Product Monograph

The type 1 and type 2 pneumocytes are responsible for producing & maintaining Type-1 pneumocytes, production of surfactants & alveolar fluid shunt. An increased rate & extent of damage to type-2 pneumocytes in ARDS leads to reduced production of surfactants, Reduced fluid shunt & disruption in alveolar epithelium. This can lead to a compromised gas exchange leading to increased mortality in ARDS.

The American European Consensus Conference (AECC) 1994 defined ARDS as ‘an acute inflammatory syndrome manifesting as diffuse pulmonary oedema and respiratory failure that cannot be explained by, but may co-exist with, left-sided heart failure’. In 2012, the AECC definition was re-evaluated and minor alterations were proposed by the European Society of Intensive Care Medicine ARDS Definition Task Force.

This restatement recognised 3 grades of severity depending on the degree of hypoxaemia and stipulated the application of at least 5 cmH2O of positive end-expiratory pressure (PEEP) or continuous positive airway pressure. This so-called Berlin definition was validated using retrospective cohorts and captures patients with a mortality of 24% in patients with mild ARDS, rising to 48% in the group of patients with the most severe respiratory failure.

Table 1. Comparison of the American-European Consensus Conference (AECC) and Berlin Deﬁnitions of Acute Respiratory Distress Syndrome (ARDS).

	AECC		Current Berlin 10 Deﬁnition
	8 Deﬁnition	Limitations	How AECC Limitations Were Addressed	Definition
Timing	Acute onset.	No definition of acute.	Acute time frame specified.	Within 1 week of a known clinical insult or new or worsening respiratory symptoms.
ALI Category	All patients with PaO₂/FiO₂ Ç300 mm Hg.	ALI often misinterpreted as only referring to patients with PaO₂/FiO₂ = 201-300mm Hg, leading to confusing “ALI/ARDS” term.	3 mutually exclusive subgroups of ARDS by severity; ALI term removed.	Mild : 200 mm Hg PaO₂/FiO₂ <300mm Hg, with PEEP or CPAP 5 cm H₂O; Moderate : 100 mm Hg PaO₂/FiO₂ Ç 200mm Hg, Severe : PaO₂/FiO₂ Ç 100 mm Hg.
Oxygenation	PaO₂/FiO₂ Ç300 mm Hg (regardless of PEEP).	Inconsistency of PaO₂/FiO₂ ratio due to the effect of PEEP and FiO₂.	Minimal PEEP level added across subgroups; FiO₂ less relevant in severe ARDS subgroup.	Mild : PEEP or CPAP í 5 cmH₂O; Moderate or Severe : PEEP í 5 cmH₂O.
Chest Radiograph	Bilateral infiltrates observed on frontal chest radiograph.	Poor inter-observer reliability of chest radiograph interpretation.	Chest radiograph criteria clariﬁed; example radiographs created.	Bilateral opacities-not fully explained by eﬀusions, lobar or lung collapse, or nodules.
PAWP	PAWP Ç18 mm Hg when measured or no clinical evidence of left atrial hypertension.	High PAWP and ARDS may coexist; poor inter-observer reliability of PAWP and clinical assessments of left atrial hypertension.	PAWP requirement removed; hydrostatic edema not the primary cause of respiratory failure; clinical vignettes created to help exclude hydrostatic edema.	Respiratory failure not fully explained by cardiac failure or ﬂuid overload.
Risk Factor	None.	Not formally included in definition.	Included (eg, pneumonia, trauma, sepsis, pancreatitis); when none identified need to objectively rule out hydrostatic edema.	Need objective assessment (eg, echocardiography) to exclude hydrostatic edema if no risk factor present.

Abbreviations : AECC : American-European Consensus Conference, ALI : Acute Lung Injury, ARDS : Acute Respiratory Distress Syndrome, CPAP : Continuous Positive Airway Pressure, FIO₂: Fraction of Inspired Oxygen, PaO₂: Partial Pressure of Arterial Oxygen, PAWP : Pulmonary Artery Wedge Pressure, PEEP : Positive End-Expiratory Pressure.

Globally, ARDS affects approximately 3 million patients annually, accounting for 10% of intensive care unit (ICU) admissions, and 24% of patients receiving mechanical ventilation in the ICU with an estimated mortality rate of approximately 40-60% depending on disease severity.

The incidence of ARDS in patients with risk factors is 30% in India with a mortality of 41.8%.

