Sildenafil

SILDENAFIL — sildenafil citrate for suspension
Camber Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

​ Adults
Sildenafil for oral suspension is indicated for the treatment of pulmonary arterial hypertension (PAH) (World Health Organization [WHO] Group I) in adults to improve exercise ability and delay clinical worsening [ see Clinical Studies (14)] .
Pediatric Patients (1 to 17 Years old)
Sildenafil for oral suspension is indicated in pediatric patients 1 to 17 years old for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) to improve exercise ability and, in pediatric patients too young to perform standardized exercise testing, pulmonary hemodynamics thought to underlie improvements in exercise [ see Clinical Studies (14)].

2 DOSAGE AND ADMINISTRATION

2.1 Sildenafil for Oral Suspension

​ Oral Dosage
The recommended dosage of sildenafil for oral suspension is 20 mg three times a day. Dose may be titrated to a maximum of 80 mg three times a day, if required, based on symptoms and tolerability [ see Clinical Studies (14)].
Although dose-response improvement in exercise ability was not observed in short-term studies in adults with PAH, the delay in clinical worsening with long-term use of sildenafil in Study A1481324 supports dosing up to a maximum of 80 mg three times a day [ see Clinical Studies (14)] .

2.2 Recommended Dosage in Pediatric Patients

​ Oral Dosage
The recommended dosage in patients ≤20 kg is 10 mg three times a day.
For pediatric patients 20 kg to 45 kg, the recommended dosage is 20 mg three times a day. For pediatric patients 45 kg and greater, the recommended dosage is 20 mg three times a day. A maximum dose in pediatric patients has not been identified. Based on the experience in adults, dose may be titrated to a maximum of 40 mg three times a day for pediatric patients >45 kg, if required, based on symptoms and tolerability [ see Clinical Studies (14)].

2.3 Reconstitution of the Powder for Oral Suspension

​ Note: Reconstitute the contents of the bottle with a total volume of 90 mL (60 mL followed by 30 mL). Refer to the detailed instructions below.
1.Tap the bottle to loosen the powder.
2. Add 60 mL of water to the bottle.
3. Replace the cap and shake the bott le vigorously for a minimum of 30 seconds.
4. Add another 30 mL of water to the bottle.
5. Replace the cap and shake the bottle vigorously for a minimum of 30 seconds.
6. Remove cap and press the bottle adaptor into the neck of the bottle. Replace the cap on the bottle.
7. Write the expiration date of the reconstituted oral suspension on the bottle label (the expiration date of the reconstituted oral suspension is 60 days from the date of reconstitution).
Incompatibilities
Do not mix with any other medication or additional flavoring agent.

3 DOSAGE FORMS AND STRENGTHS

Sildenafil for Oral Suspension
White to off-white crystalline powders containing 1.57 g of sildenafil citrate (equivalent to 1.12 g of sildenafil) in a bottle for reconstitution to 10 mg/mL. Following reconstitution with 90 mL of water, the total volume of the oral suspension is 112 mL. A 2 mL oral dosing syringe (with 0.5 mL and 2 mL dose markings) and a press-in bottle adaptor are also provided.

4 CONTRAINDICATIONS

Sildenafil for oral suspension is contraindicated in patients with:

• Concomitant use of organic nitrates in any form, either regularly or intermittently, because of the greater risk of hypotension [ see Warnings and Precautions (5.1) ].
• Concomitant use of riociguat, a guanylate cyclase stimulator. Phosphodiesterase-5 (PDE-5) inhibitors, including sildenafil, may potentiate the hypotensive effects of riociguat.
• Known hypersensitivity to sildenafil or any component of the oral suspension. Hypersensitivity, including anaphylactic reaction, anaphylactic shock and anaphylactoid reaction, has been reported in association with the use of sildenafil.

5 Sildenafil Warnings and Precautions

5.1 Hypotension

Sildenafil has vasodilatory properties, resulting in mild and transient decreases in blood pressure. Before prescribing sildenafil, carefully consider whether patients with certain underlying conditions could be adversely affected by such vasodilatory effects (e.g., patients on antihypertensive therapy or with resting hypotension [blood pressure less than 90/50], fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction). Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil.

5.2 Worsening Pulmonary Vascular Occlusive Disease

Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of sildenafil to patients with veno-occlusive disease, administration of sildenafil to such patients is not recommended. Should signs of pulmonary edema occur when sildenafil is administered, consider the possibility of associated PVOD.

5.3 Epistaxis

The incidence of epistaxis was 13% in patients taking sildenafil with PAH secondary to CTD. This effect was not seen in idiopathic PAH (sildenafil 3%, placebo 2%) patients. The incidence of epistaxis was also higher in sildenafil-treated patients with a concomitant oral vitamin K antagonist (9% versus 2% in those not treated with concomitant vitamin K antagonist). The safety of sildenafil is unknown in patients with bleeding disorders or active peptic ulceration.

5.4 Visual Loss

When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported post marketing in temporal association with the use of PDE-5 inhibitors, including sildenafil. Most patients had underlying anatomic or vascular risk factors for developing NAION, including low cup to disc ratio (“crowded disc”).
Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking sildenafil. There are no controlled clinical data on the safety or efficacy of sildenafil in patients with retinitis pigmentosa, a minority of whom have genetic disorders of retinal phosphodiesterases. Therefore, use of sildenafil in patients with retinitis pigmentosa is not recommended.

5.5 Hearing Loss

Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE-5 inhibitors, including sildenafil. In some of the cases, medical conditions and other factors were reported that may have played a role. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of sildenafil, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors. Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking PDE-5 inhibitors, including sildenafil.

5.6 Combination with other PDE-5 inhibitors

Sildenafil is also marketed as VIAGRA®. The safety and efficacy of combinations of sildenafil with VIAGRA or other PDE-5 inhibitors have not been studied. Inform patients taking sildenafil not to take VIAGRA or other PDE­5 inhibitors.