Oxyptadil Injection

Aviptadil Injection 150 µg/10 ml

Each ml contains :

Aviptadil 15 µg

Water for Injections IP q.s.

Injection 150 µg / 10 ml

4.1 Therapeutic indication

For treatment of patients with severe COVID-19 with Acute Respiratory Distress Syndrome (ARDS).

4.2 Posology and method of administration

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

• Day 1 : Aviptadil 0.166 mcg/kg/hr (equivalent to 1 vial of Aviptadil Injection)
• Day 2 : Aviptadil 0.332 mcg/kg/hr (equivalent to 2 vials of Aviptadil Injection)
• Day 3 : Aviptadil 0.498 mcg/kg/hr (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.

4.3 Contraindications

Aviptadil is contraindicated in patients who are hypersensitive to any component of this product.

4.4 Special warnings and precautions for use

Mild transient flushing of the face or trunk occurs commonly. This is rarely associated with discomfort and palpitations or tachycardia in which cases patients may be withdrawn from treatment. Aviptadil must be used with caution in patients with severe cardiovascular or cerebrovascular conditions.

4.5 Drugs interactions

No clinically relevant interaction was observed concomitantly to anti-hypertensive drugs or other cardiovascular drugs.

4.6 Use in special populations

No specific studies in special patient populations have been performed so far

4.7 Effects on ability to drive and use machines

No trials on the effect on the ability to drive a car or use machines have been carried out

4.8 Undesirable effects

Gastrointestinal Disorders e.g. Diarrhea, Vascular disorders - Hypotension, cutaneous flushing, facial flushing and Infusion related reactions.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to : medico@zuventus.com

4.9 Overdose

No case of overdose has been reported

5.1 Mechanism of action

Aviptadil is a synthetic form of Human Vasoactive Intestinal Polypeptide (VIP). VIP is highly concentrated in the lung and it blocks apoptosis, caspase-3 activation in the lung, inhibits inflammatory cytokines like IL6 and TNF alpha production and reverses CD4/CD8 ratio. VIP increases surfactant production by up regulation of choline phosphate cytidylyltransferase, which increase the incorporation of methyl choline to phosphatidylcholine, the major components of pulmonary surfactant. It also up regulate C Fos protein expression in type II alveolar cells, which increase the synthesis of pulmonary surfactant phospholipids and induce surfactant protein A expression. VIP reduces ischemia-reperfusion injury in animal models. It reduces cell death by inhibiting activation induced perforin, granzyme B and caspase activity. VIP reduces pulmonary inflammation by reducing the production of pro inflammatory cytokines. It inhibits the synthesis and activation of NF-kB, which block the production of TNF alpha. In addition to that VIP blocks SARS-CoV-2 replication in the lungs and monocyte. 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%). 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. Aviptadil a synthetic form of VIP results in rapid clinical recovery in patients with SARS-CoV-2 infection.

5.2 Pharmacodynamic properties

Pulmonary circulation

After intravenous infusion of Aviptadil an increase of heart rate, stroke volume and cardiac output was reported. Right atrial and pulmonary wedge pressure remained unchanged while pulmonary vascular resistance significantly decreased as well as pulmonary arterial systolic pressure. Aviptadil vasodilating properties are 50 times more potent than prostacyclin and independent of the endothelium.

Immunotolerogenic response

In Pulmonary Sarcoidosis, the presumed primary therapeutic mechanism of action of inhaled Aviptadil is a combination of anti-inflammatory properties and induction of tolerogenic immune response of immune cells localized in the lungs.

Systemic circulation

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.

Airway responses

During intravenous infusion (20 ng Aviptadil /kg/min, 30 min), ventilation - perfusion relationships of the lungs (VA/Q) were significantly changed. VA/Q distributions determined by inert gas elimination technique

were shifted to lower values but arterial oxygen tension remained unchanged. Therefore, Aviptadil alters the ventilation - perfusion distributions but generates no shunt and does not cause hypoxia.

