOGPS
pKa (Strongest Acidic)-0.11ChemAxon
pKa (Strongest Basic)6.74ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area106.03 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity175.36 m3·mol-1ChemAxon
Polarizability64.07 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Targets

1. Neurokinin-1 Receptor (NK1R)
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
References
  1. Coyne JW: The First Oral Fixed-Dose Combination of Netupitant and Palonosetron for the Treatment of Chemotherapy-Induced Nausea and Vomiting. J Adv Pract Oncol. 2016 Jan-Feb;7(1):66-70. Epub 2016 Jan 1. [PubMed:27713845]
  2. EMA label [File]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Navari RM: Profile of netupitant/palonosetron (NEPA) fixed dose combination and its potential in the treatment of chemotherapy-induced nausea and vomiting (CINV). Drug Des Devel Ther. 2014 Dec 17;9:155-61. doi: 10.2147/DDDT.S76158. eCollection 2015. [PubMed:25552904]
  2. Helsinn Group announces the FDA approval of the IV formulation of AKYNZEO® (fosnetupitant/palonosetron) in the United States [Link]

Drug created on May 02, 2018 09:43 / Updated on May 02, 2018 15:53