Increased permeability of the membrane manifests as high permeability pulmonary oedema. The resulting acute inflammatory exudate inactivates surfactant leading to collapse and consolidation of distal airspaces with progressive loss of the lung’s gas exchange surface area.
Hypoxic pulmonary vasoconstriction allowing deoxygenated blood to cross unventilated lung units on its way to the left- heart eventually leading to respiratory failure.
The exudative phase is the lung's initial response to injury where there is accumulation of protein-rich edema fluid within the interstitium and alveolus.
The proliferative phase is characterised by the transient expansion of resident fibroblasts, the formation of a provisional matrix, proliferation of airway progenitor cells and type II alveolar epithelial cells (AECII), with differentiation into type I alveolar epithelial cells (AECI).
The final, or fibrotic phase of ARDS does not occur in all patients but has been linked to prolonged mechanical ventilation and increased mortality.

SARS-CoV-2 binds to the ACE2 receptor which causes down-regulation of ACE2 receptors leading to the increased production of angiotensin-2 (AT2) by the related enzyme ACE1. This increased production of AT2 potentially increases pulmonary vascular permeability and may cause lung injury.
Furthermore, the 'cytokine storm' associated with SARS-CoV-2 can the epithelial cells lining and reach into the blood circulation where it causes damage to other organs.

Types of alveolus cells and their functions :

Type I pneumocytes

Cover 95% of the internal surface of each alveolus.
Thin and squamous to facilitate gas exchange.
Share a basement membrane with pulmonary capillary endothelium, forming the air-blood barrier where gas exchange occurs.
Maintain ion and fluid balance within the alveoli.
Communicate with type II pneumocytes to secrete surfactant in response to stretch.

Type II pneumocytes

Much less prevalent in each alveolus, found in between type I pneumocytes.
Large and cuboidal cells with apical microvilli. Within their cytoplasm are characteristic lamellar bodies that produce and secrete surfactant-a vital substance that reduces surface tension, preventing alveoli from collapsing.
Express of immunomodulatory proteins that are necessary for host defense.
Allows transepithelial movement of water.
Regeneration of alveolar epithelium after injury: serve as an important progenitor during homeostasis and during repair after injury.

Mononuclear phagocytes that are residents in alveoli.
The cell membrane of these cells can utilize a network of microtubules to change shape during chemotaxis or phagocytosis.

Challenges in ARDS management :

High mortality (40-60%), despite all Hi-Tech life support system no pharmacological management that can restore gas exchange and reduce mortality.

VIP and its Receptors

Vasoactive intestinal peptide (VIP) is a 28-residue amino acid peptide is widely distributed in the central and peripheral nervous system as well as in the digestive, respiratory, reproductive, and cardiovascular systems as a neurotransmitter and neuroendocrine releasing factor.
Although purified in the intestine, 70% of VIP is concentrated in the lung.
The two receptors that recognise Aviptadil (VIP), termed- VPAC1 and VPAC2.
VPAC1 is expressed in brain (cerebral cortex and hippocampus) and in peripheral tissues such as liver, lung and intestine, T-lymphocytes.
VPAC2 is expressed in the CNS and in peripheral tissues, including the pancreas, skeletal muscle.
The activation of VPAC1 and 2 receptors produces anti-inflammatory mediators which counters the inflammatory mediators produced by inflammatory stimuli.

Normal Plasma Levels of VIP

In healthy volunteers, VIP concentration ranges from 14 to 76 pg/ML.

Reference Value for Lab Test : <75 pg/ML

Patients with critical COVID-19, COPD, Asthma have elevated VIP plasma levels, compared with asymptomatic patients.
Values > 75 pg/ML may indicate the presence of an enteropancreatic tumor causing.
Hypersecretion of vasoactive intestinal polypeptide (VIP).
Values > 200 pg/ML are strongly suggestive of VIP-producing tumor (VIPoma).

Aviptadil, a synthetic form of VIP, has been granted a marketing approval in India for the treatment of Acute respiratory distress syndrome (ARDS) in patients with severe COVID-19.

Synonyms	Vasoactive Intestinal Octacosapeptide
Molecular Formula	C147H237N43O43S
Molecular Weight	3325.8 g/mol
Chemical Structure
IUPAC Condensed Formula	H-His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-GIn-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-lle-Leu-Asn-OH¹²

VIP is highly expressed in the lung tissue (approximately 70%) and nasal mucosa.

Recently, VIP was shown to block replication of the SARS-CoV-2 virus in human pulmonary epithelial cells (pneumocytes) and monocytes, while also demonstrating clinical improvement on radiographic and laboratory parameters.