5.3 Pharmacokinetic properties

Absorption

Studies with radiolabeled Aviptadil (single intravenous bolus injection of 300 pmol [1 µg]) demonstrate that after the initial rapid clearance from the circulation, the lung is the primary site of peptide binding. Within 30 min., about 45% of the radioactivity is found in the lungs. Only minimal activity was found in the gastrointestinal tract, and almost no activity was seen in normal liver or spleen during the observation period of 24 hours. The radioactivity in the lungs decreased at 4 hours to 25%, and after 24 hours to 10%. Radioactivity was excreted into the urine (35% of the injected dose after 4 hours, and 90% after 24 hours). Half-life of Aviptadil in blood was 1 minute, the metabolic clearance rate was 9 ml/kg/min and the apparent volume of distribution for Aviptadil was about 14 ml/kg.

Distribution

Aviptadil binding to its receptors occurs in discrete locations within the gastrointestinal, respiratory, and genital tracts. Aviptadil is localized on respiratory epithelium, smooth muscles of the airways, blood vessels and alveolar walls.

Elimination

After injection of 1 µg radioactively labelled Aviptadil as bolus to patients a very rapid tissue distribution was observed. Within 30 minutes about 45% of the radioactivity was found in the lungs. Over an observation period of 24 hours only minimal activity was detected in the gastrointestinal tract and almost no activity was found in the liver or spleen. Radioactivity in the lungs decreased within four hours to 25% and within 24 hours to 10%. The half-life of Aviptadil in plasma is about 1-2 minutes. After injection of radiolabelled Aviptadil radioactivity was almost completely eliminated by the kidneys, 35% within 4 hours, and 90% within 24 hours.

6.1 Animal toxicology or pharmacology

In a battery of toxicological tests including repeated dose toxicity in rats and dogs, cardiopulmonary tests in dogs and functional behavioural assays in rats, no adverse side effects were observed with NAP concentrations that were ∼ 500-fold higher than the biologically active dose.

Effect of aviptadil on fertility and early embryonal development

• Aviptadil infusions in rabbits can increase plasma progesterone from both the basal levels of estrus and from the peak levels preceding ovulation.

• Infusions of Aviptadil at the time of the preovulatory steroid surge or during ovulation have little effect upon fertility or gamete transport in the rabbit.

• Endogenous VIP may play a role in the regulation of progesterone secretion in the rabbit.

Effect of aviptadil on embryogenesis

In rats, Aviptadil binding sites in the embryo were analysed during embryonic days E10-E13. Aviptadil binding was almost exclusively located to the brain and spinal cord. The investigation of expression of Aviptadil mRNA from embryo in this stage (E11) revealed totally negative results, indicating extraembryonic, maternal Aviptadil supply to the embryo. Indeed, beginning at day E9, there is an enormous increase of Aviptadil concentration in maternal blood, 6-10 times greater than later on during pregnancy. Data indicate that Aviptadil from maternal tissues may be the source of Aviptadil acting on the embryonic tissues, transferred to the embryo undegraded. On day E17, Aviptadil mRNA expression was easily detectable all over the embryo, and maternal Aviptadil concentration in the blood decreased to very low levels. Aviptadil is required for embryonic development.

Genotoxicity

No evidence of genotoxic potential has been found in in vitro and in vivo studies.

Non-proprietary name : Aviptadil

Other name : VIP (Vasoactive Intestinal Peptide)

Structure of Aviptadil

Aviptadil (VIP) is a linear, 28-AA peptide with an amidated C-terminus. All amino acids of Aviptadil are in Lconfiguration.

Chemical name : H-His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-ValLys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH2

Molecular formula : C₁₄₇H₂₃₈N₄₄O₄2S

Molecular weight : 3325.8 g/mol

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

A vial of 10 ml.

8.4 Storage and handing instructions

Store in a refrigerator (2°C - 8°C). Do not freeze.

Keep out of reach of children.

Do not use in case any foreign particulate matter is observed inside the vial.