Isoket (Isosorbide Dinitrate) is a direct vasodilator primarily affecting the veins (venodilator). It reduces cardiac preload and is used in the treatment and prevention of angina.
Isosorbide dinitrate Uses:
-
Prevention of Angina pectoris:
- Used to prevent angina pectoris secondary to coronary artery disease.
Note: It has a slower onset of action making it inappropriate to abort an acute anginal episode.
-
Off Label Use of Isosorbide dinitrate in Adults:
- Achalasia
- HFrEF
Isoket (Isosorbide Dinitrate) Dose in Adults:
Isoket (Isosorbide Dinitrate) Dose in the treatment of Achalasia (off-label): Sublingual:
-
Immediate release:
- 5 mg administered 10 to 15 minutes pre meal.
Note: Clinical response is short acting and complete relief of symptoms does not occur with its use; risks should be considered before use.
Isoket (Isosorbide Dinitrate) Dose in the prevention of Angina pectoris:
Note: It has a slower onset of action making it inappropriate to abort an acute anginal episode. Chronic exposure results in tolerance to nitrates and this effect are not overcome by dose escalation. The only way to overcome tolerance is by short periods of nitrate absence from the body. Nitrate-free intervals of 14 or more hours (immediate-release products) or more than 18 hours (sustained-release products) may help minimize tolerance. Oral:
-
Immediate-release:
- Initial: 5 to 20 mg 2 to 3 times a day; Maintenance: 10 to 40 mg 2 to 3 times a day or 5 to 80 mg 2 to 3 times a day.
-
Sustained-release:
- 40 to 160 mg/day has been used in clinical trials (it is recommended to have more than 18 hours of the nitrate-free interval; however, a clinically efficacious dosage interval has not been clearly established) or 40 mg 1 to 2 times a day.
- The maximum dose: 160 mg/day (Dilatrate-SR only).
-
Sublingual [Canadian product]:
- 5 to 10 mg every 2 to 4 hours for prophylaxis of acute anginal attack; supplementation with 5 to 10 mg may be done prior to activities that may provoke an anginal episode.
Isoket (Isosorbide Dinitrate) Dose in the Heart failure with reduced ejection fraction (off-label):
Note: As an additional therapy for persistent NYHA class III or IV heart failure with reduced ejection fraction (HFrEF) when symptoms are not controlled despite optimal medical therapies or in patients with tolerance issues to an ACE inhibitor, angiotensin II receptor blocker (ARB), or angiotensin II-neprilysin inhibitor (ARNI). Oral:
-
Immediate-release:
- Initial: 20 to 30 mg 3 or 4 times a day in combination with hydralazine 3 or 4 times a day; dose should be titrated every 2 to 4 weeks;
- The maximum dose: 120 mg/day in divided doses.
- Some experts start with 20 mg thrice daily in combination with hydralazine thrice daily; evaluation should be done every 2 to 4 weeks and the dose should be gradually titrated as tolerated to a target dose of 40 mg thrice a day in combination with hydralazine thrice a day.
Note: Use of the fixed-dose combination of isosorbide dinitrate/hydralazine instead of separate components may also be considered.
Use in Children:
The safety and efficacy of the drug in children have not been established.
Pregnancy Risk Category: C
- Certain animal reproduction studies have shown negative effects.
- The use of nitric oxide donors, such as isosorbide for cervical ripening and pre-eclampsia has been evaluated.
Use during breastfeeding:
- It is not known if there is any isosorbide dinitrate in breast milk.
- Manufacturer suggests being cautious when giving isosorbide dinitrates to nursing mothers.
Dose in Kidney Disease:
No dosage adjustments are provided in the manufacturer’s labeling.
- Hemodialysis: Requires supplemental dose.
- Peritoneal dialysis: Supplemental dose is not required.
Dose in Liver disease:
No dosage adjustments are provided in the manufacturer’s labeling.
Side effects of Isoket (Isosorbide Dinitrate):
-
Cardiovascular:
- Hypotension
- Rebound hypertension
- Syncope
- Unstable angina pectoris
-
Central nervous system:
- Headache
Contraindications to Isoket (Isosorbide Dinitrate):
- Hypersensitivity (To isosorbide diitrate or any other component of the formulation).
- Use concurrently with phosphodiesterase inhibitors such as vardenafil or sildenafil (tadalafil), vardenafil or avanafil
- Concurrent use of riociguat
Canadian labeling: Additional contraindications not in US labeling
- Cardiogenic shock
- Cardiogenic shock: Risk of developing
Warnings and precautions
-
Hypotension/bradycardia:
- This can lead to severe hypotension, paradoxical bradycardia, and worsening angina pectoris.
- It can also lead to orthostatic hypotension, which can be made worse by ethanol.
- Be cautious in hypotension and volume depletion. Extreme caution is advised for inferior wall MI and right ventricular infarctions.