In addition to blocking viral replication:

VIP protects the Alveolar Type II (ATII) cell by up-regulating surfactant production, blocking apoptosis, and blocking cytokine effects.
VIP blocks cytokine synthesis and cytopathy in human pneumocytes and up-regulates surfactant production.

Anti-inflammatory action

Inhibits inflammatory cytokines like IL6 and TNF alpha production.
Reverses CD4/CD8 ratio.
Reduces pulmonary inflammation by reducing production of pro-inflammatory cytokines.
Protects against HCl-induced pulmonary edema.
Inhibits the synthesis & activation of NF-KB, which block the production of TNF-α.

Increases pulmonary surfactant production

By up regulation of choline phosphate cystidylyltransferase, which increase the incorporation of methyl choline to phosphatidylcholine, the major components of pulmonary surfactant.
Also up regulate c fos protein expression in type ii alveolar cells, which increase the synthesis of surfactant phospholipids & induce surfactant protein A expression.

Inhibits alveolar epithelial cell Apoptosis

Reduces cell death by inhibiting activation induced perforin, granzyme B and caspase activity.
Restores barrier function at the endothelial/alveolar interface.

Preservation of Pulmonary Tissue

Prevents NMDA-induced caspase-3 activation in the lungs.

VIP reduces ischemia-reperfusion injury

SARS CoV-2 attack mainly type II cells and results in the death of alveolar type II (AT 11) cells which produces surfactant, resulting in profound defect in oxygenation, leading to hypoxia.
VIP and pituitary adenylate cyclase activating polypeptide (PACAP) inhibit SARS CoV-2 RNA.
Synthesis in human lung epithelial cell (by 41%) and human primary monocytes (by 33-45%).
It also blocks viral cytopathic effect demonstrated by reduced LDH release (by 40%).

Aviptadil has vasodilating properties which re 50 times more potent than prostacyclin and independent of the endothelium.
In healthy volunteers intravenous Aviptadil reduced systemic vascular resistance due to its potent vasodilatory effects, followed by increase of heart rate and decrease of blood pressure.
Aviptadil alters the ventilation –perfusion distributions but generates no shunt and does not cause hypoxia.

After injection of 1 μg radioactively labelled Aviptadil within 30 minutes about 45% of the radioactivity is found in the lungs.
The half-life of Aviptadil in plasma is about 1-2 minutes. After injection of radio-labelled Aviptadil, radioactivity is almost completely eliminated by the kidneys, 35% within 4 hours, and 90% within 24 hours.

Therapeutic Indication

Aviptadil has been approved by Central Drugs Standard Control Organisation (CDSCO) in India for treatment of Acute respiratory distress syndrome (ARDS) in patients with severe COVID-19 in April 2022.

Aviptadil intravenous infusion is administered by infusion pump in escalating doses for 3 successive days.

Day 1

Aviptadil 0.166 mcg/kg/hr intravenous infusions over 12- hour (equivalent to 1 vial of Aviptadil Injection).

Day 2

Aviptadil 0.332 mcg/kg/hr intravenous infusions over 12- hour (equivalent to 2 vials of Aviptadil Injection).

Day 3

Aviptadil 0.498 mcg/kg/hr intravenous infusions over 12- hour (equivalent to 3 vials of Aviptadil Injection).

Duration of infusion depends on the patient's body weight:

Body weight < 60 kg - 14 hour infusions of Aviptadil at escalating doses on 3 successive days.
Body weight 60 - 90 kg - 12 hour infusions of Aviptadil at escalating doses on 3 successive days.
Body weight > 90 kg - 10 hour infusions of Aviptadil at escalating doses on 3 successive days.

Drugs Interactions

There is no significant drug-drug interaction.
No clinically relevant interaction was observed concomitantly to anti-hypertensive drugs or other cardiovascular drugs.

Pregnancy

Limited data regarding Aviptadil safety in pregnancy. Single clinical report suggests that vasoactive intestinal peptide is a safe treatment of severe coronavirus disease 2019 respiratory failure during pregnancy.

Special Warnings and Precautions for Use

Mild transient flushing of the face or trunk occurs commonly.
Rarely associated with discomfort and palpitations or tachycardia in which cases patients may be withdrawn from treatment.
Caution in patients with severe cardiovascular or cerebrovascular conditions.

Contraindications

Patients who are hypersensitive to any component of this product.

Undesirable Effects

Gastrointestinal Disorders- Diarrhoea.
Vascular disorders- Hypotension, cutaneous and facial flushing.
Infusion related reactions.

Overdose

No case of overdose has been reported.

India

Aviptadil has been approved by Central Drugs Standard Control Organisation in India for treatment of ARDS in patients with severe COVID-19 in April 2022.

USA

VIP was awarded Orphan Drug* Designation for treatment of Acute Respiratory Distress Syndrome in 2001 by USFDA.
Aviptadil was awarded Orphan Drug Designation for treatment of Pulmonary Arterial Hypertension in 2005 by USFDA.
Aviptadil was awarded Orphan Drug Designation for treatment of Sarcoidosis in 2020 by USFDA.

Europe

Aviptadil was awarded Orphan Drug Designation for treatment of Acute Lung Injury in 2006 by EMA.
Aviptadil was awarded Orphan Drug Designation for treatment of Sarcoidosis in 2007 by EMA.

*An orphan drug is defined as one "intended for the treatment, prevention or diagnosis of a rare disease or condition, which is one that affects less than 200,000 persons in the US" (approx. 6 cases per 10,000 population) "or meets cost recovery provisions of the act.

1. A prospective, open label, administratively controlled trial demonstrates a dramatic multi-dimensional treatment effect, consistent with FDA and ICH-10 guidance for acceptance of externally controlled, open label trials in high lethality conditions.

Four out of five Aviptadil treated patients initially on Extracorporeal Membrane Oxygenation (ECMO) were decannulated, compared to 3 of 13 ECMO treated controls (80% vs 23%; P=0.045).
At day 60, a similar 5.5-fold advantage was seen in the cumulative probability of Recovery from Respiratory Failure (55% vs 10%; P=0.002) at 60 days. The hazard ratio is 0.115 (95% CL: 0.0254, 0.5219).

2. A study assessing the safety/effectiveness of VIP in the treatment of ARDS related to sepsis, VIP demonstrated a successful course during intensive care and successfully removal from mechanical ventilation and discharged from intensive care. It also demonstrated a safety profile consistent with previous studies in normal volunteers.

The study showed that VIP is a promising treatment of other infectious conditions that damage the pulmonary epithelium, particularly COVID-19.

3. A randomized double-blind trial assessing the safety and efficacy of intravenous Aviptadil demonstrated that Aviptadil patients treated with high flow nasal cannula were 35% - 46% more likely to recover, return home, and survive to 28 days compared to placebo-treated patients, with a trend level of significance.

Aviptadil patients additionally demonstrated a highly statistically significant and clinically dramatic ten-day reduction in hospitalisation time.

A randomized, double-blind, comparative Phase III clinical trial assessed the efficacy and safety of Intravenous Aviptadil as an add-on to the “Standard of Care” treatment in severe COVID-19 patients with respiratory failure. It was observed that-

An earlier resolution from the respiratory failure, with a median duration of 7 days was noted in the Aviptadil-treated group as compared to 14 days in the placebo group.
A higher proportion of patients on Aviptadil shifted to the milder clinical state (32.43% vs 17.80%; p=0.0410 on Day 3 and 70.27% vs 45.21%; 0.0035 on Day 7) without the requirement of oxygen than the placebo group.
A reduction of severity (based on WHO 7-point ordinal scale) in clinical status were also observed on Day 14 (p = 0.0005 by Wilcoxon rank sum test) & Day 28 (p = 0.0009 by Wilcoxon rank sum test).
Aviptadil reduced the risk of death by 20% (relative risk 0.80; 95% CI: 0.35, 1.66) in ARDS.
Patients treated with Aviptadil demonstrated significant improvement in PaO2/FiO2 ratio vs. placebo from day 2 to over the week (p< 0.05) and beyond. There were 15 deaths in the Aviptadil group and 18 deaths in the placebo group.

In conclusion, the use of Aviptadil was safe and effective in improving the resolution of respiratory failure, shortening the time to recovery, decreasing respiratory distress and preventing death in respiratory failure patients.

Incompatibilities	Not Applicable
Shelf-life	9 months
Packaging information	Vial of 10 ml
Storage and handing instructions	Store in a refrigerator (20C – 80C). Protect from light. Keep out of reach of children. Do not use in case any foreign particulate matter is observed inside the vial. Do not freeze.
Details of manufacturer	Zuventus Healthcare Ltd, Mumbai. Block No. 33/1, Kanchan Pharma House, N. H. No. 08, Aslali, Taluka Daskroi, District Ahmedabad - 382 427. At : 141-142, Gallops Industrial Park, Plot No. G/5 & G/6, Vasna-Chacharvadi, Taluka Sanand, District Ahmedabad - 382 210. Registered Trade Mark of Zuventus.