- Even small amounts can lead to severe hypotension, especially if you are upright.
-
The intracranial pressure rose:
- An increase in intracranial pressure could be caused or aggravated with the use of Nitrates.
- This may then be linked to worse outcomes for patients suffering from neurologic injury (eg intracranial hemorhage, trauma brain injury).
-
Cardiovascular disease
- It is not recommended for patients suffering from acute MI or HF.
-
Hypertrophic cardiomyopathy, (HCM)
- Patients with HCM and outflow tract obstruction should not use.
- Nitrates can reduce preload, which can lead to exacerbation or worsening heart failure.
Isosorbide dinitrate: Drug Interaction
|
Risk Factor C (Monitor therapy) |
|
|
Alcohol (Ethyl) |
May enhance the vasodilatory effect of Vasodilators (Organic Nitrates). |
|
Alfuzosin |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Antipsychotic Agents (Second Generation [Atypical]) |
Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). |
|
Aprepitant |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Barbiturates |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Benperidol |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Blood Pressure Lowering Agents |
May enhance the hypotensive effect of HypotensionAssociated Agents. |
|
Bosentan |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Brimonidine (Topical) |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Clofazimine |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
CYP3A4 Inducers (Moderate) |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
CYP3A4 Inhibitors (Moderate) |
May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). |
|
Dapoxetine |
May enhance the orthostatic hypotensive effect of Vasodilators (Organic Nitrates). |
|
Dapsone (Topical) |
May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. |
|
Deferasirox |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Diazoxide |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
DULoxetine |
Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. |
|
Duvelisib |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Erdafitinib |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Erdafitinib |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Fosaprepitant |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Fosnetupitant |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Herbs (Hypotensive Properties) |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Hypotension-Associated Agents |
Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. |
|
Ivosidenib |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Larotrectinib |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Levodopa-Containing Products |
Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. |
|
Local Anesthetics |
Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. |
|
Lormetazepam |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Molsidomine |
May enhance the hypotensive effect of Vasodilators (Organic Nitrates). |
|
Molsidomine |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Naftopidil |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Netupitant |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Nicergoline |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Nicorandil |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Nitric Oxide |
May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. |
|
Nitroprusside |
Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. |
|
Palbociclib |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Pentoxifylline |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Pholcodine |
Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. |
|
Prilocaine |
Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. |
|
Prostacyclin Analogues |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Quinagolide |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. |
|
Rilmenidine |
Vasodilators (Organic Nitrates) may enhance the hypotensive effect of Rilmenidine. |
|
Rosiglitazone |
Vasodilators (Organic Nitrates) may enhance the adverse/toxic effect of Rosiglitazone. Specifically, a greater risk of ischemia and other adverse effects has been associated with this combination in some pooled analyses. |
|
Sarilumab |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Siltuximab |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Simeprevir |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Sodium Nitrite |
Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. |
|
Tocilizumab |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
|
Risk Factor D (Consider therapy modification) |
|
|
Amifostine |
Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. |
|
CYP3A4 Inducers (Strong) |
May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. |
|
CYP3A4 Inhibitors (Strong) |
May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). |
|
Dabrafenib |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). |
|
Enzalutamide |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. |
|
Lorlatinib |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. |
|
MiFEPRIStone |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. |
|
Mitotane |
May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. |
|
Obinutuzumab |
May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. |
|
Stiripentol |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. |
|
Risk Factor X (Avoid combination) |
|
|
Bromperidol |
Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents. |
|
Conivaptan |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Fusidic Acid (Systemic) |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Idelalisib |
May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
|
Phosphodiesterase 5 Inhibitors |
May enhance the vasodilatory effect of Vasodilators (Organic Nitrates). |
|
Riociguat |
Vasodilators (Organic Nitrates) may enhance the hypotensive effect of Riociguat. |
Monitoring parameters:
- Bp
- Pulse rate
How to administer Isoket (Isosorbide Dinitrate)?
- Should not be administered around the clock; nitrate-free interval ≥14 hours should be allowed (immediate-release products) and >18 hours (sustained-release products).
- Sublingual tablets or sustained-release formulations should not be chewed or crushed.
Immediate-release products:
- Consider administering at 8 AM and 1 PM, for a twice-daily dosing regime.
- Consider 8 AM, 1 PM, and 6 PM, for a thrice-daily dosing regime.
Sustained-release products:
- Consider once a day in the morning or twice a day dosing at 8 AM and between 1 PM and 2 PM.
Mechanism of action of Isoket (Isosorbide Dinitrate):
- Free radical nitric dioxide is formed when nitrates and isosorbide dinitrate are combined.
- Nitric oxide activates guanylate cyclease in smooth muscle, which leads to guanosine 5' monophosphate (cGMP), and dephosphorylation myosin light chain.
- Although it has a vasodilator action on both the arteries and peripheral veins, its primary effect is on the veins.
- It reduces cardiac oxygen demand by decreasing preload (left-ventricular end-diastolic tension); it may also cause a slight reduction in afterload.
- Also, the collateral flow to ischemic areas is improved by dilation of coronary arteries.
The onset of action:
- S/L tablet: Almost 2 to 5 mins
- P/O tablet and capsule (includes extended-release formulations): Almost 1 hour
Duration:
- S/L tablet: 1 - 2 hours
- P/O tablet and capsule (includes extended-release formulations): Up to 8 hours
Metabolism:
- Mabolised extensively in the liver to conjugated active metabolites isosorbide 5-mononitrate and 2-mononitrate
Bioavailability:
- Highly variable (10% - 90%); chronic therapy increases bioavailability.
Half-life elimination:
- Parent drug: Almost 1 hour
- Metabolites (5-mononitrate: 5 hours; 2-mononitrate: 2 hours)
International Brand Names of Isosorbide dinitrate:
- Dilatrate-SR
- Isordil Titradose
- ISDN
- PMS-Isosorbide
- Angibid SR
- Angitrit
- Angsobide
- Cardil
- Cardonit
- Cardopax
- Carsodil
- Carvasin
- Cedocard
- Cedocard Retard
- Coronex
- Diconpin
- Dicor
- Dilatrate-SR
- Flindix
- Gasrobid
- Hartsorb
- Huma-Sorbide
- Imtack
- ISDN
- ISDN AL
- ISDN-Q
- ISDNratiopharm
- Iso Mack
- Iso Mack Retard
- Iso-Lacer
- Iso-Puren
- Isobide
- Isobinate
- Isocard
- Isocard Retard
- Isocord
- Isoday 40
- Isodex
- Isodinit
- Isoket
- Isoket Retard
- Isoket Spray
- Isomack
- Isomack Spray
- Isorbid
- Isorbide
- Isordil
- Isorem
- Isotonax
- Langoran
- Langoran LP
- Maycor
- Nitrol R
- Nitrosid
- Nitrosid Retard
- Nitrosorbide
- Nitrosorbon
- Pensodril
- Risordan
- Risordan LP
- Soni-Slo
- Sorbangil
- Sorbid
- Sorbidilat
- Sorbidin
- Sorbitrate
- Sorbonit
- TD Spray Iso Mack
- Tinidil
- Vascarbine
- Vascardin
- Vasot
Isosorbide dinitrate Brand Names in Pakistan:
Isosorbide Dinitrate Injection 10 Mg in Pakistan |
|
| Streight | Werrick Pharmaceuticals |
Isosorbide Dinitrate Injection IV 1 Mg/Ml in Pakistan |
|
| Isoket | Atco Laboratories Limited |
Isosorbide Dinitrate Infusion 10 Mg/10ml in Pakistan |
|
| Carsodil | Accurate Medical Suppliers |
| Sorbid | Hoffman Health Pakistan Ltd. |
Isosorbide Dinitrate Tablets 5 Mg in Pakistan |
|
| Isocord | Opal Laboratories (Pvt) Ltd. |
| Isonit | Benson Pharamceuticals. |
Isosorbide Dinitrate Tablets 10 Mg in Pakistan |
|
| Cardiowel | Medicraft Pharmaceuticals (Pvt) Ltd. |
| Di Card | Valor Pharmaceuticals |
| Isdin | Efroze Chemical Industries (Pvt) Ltd. |
| Isobid | Ferozsons Laboratoies Ltd. |
| Isocord | Opal Laboratories (Pvt) Ltd. |
| Isoket | Atco Laboratories Limited |
| Isonit | Benson Pharamceuticals. |
| Isornit | Reko Pharmacal (Pvt) Ltd. |
| Mantan | Zephyr Pharmatec (Pvt) Ltd. |
Isosorbide Dinitrate Tablets 20 Mg in Pakistan |
|
| Isobid | Caraway Pharmaceuticals |
| Isolive | Olive Laboratories |
| Monorid | Regent Laboratories Ltd. |
Isosorbide Dinitrate Tablets 40 Mg in Pakistan |
|
| Isolive | Olive Laboratories |
| Monorid | Regent Laboratories Ltd. |
Isosorbide Dinitrate Tablets Sr 20 Mg in Pakistan |
|
| Isoket Rtd | Reko Pharmacal (Pvt) Ltd. |
Isosorbide Dinitrate Tabs Sr 60 Mg in Pakistan |
|
| Flo | Wilsons Pharmaceuticals |
Isosorbide Dinitrate Tablets Sl 5 Mg in Pakistan |
|
| Tinidil | Pliva Pakistan (Pvt) Limited |
Isosorbide Dinitrate Caps Sr 40 Mg in Pakistan |
|
| Isoday | A.J. & Company. |
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